WO2021252900A1 - Biomarkers for response to exportin-1 inhibitors in multiple myeloma patients - Google Patents

Abstract

A computer-implemented method of treating a patient suffering from multiple myeloma, comprising: determining whether the patient is a responder based on an output of a classifier, wherein the input to the classifier is a feature vector comprising protein activity values corresponding to a set of proteins in the subject; and administering to the responder a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof. The values and preferred values of the variables of structural formula (I) are defined herein.

Description

BIOMARKERS FOR RESPONSE TO EXPORTIN-1 INHIBITORS IN MULTIPLE

MYELOMA PATIENTS

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63/037,906, filed on June 11, 2020. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Multiple Myeloma (MM) is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, or M protein in the serum or urine, bone disease, kidney disease, and immunodeficiency. MM is the second most common hematological malignancy (after non- Hodgkin’s lymphoma), representing 1% of all cancers and 2% of all cancer deaths. The treatment of MM has improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, the introduction of immunomodulatory agents, such as thalidomide, lenalidomide, and pomalidomide, and the proteasome inhibitors, bortesomib and carfilzomib. However, despite the increased effectiveness of these agents, motst patients develop resistant MM and succumb to the disease. As such, there remains a high unmet need to develop anti-MM agents and to tailor anti-MM therapies more closely to patients to achieve a higher likelihood of response.

SUMMARY OF THE INVENTION

[0003] In an example embodiment, the present invention is a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in the subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (I); and administering a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to be responder. The values and preferred values of the variables in structural formula (I) are defined herein.

[0004] In another example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject. The values and preferred values of the variables in structural formula (I) are defined herein.

[0005] In another example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

[0006] In another example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values. The values and preferred values of the variables in structural formula (I) are defined herein.

[0007] In another example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma (MM), comprising the steps of obtaining a sample of from the subject; determining a sequence of one or more of the following genes in the sample ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I)

to the subject determined to have a mutation in one or more of the genes. The values and preferred values of the variables in structural formula (I) are defined herein.

[0008] In another example embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound represented by structural formula (I) [0009] to the subject, wherein the subject is determined to have determined to have a mutation in one or more of the following genes ZNF518A, DE8A, HNRNPULl , GRIA2, ADGRV1, and NOTCH3. The values and preferred values of the variables in structural formula (I) are defined herein.

[0010] In another example embodiment, the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of selecting the subject only if the subject has been determined to have a mutation in at least one of the following genes ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, and NOTCH3; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I):

[0011] The values and preferred values of the variables in structural formula (I) are defined herein.

[0012] In another example embodiment, the present invention is a method of treating a patient suffering from a multiple myeloma, comprising the steps of receiving information about a mutation in one or genes present in the patient: ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I)

to the patient only if the subject has a mutation in one or more of the genes. The values and preferred values of the variables in structural formula (I) are defined herein.

[0013] In another example embodiment, the present invention is a method of identifying a subject as a responder or a non-responder, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof; and obtaining from the classifier a classification of the subject as a responder or non-responder,

[0014] The values and preferred values of the variables in structural formula (I) are defined herein.

[0015] In another example embodiment, the present invention is a computer program product for identifying responders and non-responders, the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder,

The values and preferred values of the variables in structural formula (I) are defined herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0017] The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention.

[0018] FIG.1 A and IB illustrate analysis of 35 available interactomes based on tissue lineage supervised classification and network representation. Identification of the most appropriate tissue context-specific interactomes for MM was based on the likelihood predicted by a tissue-type classifier based on gene expression (FIG. 1 A), and the Network Score (FIG. IB), representing how well each evaluated interactome can explain the transcriptional state of the MM samples.

[0019] FIG. 2A and 2B show heatmaps of eltanexor and selinexor responder patients, constructed using protein activity signatures estimated from RNA sequencing data. Colors in the heatmap indicate the level of correlation among the proteins (by Pearson’s correlation analysis).

[0020] FIG. 3 A and FIG. 3B illustrate gene set enrichment analysis (GSEA) comparing selinexor and eltanexor response signatures 1 and 2. FIG. 3 A illustrates comparisons between signature 1 and signature 2. FIG. 3B illustrates comparisons between eltanexor and selinexor treated patients.

[0021] FIG. 4 shows protein activity heatmaps according to meta VIPER algorithm described herein. The protein activity signatures were computed for each patient and then integrated across all responders and all non-responders taking the average Z-scores.

[0022] FIG. 5 is a schematic of an example of a computing node

DETAILED DESCRIPTION OF THE INVENTION

[0023] A description of example embodiments of the invention follows.

[0024] Targeting exportin 1 (XPOl) is a promising therapeutic option for patients with multiple myeloma (MM). Exemplary XPOl inhibitors useful for practicing the present invention are compounds represented by structural formula (I): [0025] In structural formula (I):

[0026] Ring A is phenyl or pyridyl;

[0027] X is -N- or -C(H)-;

[0028] each R¹ is independently selected from -CN, halo, - OH, C1-C3 alkyl, C3-C₆ cycloalkyl, C₃-C12 heterocycloalkyl, halo-Ci-C₃ alkyl, -NH2, -NO2, -NH(CI-C3 alkyl), -N(Ci- C3 alkyl)(Ci-C₃ alkyl), -C(0)OH, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C₃ alkyl);

[0029] R² is selected from -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶),

[0030] -CN, -CF₃, -S(0)i-2(Ci-C4 alkyl), optionally substituted C5-C18 heteroaryl, and optionally substituted C6-C18 aryl;

[0031] R^a is hydrogen and R^b is selected from hydrogen, -C(0)-0-R³,

[0032] -C(0)-N(R^5’)(R^6’), -C(0)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-0-R^3’, -C(S)-N(R^5’)(R^6’)

, -C(S)-N(R⁷ )-N(R⁵ )(R⁶ ), and C5-C18 heteroaryl, wherein:

[0033] R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

[0034] R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, C1-C4 alkyl,

C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5- Ci8 heteroaryl; or

[0035] R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl;

[0036] each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and [0037] n is 0, 1, 2, 3, 4 or 5;

[0038] wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

[0039] The term “aliphatic” or “aliphatic group,” as used herein, denotes a monovalent hydrocarbon radical that is straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic). An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. However, in some embodiments, an aliphatic group contains 1-10 or 2-8 carbon atoms. In some embodiments, aliphatic groups contain 1- 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. An aliphatic group can be optionally substituted as described herein. [0040] The term “alkyl,” as used herein, means a saturated, straight-chain or branched aliphatic group. In one aspect, an alkyl group contains 1-6 or 1-4 carbon atoms. Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, and the like. An alkyl group can be optionally substituted as described herein.

[0041] The term “alkenyl,” as used herein, means a straight-chain or branched aliphatic group having one or more carbon-carbon double bonds {i.e., -CH=CH-). In one aspect, an alkenyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like. The term “alkenyl” encompasses radicals having carbon-carbon double bonds in the “cis” and “trans” or, alternatively, the Έ” and “Z” configurations. If an alkenyl group includes more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof. An alkenyl group can be optionally substituted as described herein.

[0042] The term “alkynyl,” as used herein, means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -CºC-). In one aspect, an alkyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like. An alkynyl group can be optionally substituted as described herein.

[0043] The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic,” used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. In some embodiments, a cycloaliphatic group has 3-6 carbon atoms. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic” also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane. These aliphatic rings can be optionally substituted as described herein.

[0044] The term “cycloalkyl,” as used herein, means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-18, for example 3-12 members. A cycloalkyl can be optionally substituted as described herein. In some embodiments, a cycloalkyl has 3-6 carbons. A cycloalkyl group can be optionally substituted as described herein.

[0045] The term “heterocyclyl,” as used herein, means a saturated or unsaturated aliphatic ring system having from 3 to 18, for example 3-12 members in which at least one carbon atom is replaced with a heteroatom selected from N, S and O. A heterocyclyl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In one aspect, a heterocyclyl is a three- to seven-membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like. A heterocyclyl group can be optionally substituted as described herein.

[0046] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

[0047] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0048] The term “alkoxy,” as used herein, means -O-alkyl. “Alkoxy” can include a straight-chained or branched alkyl. In one aspect, “alkoxy” has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like. An alkoxy group can be optionally substituted as described herein.

[0049] The term “halo” or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. [0050] The term “haloalkyl,” as used herein, means an alkyl group that is substituted with one or more halogen atoms. In some embodiments, haloalkyl refers to a perhalogenated alkyl group. In some embodiments, haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms. Exemplary haloalkyl groups include -CF3, -CF2H, -CCI3, - CF2CH3, -CH2CF3, -CH2(CF 3)2, -CF2(CF₃)2, and the like. Preferred haloalkyl groups include -CF3 and -CF2H. A preferred haloalkyl group is -CF3.

[0051] The term “alkylene,” as used herein, means a bivalent branched or unbranched saturated hydrocarbon radical. In one aspect, “alkylene” has one to six carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like. An alkylene group can be optionally substituted as described herein. [0052] The term “alkenylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon double bonds {i.e., -CH=CH-). In one aspect, “alkenylene” has two to six carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like. An alkenylene group can be optionally substituted as described herein.

[0053] The term “alkynylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -CºC-). In one aspect, “alkynylene” has two to six carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like. An alkynylene group can be optionally substituted as described herein.

[0054] The term “aryl,” alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, an aryl has one, two or three rings. In one aspect, the aryl has six to twelve ring atoms. The term “aryl” encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl. An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

[0055] The term “heteroaryl,” alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O. A heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, a heteroaryl has one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms. The term “heteroaryl” encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl, and the like. A “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

[0056] It is understood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted group” can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an “optionally substituted group” can be unsubstituted.

[0057] Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0058] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted group” are independently halogen; haloalkyl; -(CH2)o-4R°; -(CH2)o-40R°; - 0(CH₂)O-4R°, -0-(CH₂)O-4C(0)OR°; -(CH₂)O-4CH(OR°)2; -(CH₂)O^SR°; -(CH₂)o^Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -Ns; -(CH₂)o^N(R°)2; -(CH₂)o^N(R⁰)C(0)R°; - N(R°)C(S)R°; -(CH₂)O-4N(R⁰)C(0)NR°2; -N(R⁰)C(S)NR°₂; -(CH₂)O- ₄N(R°)C(0)0R°; -N(R°)N(R°)C(0)R°; -N(R⁰)N(R⁰)C(0)NR⁰ ₂; -N(R°)N(R°)C(0)OR°; - (CH₂)O-4C(0)R°; -C(S)R°; -(CH₂)O-4C(0)OR°; -(CH₂)O^C(0)SR°; -(CH₂)o-4C(0)OSiR°3; - (CH₂)O-40C(0)R°; -OC(0)(CH₂)O-4SR-, SC(S)SR°; -(CH₂)O-4SC(0)R°; -(CH₂)O-4C(0)NR°2; -C(S)NR°₂; -C(S)SR°; -SC(S)SR°, -(CH₂)O-40C(0)NR°2; -C(0)N(OR°)R°; - C(0)C(0)R°; -C(0)CH₂C(0)R°; -C(NOR°)R°;-(CH₂)O^SSR°; -(CH₂)O-₄S(0)₂R°; -(CH₂)O- ₄S(0)₂0R°; -(CH₂)O^OS(0)₂R°; -S(0)₂NR°₂; -(CH₂)O^S(0)R°; -N(R°)S(0)₂NR°₂; - N(R°)S(0)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(0)₂R°; -P(0)R°₂; -0P(0)R°₂; -0P(0)(0R°)₂; SiR°3; — ( C I -4 straight or branched alkylene)0-N(R°)₂; or -(Ci-₄ straight or branched alkylene)C(0)0-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-₆ aliphatic, -CHzPh, -0(CH₂)o-iPh, -CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[0059] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)o-₂R*, -(haloR*), -(CH₂)o-₂OH, -(CH₂)o-₂OR*, -(CH₂)o- ₂CH(OR*)₂; -0(haloR·), -CN, -Ns, -(CH₂)o-₂C(0)R*, -(CH₂)o-₂C(0)OH, -(CH₂)o- ₂C(0)OR·, -(CH₂)O-₂SR*, -(CH₂)O-₂SH, -(CH₂)O-₂NH₂, -(CH₂)O-₂NHR·, -(CH₂)O-₂NR*₂, - N0₂, -SiR*3, -OSiR*3, -C(0)SR* -(Ci-₄ straight or branched alkylene)C(0)OR·, or-SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-₄ aliphatic, -CHzPh, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0060] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted group” include the following: =0, =S, =NNR^* ₂, =NNHC(0)R^*, =NNHC(0)OR^*, =NNHS(0)₂R^*, =NR^*, =NOR^*, -0(C(R%))_2-30-, and -S(C(R^* ₂))_2-3S-, wherein each independent occurrence of R^* is selected from hydrogen, Ci-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR^* ₂)_2-30-, wherein each independent occurrence of R^* is selected from hydrogen, Ci-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] Suitable substituents on the aliphatic group of R^* include halogen, - R·, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, NHR*, -NRN, and -N0₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C i—i aliphatic, -CHzPh, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] Suitable substituents on a substitutable nitrogen of an “optionally substituted group” include -R^†, -NR^† ₂, -C(0)R^†, -C(0)OR^†, -C(0)C(0)R^†, -C(0)CH₂C(0)R^†, - S(0)₂R^†, -S(0)₂NR^† ₂, -C(S)NR^† ₂, -C(NH)NR^† ₂, and -N(R^†)S(0)₂R^†; wherein each R^† is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0063] Suitable substituents on the aliphatic group of R^† are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, -NHR*, -NR*₂, or -N0₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CHzPh, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0064] Example embodiments of compounds of structural formula (I) are selinexor, eltanexor, and vedinexor.

[0065] Eltanexor is a compound represented by the following structural formula, [0066] Eltanexor is a second-generation oral selective inhibitor of nuclear export (SINE) that binds to XPOl and prevents it from shuttling its cargo from the nucleus to the cytoplasm, resulting in nuclear accumulation of tumor suppressor proteins and oncogene mRNAs. The first generation XPOl inhibitor selinexor, compound represented by the following structural formula,

is approved in the USA for treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents and an anti-CD38 monoclonal antibody. [0067] Verdinexor, represented by structural formula (3), is an oral inhibitor or XPOl also described in WO2013/019548.

[0068] Eltanexor has demonstrated potent anti-cancer activity in cell line and murine models of multiple solid tumor and hematologic malignancies.

[0069] Oral eltanexor is being assessed in a large multicenter phase I dose escalation study (NCT02649790). A subset of these patients (n = 39) with relapsing remitting multiple myeloma (RRMM) were treated with eltanexor (5-60 mg) with or without dexamethasone. [0070] To identify molecular markers of eltanexor response in patients with RRMM molecular markers related to eltanexor response were analyzed in bone marrow biopsies of 17 patients with RRMM who were sampled prior to treatment. Following treatment with eltanexor, 6 patients were classified as responders (4 minimal response, 1 partial response, 1 very good partial response) and 11 were classified as non-responders (7 stable disease, 4 progressive disease).

[0071] Ribosomal RNA-depleted total transcriptome RNA sequencing was performed on CD 138+ cells from the patients’ bone marrow biopsies. These RNA expression profiles (approximately 23,000 genes) were used to estimate the relative activity of 5,451 regulatory proteins was for each sample using the meta VIPER algorithm, using acute myeloid leukemia and thymoma context-specific models of transcriptional regulation (interactomes). The VIPER algorithm is described, for example, in W02017/040311 Al, the entire teachings of which are incorporated herein by reference.

[0072] A similar analysis was performed on bone marrow samples from patients with RRMM who responded to selinexor, as previously published by Chari P et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl JMed 2019; 381:727-738.

[0073] Extraction of features (proteins) used in predictive models is described below (Associations Between Inferred Protein Activity and Response to SINE Compounds and Master Regulators Predictive of Response).

[0074] Table 1 describes the MM patients treated with Eltanexor selected for the molecular markers analysis.

[0075] Table 1 : Treatment and Responses for Patient Subset Used for Molecular Marker Analyses

[0076] In Table 1, the entries marked (*) represent refractory MM to at least one proteasome inhibitor and one immunomodulatory agent; the entries marked (^†) represent refractory MM to at least one proteasome inhibitor, one immunomodulatory agent, and an anti-CD38 monoclonal antibody; the entries marked (^*) represents that Eltanexor was administered in 28 day cycles on days 1-5, 8-12, 15-19, and 22-26, unless otherwise specified; and the entries marked ( ^§) represent that Dexamethasone was administer at 20mg on days 1, 3, 8, 10, 15, 17, 22 and 24.

[0077] Associations Between Gene Mutations and Response

[0078] Somatic mutations were compared between responder and non-responder patients. Genes known to be frequently mutated in patients with multiple myeloma as indicated by TCGA(Lohr JG et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014; 25:91-101), and genes mutated exclusively in at least two patients classified as responders are shown in Table 2.

[0079] Table 2: Notable mutated genes in pre-eltanexor treatment bone marrow samples

[0080] The following genes were found to be mutated in at least two patients classified as responders and none of the non-responder patients: Zinc finger protein 518A, likely a nuclear transcriptional regulator ( ZNF518A , NCBI Gene ID: 9849), High Affinity CAMP-Specific And IBMX-Insensitive 3',5'-Cyclic Phosphodiesterase 8A ( PDE8A , NCBI Gene ID: 5151), Notch Receptor 3 NOTCH3 , NCBI Gene ID: 4854), Heterogeneous Nuclear Ribonucleoprotein U-like 1 (HNRNPUL1, Gene ID: 11100), Glutamate Ionotropic Receptor AMPA-type Subunit 2 ( GRIA2 , Gene ID: 2891), and Adhesion G-protein-coupled Receptor VI ( ADGRVl , Gene ID: 84059).

[0081] Associations Between Inferred Protein Activity and Response to SINE Compounds

[0082] RNAseq was used to infer master regulator protein activities for eltanexor treated patients as was previously done with selinexor-treated patients with RRMM (Chari P et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. NEngl J Med 2019; 381:727-738).

[0083] Unsupervised clustering showed similar patterns for eltanexor and selinexor response, with two responder signatures present for each SINE compound (FIGs. 2).

[0084] As used herein, the term “signature” refers to a set of proteins with a characteristic pattern of activities that is reflective of the underlying biologic state of the population of cells that exhibit the signature and that can be causally associated with specific properties of the cells such as response to drug treatment

[0085] FIG. 2A and FIG. 2B depict heatmaps showing the similarity between individual eltanexor responder signatures and selinexor responder signatures based on gene expression signatures or MR protein activity signatures. Red, white, and blue colors in the heatmap indicate whether samples are similar, independent or different to each other, based on Pearson’s correlation analysis. The top orange/green or yellow/black bar indicate two different clusters for each drug. The samples were sorted according to unsupervised hierarchical cluster analysis, using on Pearson’s correlation as similarity metric and simple linkage.

[0086] Interestingly, unsupervised cluster analysis of the eltanexor responder gene expression and protein activity signatures showed also the presence of at least 2 distinct eltanexor responder phenotypic states. In both cohorts, the signatures between responder phenotypic states were partially anti correlated.

[0087] The eltanexor responder signatures were very similar to the selinexor responder signatures, as shown by reciprocal gene set enrichment analysis (GSEA) (FIG. 3 A). GSEA also showed signature 1 and signature 2 were inversely correlated, especially in eltanexor treated patients (FIG. 3B).

[0088] Among the activated proteins in cluster 1 were hematopoietic regulators RARA and MAFB, and inactivated proteins included general regulators of RNA transcription NOLC1, POLR2I, TAF9, and TOP2A.

[0089] Cluster 2 was hallmarked by altered MYC signaling, with inactivation of MYB and MYCBP, and activation of ZBTB17 (MIZ-1).

[0090] To obtain the representative signature for each of the clusters, all signatures within the same cluster for each cohort were averaged. This generated a total of four integrated signatures, representing two different selinexor and eltanexor responder phenotypic states per cohort. Comparison of these integrated protein activity signatures between clusters for each of the cohorts confirmed that they are negatively correlated. In fact, the positive MR proteins for the selinexor responder cluster- 1 - the 25 most activated proteins in this group of patients - were significantly and negatively enriched in the protein activity signature for the selinexor responder cluster-2 (p < 10⁷). Similarly, the positive MRs for the selinexor responder cluster- 2 were significantly and negatively enriched in the protein activity signature for the selinexor responder cluster- 1 (p < 10⁴). Interestingly, the negative MRs - the 25 most inactivated proteins in the group of patients evaluated - of each of the selinexor responder clusters was significantly, albeit borderline, enriched in the protein activity signature for the other selinexor responder cluster (p < 0.05 and p < 0.01 for the negative MRs of cluster-1 and -2, respectively). The inverse activity of the MRs between clusters is even stronger for the eltanexor cohort, with strong negative enrichment for the MRs of eltanexor responder cluster- 1 on the protein activity signature for eltanexor responder cluster-2 (p < 10²³), with both positive and negative MRs showing a significant enrichment (p < 10²⁵ and p < 10⁴, respectively); and strong negative enrichment for the MRs of eltanexor responder cluster-2 on the protein activity signature for eltanexor responder cluster- 1 (p < 10²²), with both positive and negative MRs showing a significant enrichment (p < 10²¹ and p < 10⁵, respectively). [0091] Most remarkably, correlation analysis revealed that the two distinct responder phenotypic states for each drug are actually conserved between cohorts. More specifically, the integrated protein activity signature for the selinexor responder phenotype cluster- 1 is significantly similar to the protein activity signature for the eltanexor responder phenotype cluster- 1 (Pearson’s correlation R = 0.261, p < 2.2 x 10 ¹⁶), while the selinexor cluster-2 integrated protein activity signature is significantly similar to the eltanexor cluster-2 integrated protein activity signature (Pearson’s correlation R = 0.434, p < 2.2 x 10 ¹⁶).

[0092] Reciprocal GSEA for the enrichment of the top 50 most differentially active MR proteins - top 25 most activated and top 25 most inactivated proteins in the signatures - shows a very significant conservation of MR proteins between selinexor cohort cluster- 1 and eltanexor cohort cluster-1 (NES = 5.56, p < 10⁷), and between selinexor cohort cluster-2 and eltanexor cohort cluster-2 (NES = 11.7, p < 10³⁰). Both, positive and negative MRs for each of the selinexor clusters were significantly enriched on the protein activity signatures for the corresponding eltanexor clusters. Similarly, both positive and negative MRs for each of the eltanexor clusters were significantly enriched on the protein activity signatures for the corresponding selinexor clusters. The weak negative correlation between selinexor cluster- 1 and eltanexor cluster-2 (NES = -5.48, p < 10⁷, reciprocal GSEA) was mostly driven by the selinexor responder cluster- 1 positive MRs. Specifically, the selinexor cluster- 1 positive MRs were significantly and negatively enriched on the eltanexor responder cluster-2 protein activity signature (p < 10 ¹⁴), while no significant enrichment was observed for the selinexor responder cluster- 1 negative MRs on the eltanexor responder cluster-2 protein activity signature, as well as for the eltanexor responder cluster-2 MRs on the selinexor responder cluster- 1 protein activity signature.

[0093] A very strong and negative correlation was also observed between selinexor cluster-2 and eltanexor cluster- 1 (NES = -14.2, p < 10⁴⁴, reciprocal GSEA), with all positive and negative MRs for each of the evaluated clusters very significantly and negatively enriched on the protein activity signature of the other cluster. [0094] Finally, the candidate responder phenotype MR proteins was identified, conserved between selinexor and eltanexor cohorts, as the leading-edge proteins from the reciprocal GSEA.

[0095] Master Regulators Predictive of Response

[0096] Master Regulators predictive of response were identified as the leading-edge proteins from the reciprocal GSEA shown in FIGs. 3A and 3B.

[0097] The results are shown in FIG. 4. FIG. 4 depicts heatmaps that show the activities of the top up and down regulated protein activities in responders in the eltanexor signature 1 proteins (top) and eltanexor signature 2 proteins (bottom). The protein activity signatures were computed for each patient and then integrated across all responders and all non responders taking the average Z-scores.

[0098] Biomarkers for Response in Multiple Myeloma Patients

[0099] In an example embodiment, the following four MR proteins can be used as biomarkers of Selinexor response in MM patients.

[00100] Cluster 1

[00101] SLC11A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID: 51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), ILIO (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655), MY SMI (NCBI Gene ID: 114803), PRMTl (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF2 (NCBI Gene ID: 3608), YEATS4 (NCBI Gene ID: 8089), TIMM50 (NCBI Gene ID: 92609), PARK7 (NCBI Gene ID: 11315), PA2G4 (NCBI Gene ID: 5036), RUVBL2 (NCBI Gene ID: 10856), C1QBP (NCBI Gene ID: 708), MRPL12 (NCBI Gene ID: 6182), GMNN (NCBI Gene ID: 51053), and PHB (NCBI Gene ID: 5245).

[00102] In an example embodiment, the MRs predictive of the response of an MM patient to eltanexor are PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11 Al, NACC2, BCL6, CD86, and BAZ2A.

[00103] Cluster 2

[00104] ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), ZNHIT6 (NCBI Gene ID: 54680), ESF1 (NCBI Gene ID: 51575), C18orf32 (NCBI Gene ID: 497661), ZNF277 (NCBI Gene ID: 11179), TCEAL8 (NCBI Gene ID: 90843), PARK7 (NCBI Gene ID: 11315), ZBTB80S (NCBI Gene ID: 339487), RPS3 (NCBI Gene ID: 6188), TDG (NCBI Gene ID: 6996), RPS27A (NCBI Gene ID: 6233), MSH2 (NCBI Gene ID: 4436), MYB (NCBI Gene ID: 4602), ARHGDIA (NCBI Gene ID: 396), ZNF524 (NCBI Gene ID:

147807), LRCH4 (NCBI Gene ID: 4034), AKNA (NCBI Gene ID: 80709), TFE3 (NCBI Gene ID: 7030), CRTC2 (NCBI Gene ID: 200186 ), CCNL2 (NCBI Gene ID: 81669), CHMP1A (NCBI Gene ID: 5119), CIC (NCBI Gene ID: 23152), PTOV1 (NCBI Gene ID: 53635), CNOT3 (NCBI Gene ID: 4849), SPI1 (NCBI Gene ID: 6688), SUPT5H (NCBI Gene ID: 6829), ZBTB17 (NCBI Gene ID: 7709), MED22 (NCBI Gene ID: 6837), TYK2 (NCBI Gene ID: 7297), SLC11A1 (NCBI Gene ID: 6556), SBN02 (NCBI Gene ID: 22904), FLYWCH1 (NCBI Gene ID: 84256), NACC2 (NCBI Gene ID: 138151), E4F1 (NCBI Gene ID: 1877), HDAC10 (NCBI Gene ID: 83933), HGS (NCBI Gene ID: 9146), RHOT2 (NCBI Gene ID: 89941), CAMTA2 (NCBI Gene ID: 23125), ZNF335 (NCBI Gene ID: 63925), and MED15 (NCBI Gene ID: 51586).

[00105] In an example embodiment, the MRs predictive of an MM patient response to eltanexor are MED 15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2. [00106] Determining Protein Activity

[00107] In various embodiments, protein activity is determined for one or more subjects based on genetic data. Protein activity for a population of subjects is used to identify MR proteins as described above, and to train classifiers based on sets of known responders and non-responders. Similarly, protein activity for an individual subject is used to classify that subject as a responder or non-responder. In particular, a feature vector is constructed for a given subject that comprises protein activity values for one or more proteins.

[00108] Various measures of protein activity are suitable for use according to the present disclosure. For example, as described further below, VIPER provides protein activity values in terms of normalized enrichment scores, which express activity for all the regulatory proteins in the same scale. However, it will be appreciated that alternative methods of determining protein activity provide alternative measures of protein activity values, for example, absolute or relative abundance in a sample, or absolute enrichment.

[00109] Various embodiments described herein employ the VIPER algorithm to determine protein activity in the form of normalized enrichment scores for a plurality of proteins based on a predetermined model of transcriptional regulation. The VIPER algorithm is described further in PCT Pub. No. W02017040311 Al, which is hereby incorporated by reference in its entirety.

[00110] It will be appreciated that alternative methods of determining protein activity in a subject are also applicable for practicing the methods described herein. Exemplary alternative algorithms for inferring protein activity from gene expression data include: ChlP- X Enrichment Analysis (ChEA), which is described further in Keenan, A. B. et al. ChEA3: transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Res. 47, W212-W224 (2019); TFEA.ChIP, which is described further in Puente-Santamaria, L., Wasserman, W. W. & Del Peso, L. TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets. Bioinformatics 35, 5339-5340 (2019); Binding Analysis for Regulation of Transcription (BART), which is described further in Wang, Z. et al. BART: a transcription factor prediction tool with query gene sets or epigenomic profiles. Bioinformatics 34, 2867-2869 (2018); Mining Gene Cohorts for Transcriptional Regulators Inferred by Kolmogorov-Smimov Statistics (MAGICTRICKS), which is described further in Roopra A. MAGICTRICKS: A tool for predicting transcription factors and cofactors that drive gene lists https://doi.org/10.1101/492744; DoRothEA, which is described further in Garcia-Alonso, L. et al. Transcription factor activities enhance markers of drug sensitivity in cancer. Cancer Res. 78, 769-780 (2018); and NetF actor, which is described further in Ahsen, M. E. et al. NeTF actor, a framework for identifying transcriptional regulators of gene expression-based biomarkers. Sci. Rep. 9, 12970 (2019). [00111] In addition, biochemical approaches can be used to estimate abundance of the proteins included in a given biomarker, such us immunostaining (immunofluorescence or immunochemistry) of tissue samples followed by histological examination, flow cytometry, mass cytometry or cytometric bead arrays, reverse-phase protein arrays, bead-based IVD assays such as Luminex and mass spectrometry.

[00112] Classification of Subjects

[00113] A set of MR proteins may be determined by a variety of methods, including those described in connection with the examples below. For example, cluster analysis may be performed with or without separate dimensionality reduction in order to determine the heterogeneity of responder and non-responder clusters in an «-dimensional vector space, with n corresponding to a number of proteins considered. It will be appreciated that a variety of methods are available for dimensionality reduction, including unsupervised dimensionality reduction techniques such as principal component analysis (PCA), random projection, and feature agglomeration analysis. It will further be appreciated that a variety of cluster analysis methods are available, including hierarchical clustering and &-means clustering. It will be appreciated that a variety of statistical methods are available for determining the correlation of a given protein value to the classification as a responder or non-responder.

[00114] In various embodiments described, the DarwinOncoTarget™ system is used to identify and rank potential protein predictors of responsiveness and non-responsiveness. The top proteins showing differential activity between responder and non-responder patients, can be sorted by the False Discovery Rate (FDR)-corrected p-value.

[00115] In various embodiments, a subset of proteins is selected by performing a cross- validation process such as leave-one-out cross validation. In such embodiments, a model is trained on all data except for one point and a prediction is made for that point. It will be appreciated that cross-validation may be used to optimize the selection of proteins and/or the number of proteins. In addition, repeated application of cross-validation may be employed with multiple models in order to select an optimal pairing of model and proteins.

Accordingly, it will be appreciated that a variable number of proteins may be selected for training a classifier as set out herein. It will be appreciated that while there may be computational advantages to reduction in the number of MR proteins used to train a given classifier, a classifier may be trained with all or some of the potential proteins while still arriving at a trained classifier suitable for identification of responders and non-responders. In particular, while inclusion of additional low value proteins may increase training time, a given classifier will de-emphasize low value proteins while emphasizing high value proteins by virtue of the training process. In some embodiments, a predetermined number of proteins having the highest differential activity between responder and non-responder patients are selected.

[00116] A training set including responders and non-responders is determined by RNA sequencing of a plurality of subjects. Normalized enrichment scores (NES) are determined for a plurality of proteins across the training set. In some embodiments, normalized enrichment scores are determined by application of VIPER.

[00117] During a training phase according to various embodiments, protein activity scores for responsive and non-responsive subjects are determined as set forth above. A feature vector is constructed for each of the responsive and non-responsive subjects, and provided to a classifier. In some embodiments, the classifier comprises a SVM. In some embodiments, the classifier comprises an artificial neural network. In some embodiments, the classifier comprises a random decision forest. It will be appreciated that a variety of other classifiers are suitable for use according to the present disclosure, including linear classifiers, support vector machines (SVM), Linear Discriminant Analysis (LDA), Logistic regression, Random Forest, Ridge regression methods, or neural networks such as recurrent neural networks (RNN). In addition, it will be apprecaited that an ensemble model of any of the forgoing may also be employed. For example, a combination of any of the models can be used and the outputs of each model averaged (integrated).

[00118] Suitable artificial neural networks include but are not limited to a feedforward neural network, a radial basis function network, a self-organizing map, learning vector quantization, a recurrent neural network, a Hopfield network, a Boltzmann machine, an echo state network, long short term memory, a bi-directional recurrent neural network, a hierarchical recurrent neural network, a stochastic neural network, a modular neural network, an associative neural network, a deep neural network, a deep belief network, a convolutional neural networks, a convolutional deep belief network, a large memory storage and retrieval neural network, a deep Boltzmann machine, a deep stacking network, a tensor deep stacking network, a spike and slab restricted Boltzmann machine, a compound hierarchical-deep model, a deep coding network, a multilayer kernel machine, or a deep Q-network.

[00119] Based upon the training set, the classifier is trained to classify a subject as either responsive or non-responsive.

[00120] In a classification phase according to various embodiments, a protein activity of a given subject is determined. The protein activity values are provided as a feature vector to a trained classifier, which provides an output classification as either a responder or a non responder.

[00121] In various embodiments, the output of a classifier (or an averaged/integrated outputs of multiple classifiers) is a probability that the subject being classified will respond to the therapy described herein. As used herein, a “responder” is a subject whose probability to respond is at least 0.5 (0.5-1), for example, at least 0.6 (0.6-1), at least 0.7 (0.7-1), at least 0.8 (0.8-1), at least 0.9 (0.9-1).

[00122] Methods of Treating

[00123] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. In particular, subjects are humans, such as adult humans. In one embodiment, the subject is an adult human. In a specific aspect, the adult human subject is suffering from relapsed refractory multiple myeloma. In a further aspect, the adult human subject has received at least four prior therapies to treat the relapsed refractory multiple myeloma. In yet a further aspect, the adult human subject has received at least four prior therapies to treat the relapsed refractory multiple myeloma and the relapsed refractory multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

[00124] The term “treating” means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. Treatment includes treating a symptom of a disease, disorder or condition. [00125] The phrase “combination therapy” or “co-administration” embraces the administration of the XPOl inhibitors of the present invention and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each. When administered as a combination, the XPOl inhibitors of the present invention and an additional therapeutic agent can be formulated as separate compositions. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).

[00126] “Combination therapy” or “co-administration” is intended to embrace administration of these therapeutic agent (the XPOl inhibitors of the present invention and an additional therapeutic agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence wherein the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non drug therapies ( e.g surgery or radiation). In a particular embodiment, dexamethasone is co administered with the XPOl inhibitors of the present invention. In an even more particular embodiment, the dexamethasone is administered at 20 mg per administration.

[00127] In another embodiment, combination treatment comprises the administration of the XPOl inhibitors of the present invention in combination with at least one (e.g„ 1, 2 or 3) of the following: lenalidomide, pomalidomide, carfilzomib, bortezomib or duratumumab and optionally dexamethasone. The combination administration of this embodiment can be twice a week (e.g., Days 1 and 3) or once per week. In one aspect, the treatment comprises administering a combination of the XPOl inhibitors of the present invention, bortezomib and optionally dexamethasone. In a particular aspect of this embodiment, the subject has not been previously treated with a proteasome inhibitor (PI naive). In an example embodiment having a 35 day cycle, selinexor is administered on Days 1, 8, 15, 22, and 29 of a 35-day cycle (e.g., at 100 mg per dose); bortezomib is administered on Days 1, 8, 15, and 22 of a 35- day cycle (e.g., at 1,3 mg/m2) and dexamethasone is administered Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle at 20 mg per dose. The length of the cycle can be adjusted accordingly, maintaining the once weekly administration for selinexor and bortezomib and the twice weekly administration of dexamethasone.

[00128] The XPOl inhibitors of the present invention can be present in the form of pharmaceutically acceptable salt. For use in medicines, the salts of the XPOl inhibitors of the present invention refer to non-toxic “pharmaceutically acceptable salts.”

Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

[00129] Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

[00130] The XPOl inhibitors of the present invention can be administered orally, nasally, ocularly, transdermally, topically, intravenously (both bolus and infusion), and via injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) either as alone or as part of a pharmaceutical composition comprising the XPOl inhibitors of the present invention and a pharmaceutically acceptable excipient. The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.

[00131] In a particular embodiment, the XPOl inhibitors of the present invention and optionally a second agent (e.g., dexamethasone) is administered orally. Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.

[00132] As used herein, prior therapies refers to known therapies for multiple myeloma involving administration of a therapeutic agent. Prior therapies can include, but are not limited to, treatment with proteasome inhibitors (PI), Immunomodulatory agents, anti-CD38 monoclonal antibodies or other agents typically used in the treatment of multiple myeloma such as glucocorticoids. Specific prior therapies can include bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids or an alkylating agent.

[00133] Accordingly, in a first example embodiments, the present invention is a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (I); and administering a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to be responder.

[00134] Alternatively, in a first example embodiment, the present invention is a computer- assisted method of treating a subject suffering from multiple myeloma, comprising: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a treatment of MM with a compound of formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the responder a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof. [00135] In a second example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject.

[00136] Alternatively, in a second example embodiment, the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to treatment by the compound represented by structural formula (I) by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.

[00137] In a third example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof. [00138] Alternatively, in a third example embodiment, the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to treatment by a compound represented by structural formula (I), wherein the subject is determined to be a responder by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.

[00139] In a fourth example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma, comprising receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values.

[00140] Alternatively, in a fourth example embodiment, the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder.

[00141] In a fifth example embodiment, the present invention is a method of treating a subject suffering from multiple myeloma (MM), comprising the steps of obtaining a sample of from the subject; determining a sequence of one or more of the following genes in the sample: ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject determined to have a mutation in one or more of the genes.

[00142] In a sixth example embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject, wherein the subject is determined to have determined to have a mutation in one or more of the following genes: ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3.

[00143] In a seventh example embodiment, the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of selecting the subject only if the subject has been determined to have a mutation in at least one of the following genes ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I).

[00144] In an eighth example embodiment, the present invention is a method of treating a patient suffering from a multiple myeloma, comprising the steps of receiving information about a mutation in one or genes present in the patient: ZNF518A, DE8A, HNRNPIJL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the patient only if the subject has a mutation in one or more of the genes.

[00145] Any of the first through fourth example embodiments and their alternatives can include any one or more of the following aspects.

[00146] The set of proteins can consist of proteins having at least a pre-determined value of differential protein activity between responders and non-responders.

[00147] The protein activity value can be a normalized enrichment score.

[00148] Determining the plurality of protein activity values can comprise applying VIPER algorithm to gene expression data of the subject.

[00149] The trained classifier can comprise one or more of a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.

[00150] Any of the first through eighth example embodiments can include any one or more of the following aspects.

[00151] The XPOl inhibitors can be represented by the following structural formula: [00154] The set of proteins can be SLC11 A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID:

51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655),

MY SMI (NCBI Gene ID: 114803), PRMTl (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP 13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF2 (NCBI Gene ID: 3608), YEATS4 (NCBI Gene ID: 8089), TIMM50 (NCBI Gene ID: 92609), PARK7 (NCBI Gene ID: 11315), PA2G4 (NCBI Gene ID: 5036), RUVBL2 (NCBI Gene ID: 10856), C1QBP (NCBI Gene ID: 708), MRPL12 (NCBI Gene ID: 6182), GMNN (NCBI Gene ID: 51053), and PHB (NCBI Gene ID: 5245).

[00155] For example, the set of proteins is PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11 Al, NACC2, BCL6, CD86, and BAZ2A. [00156] The set of proteins is ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), ZNHIT6 (NCBI Gene ID: 54680), ESF1 (NCBI Gene ID: 51575), C18orf32 (NCBI Gene ID: 497661), ZNF277 (NCBI Gene ID: 11179), TCEAL8 (NCBI Gene ID: 90843), PARK7 (NCBI Gene ID: 11315), ZBTB80S (NCBI Gene ID: 339487), RPS3 (NCBI Gene ID: 6188), TDG (NCBI Gene ID: 6996), RPS27A (NCBI Gene ID: 6233), MSH2 (NCBI Gene ID: 4436), MYB (NCBI Gene ID: 4602), ARHGDIA (NCBI Gene ID: 396), ZNF524 (NCBI Gene ID: 147807), LRCH4 (NCBI Gene ID: 4034), AKNA (NCBI Gene ID: 80709), TFE3 (NCBI Gene ID: 7030), CRTC2 (NCBI Gene ID: 200186 ), CCNL2 (NCBI Gene ID: 81669), CHMP1A (NCBI Gene ID: 5119), CIC (NCBI Gene ID: 23152), PTOV1 (NCBI Gene ID: 53635), CNOT3 (NCBI Gene ID: 4849), SPI1 (NCBI Gene ID: 6688), SUPT5H (NCBI Gene ID: 6829), ZBTB17 (NCBI Gene ID: 7709), MED22 (NCBI Gene ID: 6837), TYK2 (NCBI Gene ID: 7297), SLC11A1 (NCBI Gene ID: 6556), SBN02 (NCBI Gene ID: 22904), FLYWCH1 (NCBI Gene ID: 84256), NACC2 (NCBI Gene ID: 138151), E4F1 (NCBI Gene ID: 1877), HDAC10 (NCBI Gene ID: 83933), HGS (NCBI Gene ID: 9146), RHOT2 (NCBI Gene ID: 89941), CAMTA2 (NCBI Gene ID: 23125), ZNF335 (NCBI Gene ID: 63925), and MED15 (NCBI Gene ID: 51586).

[00157] For example, the set of proteins is MED 15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.

[00158] The methods of any of the example embodiments can further comprise collecting a bone marrow sample from the subject; separating CD131+ cells in the bone marrow sample; and identifying the activity pattern of the MR proteins in the CD131+ cells.

[00159] Multiple myeloma is a relapsed or refractory multiple myeloma.

[00160] The subject could have received from 1 to 7 prior therapies.

[00161] The subject could have received at least two, at least three, at least four prior therapies.

[00162] The subject could be a human, for example an adult human.

[00163] The XPOl inhibitors of the invention could be administered orally. [00164] Multiple myeloma can be refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

[00165] The methods of any of the example embodiments could comprise administering at least one additional therapeutic agent.

[00166] The additional therapeutic agent can be dexamethasone.

[00167] The dexamethasone can be orally administered at an amount of 20 mg/day.

[00168] The methods of any one of the example embodiments can further comprise administering bortezomib.

[00169] Multiple myeloma can be relapsed or refractory multiple myeloma, the subject could be an adult human who has received at least four prior therapies and the multiple myeloma could be refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

[00170] The XPOl inhibitor of the invention can be administered at 80 mg/per day on days 1 and 3 of each week of treatment.

[00171] An additional therapeutic agent can be administered.

[00172] The additional therapeutic agent can be dexamethasone.

[00173] Dexamethasone can be administered at 20 mg/day on days 1 and 3 of each week of treatment.

[00174] Multiple myeloma can be relapsed or refractory multiple myeloma, the subject can be an adult human who has received from 1 to 3 prior therapies.

[00175] The XPOl inhibitor if the invention can be administered at 100 mg once a week. [00176] At least one additional therapeutic agent can be administered.

[00177] The additional therapeutic agents can be bortezomib administered at 1.3 mg/m2 once a week and dexamethasone administered twice a week at 20 mg per administration.

[00178] Computer-Implemented Methods

[00179] In a sixth example embodiment, the present invention is a computer program product for identifying responders and non-responders, the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non- responders to a therapy by the XPOl inhibitors of the present invention; and obtaining from the classifier a classification of the subject as a responder or non-responder.

[00180] Referring now to FIG. 5, a schematic of an example of a computing node is shown. Computing node 10 is only one example of a suitable computing node and is not intended to suggest any limitation as to the scope of use or functionality of embodiments described herein. Regardless, computing node 10 is capable of being implemented and/or performing any of the functionality set forth hereinabove.

[00181] In computing node 10 there is a computer system/server 12, which is operational with numerous other general purpose or special purpose computing system environments or configurations. Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with computer system/server 12 include, but are not limited to, personal computer systems, server computer systems, thin clients, thick clients, handheld or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputer systems, mainframe computer systems, and distributed cloud computing environments that include any of the above systems or devices, and the like.

[00182] Computer system/server 12 may be described in the general context of computer system-executable instructions, such as program modules, being executed by a computer system. Generally, program modules may include routines, programs, objects, components, logic, data structures, and so on that perform particular tasks or implement particular abstract data types. Computer system/server 12 may be practiced in distributed cloud computing environments where tasks are performed by remote processing devices that are linked through a communications network. In a distributed cloud computing environment, program modules may be located in both local and remote computer system storage media including memory storage devices.

[00183] As shown in FIG. 5, computer system/server 12 in computing node 10 is shown in the form of a general-purpose computing device. The components of computer system/server 12 may include, but are not limited to, one or more processors or processing units 16, a system memory 28, and a bus 18 that couples various system components including system memory 28 to processor 16.

[00184] Bus 18 represents one or more of any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures. By way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, Peripheral Component Interconnect (PCI) bus, Peripheral Component Interconnect Express (PCIe), and Advanced Microcontroller Bus Architecture (AMBA).

[00185] Computer system/server 12 typically includes a variety of computer system readable media. Such media may be any available media that is accessible by computer system/server 12, and it includes both volatile and non-volatile media, removable and non removable media.

[00186] System memory 28 can include computer system readable media in the form of volatile memory, such as random access memory (RAM) 30 and/or cache memory 32. Computer system/server 12 may further include other removable/non-removable, volatile/non-volatile computer system storage media. By way of example only, storage system 34 can be provided for reading from and writing to a non-removable, non-volatile magnetic media (not shown and typically called a "hard drive"). Although not shown, a magnetic disk drive for reading from and writing to a removable, non-volatile magnetic disk ( e.g ., a "floppy disk"), and an optical disk drive for reading from or writing to a removable, non-volatile optical disk such as a CD-ROM, DVD-ROM or other optical media can be provided. In such instances, each can be connected to bus 18 by one or more data media interfaces. As will be further depicted and described below, memory 28 may include at least one program product having a set (e.g., at least one) of program modules that are configured to carry out the functions of embodiments of the disclosure.

[00187] Program/utility 40, having a set (at least one) of program modules 42, may be stored in memory 28 by way of example, and not limitation, as well as an operating system, one or more application programs, other program modules, and program data. Each of the operating system, one or more application programs, other program modules, and program data or some combination thereof, may include an implementation of a networking environment. Program modules 42 generally carry out the functions and/or methodologies of embodiments as described herein.

[00188] Computer system/server 12 may also communicate with one or more external devices 14 such as a keyboard, a pointing device, a display 24, etc.; one or more devices that enable a user to interact with computer system/server 12; and/or any devices (e.g, network card, modem, etc.) that enable computer system/server 12 to communicate with one or more other computing devices. Such communication can occur via Input/Output (I/O) interfaces 22. Still yet, computer system/server 12 can communicate with one or more networks such as a local area network (LAN), a general wide area network (WAN), and/or a public network ( e.g ., the Internet) via network adapter 20. As depicted, network adapter 20 communicates with the other components of computer system/server 12 via bus 18. It should be understood that although not shown, other hardware and/or software components could be used in conjunction with computer system/server 12. Examples, include, but are not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, and data archival storage systems, etc.

[00189] The present disclosure may be embodied as a system, a method, and/or a computer program product. The computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present disclosure.

[00190] The computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device. The computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing. A non- exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing. A computer readable storage medium, as used herein, is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.

[00191] Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network. The network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers. A network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.

[00192] Computer readable program instructions for carrying out operations of the present disclosure may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Smalltalk, C++ or the like, and conventional procedural programming languages, such as the “C” programming language or similar programming languages. The computer readable program instructions may execute entirely on the user’s computer, partly on the user’s computer, as a stand-alone software package, partly on the user’s computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user’s computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider). In some embodiments, electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present disclosure.

[00193] Aspects of the present disclosure are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the disclosure. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer readable program instructions.

[00194] These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks. These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.

[00195] The computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.

[00196] The flowchart and block diagrams in the FIG. 5 illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present disclosure. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.

[00197] Accordingly, in a ninth example embodiments, the present invention is a method of identifying a subject as a responder or a non-responder, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.

[00198] The set of proteins can be SLC11 A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID:

51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655),

MY SMI (NCBI Gene ID: 114803), PRMTl (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP 13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF2 (NCBI Gene ID: 3608), YEATS4 (NCBI Gene ID: 8089), TIMM50 (NCBI Gene ID: 92609), PARK7 (NCBI Gene ID: 11315), PA2G4 (NCBI Gene ID: 5036), RUVBL2 (NCBI Gene ID: 10856), C1QBP (NCBI Gene ID: 708), MRPL12 (NCBI Gene ID: 6182), GMNN (NCBI Gene ID: 51053), and PHB (NCBI Gene ID: 5245).

[00199] For example, the set of proteins can be PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11A1, NACC2, BCL6, CD86, and BAZ2A.

[00200] The set of proteins can be ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), ZNHIT6 (NCBI Gene ID: 54680), ESF1 (NCBI Gene ID: 51575), C18orf32 (NCBI Gene ID: 497661), ZNF277 (NCBI Gene ID: 11179), TCEAL8 (NCBI Gene ID: 90843), PARK7 (NCBI Gene ID: 11315), ZBTB80S (NCBI Gene ID: 339487), RPS3 (NCBI Gene ID: 6188), TDG (NCBI Gene ID: 6996), RPS27A (NCBI Gene ID: 6233), MSH2 (NCBI Gene ID: 4436), MYB (NCBI Gene ID: 4602), ARHGDIA (NCBI Gene ID: 396), ZNF524 (NCBI Gene ID: 147807), LRCH4 (NCBI Gene ID: 4034), AKNA (NCBI Gene ID: 80709), TFE3 (NCBI Gene ID: 7030), CRTC2 (NCBI Gene ID: 200186 ), CCNL2 (NCBI Gene ID: 81669), CHMP1A (NCBI Gene ID: 5119), CIC (NCBI Gene ID: 23152), PTOV1 (NCBI Gene ID: 53635), CNOT3 (NCBI Gene ID: 4849), SPI1 (NCBI Gene ID: 6688), SUPT5H (NCBI Gene ID: 6829), ZBTB17 (NCBI Gene ID: 7709), MED22 (NCBI Gene ID: 6837), TYK2 (NCBI Gene ID: 7297), SLC11A1 (NCBI Gene ID: 6556), SBN02 (NCBI Gene ID: 22904), FLYWCH1 (NCBI Gene ID: 84256), NACC2 (NCBI Gene ID: 138151), E4F1 (NCBI Gene ID: 1877), HDAC10 (NCBI Gene ID: 83933), HGS (NCBI Gene ID: 9146), RHOT2 (NCBI Gene ID: 89941), CAMTA2 (NCBI Gene ID: 23125), ZNF335 (NCBI Gene ID: 63925), and MED15 (NCBI Gene ID: 51586).

[00201] For example, the set of proteins can be MED15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.

[00202] In various aspects of the ninth example embodiments, the set of proteins is selected by cross-validation. The set of proteins consists of proteins can have at least a pre determined value of differential protein activity between responders and non-responders. The protein activity value can be a normalized enrichment score.

[00203] Determining the plurality of protein activity values can comprise applying VIPER algorithm to gene expression data of the subject.

[00204] The trained classifier can comprise a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.

[00205] In a tenth example embodiment, the present invention is a computer program product for identifying responders and non-responders, the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non- responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof and obtaining from the classifier a classification of the subject as a responder or non-responder.

[00206] EXEMPLIFICATION

[00207] EXAMPLE 1 : NCT02649790 STUDY

[00208] Study Design

[00209] The study included 3 arms: Part Al, Part A2 and Part B, summarized below:

[00210]

[00211] Abbreviations: CRC = colorectal cancer; mCRPC = metastatic castration resistant prostate cancer; MDS = myelodysplastic syndrome; QDx5/week = once daily for 5 days per week; QoDx3 = once daily for 3 days per week; dex = dexamethasone; RRMM = relapsed/refractory multiple myeloma.

[00212] Relapsed/Refractory Multiple Myeloma (RRMM)

[00213] For Parts A and B, up to 10 patients may be treated at any dose cohort to evaluate safety, tolerability, and efficacy to inform dose selection for Parts C-F. These 10 patients include the patients evaluated for dose limiting toxicity (DLT) during 3+3 dose escalation. [00214] Part Al : KPT-8602 Single Agent; QDx5/Week

[00215] Patients in Part Al will receive KPT-8602 single agent QDx5/Week. For the purpose of dose escalation decisions, Cohort 1 in Part Al will use a traditional 3+3 dose escalation design and Cohort 2 and all subsequent cohorts will follow the standard 3+3 dose escalation design per increments listed in Table 4:

Table 4: Dose Escalation of Eltanexor

[00216] Part A2: KPT-8602 Single Agent; QoDx3/Week

[00217] Patients in Part A2 will receive KPT-8602 single agent QoDx3/week. The starting dose for Part A2 will be informed by Part Al. Initially, approximately 3 patients will be enrolled in Part A2.

[00218] Part B: KPT-8602 with Low Dose Dexamethasone; QDx5/Week [00219] Patients will receive KPT-8602 for 5 consecutive days (QDx5/week) in combination with low dose dexamethasone (20 mg on Days 1, 3, 8, 10, 15, 17, 22, and 24 of each 28-day cycle). Initially, approximately 3 patients will be enrolled in Part B, but additional patients may be added as needed to more completely evaluate preliminary safety, tolerability, and efficacy.

[00220] Example 2: Biomarkers for Eltanexor Response in MM [00221] Selection of MRs predictive of Eltanexor response in MM patients.

[00222] The predictor MRs were selected using reciprocal gene set enrichment analysis of the 25 most activated and 25 most inactivated eltanexor signature 1 MRs onto selinexor signature 1 (and separately the top 25 activated and top 25 inactivated selinexor 1 MRs onto eltanexor 1). Any MRs that showed similar activation/inactivation in the GSEA were selected for the final model (technically, these were the proteins that had an absolute enrichment score greater than the absolute maximum running enrichment score for either the top activated or inactivated proteins, in the reciprocal GSEA.)

[00223] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety. [00224] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is:

1. A computer-assisted method of treating a subject suffering from multiple myeloma, comprising: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a treatment of MM with a compound of formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the responder a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl; R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^r)-N(R^5’)(R^6’), and C5-C18 heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C3-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

2. A computer-assisted method of treating a subject suffering from multiple myeloma, comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to treatment by the compound represented by structural formula (I) by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C1₈ heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted. 3. A computer-assisted method of treating a subject suffering from multiple myeloma, comprising: selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to treatment by a compound represented by structural formula (I), wherein the subject is determined to be a responder by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C₃-C₆ cycloalkyl, C₃-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C₃ alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^r)-N(R^5’)(R^6’), and Cs-Cis heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

4. A computer-assisted method of treating a subject suffering from multiple myeloma, comprising: receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

only if the subject is determined to be a responder, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C1₈ heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

The method of any one of Claims 1-4, wherein the set of proteins consists of proteins having at least a pre-determined value of differential protein activity between responders and non-responders. 6. The method of any one of Claims 1-5, wherein the protein activity value is a normalized enrichment score.

7. The method of any one of Claims 1-5, wherein determining the plurality of protein activity values comprises applying VIPER algorithm to gene expression data of the subject.

8. The method of any one of Claims 1-7, wherein the trained classifier comprises one or more of a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.

9. The method of any one of Claims 1-8, wherein the set of proteins is SLC11 A1 (NCBI

Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID: 51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFDl (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655), MYSM1 (NCBI Gene ID: 114803), PRMT1 (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF2 (NCBI Gene ID: 3608), YEATS4 (NCBI Gene ID: 8089), TIMM50 (NCBI Gene ID: 92609), PARK7 (NCBI Gene ID: 11315), PA2G4 (NCBI Gene ID: 5036), RUVBL2 (NCBI Gene ID: 10856), C1QBP (NCBI Gene ID: 708), MRPL12 (NCBI Gene ID: 6182), GMNN (NCBI Gene ID: 51053), and PHB (NCBI Gene ID: 5245).

10. The method of any one of Claims 1-9, wherein the set of proteins is PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11A1, NACC2, BCL6, CD86, and BAZ2A.

11. The method of any one of Claims 1-8, wherein the set of proteins is ZNF22 (NCBI

Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFAND1 (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), ZNHIT6 (NCBI Gene ID: 54680), ESF1 (NCBI Gene ID: 51575), C18orf 2 (NCBI Gene ID: 497661), ZNF277 (NCBI Gene ID: 11179), TCEAL8 (NCBI Gene ID: 90843), PARK7 (NCBI Gene ID: 11315), ZBTB80S (NCBI Gene ID: 339487), RPS3 (NCBI Gene ID: 6188), TDG (NCBI Gene ID:

6996), RPS27A (NCBI Gene ID: 6233), MSH2 (NCBI Gene ID: 4436), MYB (NCBI Gene ID: 4602), ARHGDIA (NCBI Gene ID: 396), ZNF524 (NCBI Gene ID: 147807), LRCH4 (NCBI Gene ID: 4034), AKNA (NCBI Gene ID: 80709), TFE3 (NCBI Gene ID: 7030), CRTC2 (NCBI Gene ID: 200186 ), CCNL2 (NCBI Gene ID: 81669), CHMP1A (NCBI Gene ID: 5119), CIC (NCBI Gene ID: 23152), PTOV1 (NCBI Gene ID: 53635), CNOT3 (NCBI Gene ID: 4849), SPI1 (NCBI Gene ID: 6688), SUPT5H (NCBI Gene ID: 6829), ZBTB17 (NCBI Gene ID: 7709), MED22 (NCBI Gene ID: 6837), TYK2 (NCBI Gene ID: 7297), SLC11 A1 (NCBI Gene ID: 6556), SBN02 (NCBI Gene ID: 22904), FLYWCHl (NCBI Gene ID: 84256), NACC2 (NCBI Gene ID: 138151), E4F1 (NCBI Gene ID: 1877), HD AC 10 (NCBI Gene ID: 83933), HGS (NCBI Gene ID: 9146), RHOT2 (NCBI Gene ID: 89941), CAMTA2 (NCBI Gene ID: 23125), ZNF335 (NCBI Gene ID: 63925), and MED 15 (NCBI Gene ID: 51586). 12. The method of any one of Claims 1-8 orl 1, wherein the set of proteins is MED15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.

13. The method of any one of Claims 1-12, wherein the compound is represented by the following structural formula:

14. The method of any one of Claims 1-12, wherein the compound is represented by the following structural formula:

15. The method of any one of Claims 1-14, further comprising: collecting a bone marrow sample from the subject; separating CD131+ cells in the bone marrow sample; identifying the activity pattern of the MR proteins in the CD131+ cells.

16. The method of any one of Claims 1-15, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

17. The method of any one of Claims 1-16, wherein the subject has received from 1 to 7 prior therapies.

18. The method of Claim 17, wherein the subject has received at least two prior therapies. 19. The method of Claim 17, wherein the subject has received at least three prior therapies.

20. The method of Claim 17, wherein the subject has received at least four prior therapies.

21. The method of any one of Claims 1-20, wherein the subject is a human.

22. The method of Claim 21, wherein the human is an adult.

23. The method of any one of Claim 1-22, wherein the compound represented by formula (I) is administered orally.

24. The method of Claim 23, wherein the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

25. The method of any one of Claims 1-24, further comprising administering at least one additional therapeutic agent.

26. The method of Claim 25, wherein the additional therapeutic agent is dexamethasone.

27. The method of Claim 26, wherein the dexamethasone is orally administered at an amount of 20 mg/day.

28. The method of any one of Claims 26 or 27, further comprising administering bortezomib.

29. The method of any one of Claims 1-15, wherein the multiple myeloma is relapsed or refractory multiple myeloma, the subject is an adult human who has received at least four prior therapies and the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody. 30. The method of Claim 29, wherein the compound of formula (I) is administered at 80 mg/per day on days 1 and 3 of each week of treatment.

31. The method of Claim 30, wherein an additional therapeutic agent is administered.

32. The method of Claim 31, wherein the additional therapeutic agent is dexamethasone.

33. The method of Claim 32, wherein the dexamethasone is administered at 20 mg/day on days 1 and 3 of each week of treatment.

34. The method of any one of Claims 1-15, wherein the multiple myeloma is relapsed or refractory multiple myeloma, the subject is an adult human who has received from 1 to 3 prior therapies.

35. The method of Claim 34, wherein the compound of formula (I) is administered at 100 mg once a week.

36. The method of Claim 34 or Claim 35, wherein at least one additional therapeutic agent is administered.

37. The method of Claim 36, wherein the additional therapeutic agents are bortezomib administered at 1.3 mg/m2 once a week and dexamethasone administered twice a week at 20 mg per administration.

38. A computer-assisted method of identifying a subject as a responder or a non responder, comprising: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder,

wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C3 alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C3 alkyl), -0-(Ci-C3 haloalkyl), and -S-( C1-C₃ alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C18 heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C3-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

39. The method of Claim 38, wherein the set of proteins is SLC11 A1 (NCBI Gene ID:

6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID: 51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655), MYSM1 (NCBI Gene ID: 114803), PRMT1 (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP 13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF2 (NCBI Gene ID: 3608), YEATS4 (NCBI Gene ID: 8089), TIMM50 (NCBI Gene ID: 92609), PARK7 (NCBI Gene ID: 11315), PA2G4 (NCBI Gene ID: 5036), RUVBL2 (NCBI Gene ID: 10856), C1QBP (NCBI Gene ID: 708), MRPL12 (NCBI Gene ID: 6182), GMNN (NCBI Gene ID: 51053), and PHB (NCBI Gene ID: 5245).

40. The method of Claim 39, wherein the set of proteins is PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11 Al, NACC2, BCL6, CD86, and BAZ2A.

41. The method of Claim 38, wherein the set of proteins is ZNF22 (NCBI Gene ID:

7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), ZNHIT6 (NCBI Gene ID: 54680), ESF1 (NCBI Gene ID: 51575), C18orf32 (NCBI Gene ID: 497661), ZNF277 (NCBI Gene ID: 11179), TCEAL8 (NCBI Gene ID: 90843), PARK7 (NCBI Gene ID: 11315), ZBTB80S (NCBI Gene ID: 339487), RPS3 (NCBI Gene ID: 6188), TDG (NCBI Gene ID: 6996), RPS27A (NCBI Gene ID: 6233), MSH2 (NCBI Gene ID: 4436), MYB (NCBI Gene ID: 4602), ARHGDIA (NCBI Gene ID: 396), ZNF524 (NCBI Gene ID: 147807), LRCH4 (NCBI Gene ID: 4034), AKNA (NCBI Gene ID: 80709), TFE3 (NCBI Gene ID: 7030), CRTC2 (NCBI Gene ID: 200186 ), CCNL2 (NCBI Gene ID: 81669), CHMP1A (NCBI Gene ID: 5119), CIC (NCBI Gene ID: 23152), PTOV1 (NCBI Gene ID: 53635), CNOT3 (NCBI Gene ID: 4849), SPI1 (NCBI Gene ID: 6688), SUPT5H (NCBI Gene ID: 6829), ZBTB17 (NCBI Gene ID: 7709), MED22 (NCBI Gene ID: 6837), TYK2 (NCBI Gene ID: 7297), SLC11A1 (NCBI Gene ID: 6556), SBN02 (NCBI Gene ID: 22904), FLYWCH1 (NCBI Gene ID: 84256), NACC2 (NCBI Gene ID: 138151), E4F1 (NCBI Gene ID: 1877), HD AC 10 (NCBI Gene ID: 83933), HGS (NCBI Gene ID: 9146), RHOT2 (NCBI Gene ID: 89941), CAMTA2 (NCBI Gene ID: 23125), ZNF335 (NCBI Gene ID: 63925), and MED 15 (NCBI Gene ID: 51586).

42. The method of Claim 41, wherein the set of proteins is MED15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.

43. The method of any one of Claims 38-42, wherein the set of proteins is selected by cross-validation.

44. The method of any one of Claims 38-42, wherein the set of proteins consists of proteins having at least a pre-determined value of differential protein activity between responders and non-responders. 45. The method of any one of Claims 38-44, wherein the protein activity value is a normalized enrichment score.

46. The method of any one of Claims 38-45, wherein determining the plurality of protein activity values comprises applying VIPER algorithm to gene expression data of the subject.

47. The method of any one of Claims 38-46, wherein the trained classifier comprises a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.

48. A computer program product for identifying responders and non-responders, the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

and obtaining from the classifier a classification of the subject as a responder or non-responder, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C3 alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C₃ alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C18 heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

49. A method of treating a subject suffering from multiple myeloma (MM), comprising the steps of: obtaining a sample of from the subject; determining a sequence of one or more of the following genes in the sample: ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, andNOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject determined to have a mutation in one or more of the genes, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C1₈ heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted. 50. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound represented by structural formula (I)

to the subject, wherein the subject is determined to have determined to have a mutation in one or more of the following genes:

ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C₃-C₆ cycloalkyl, C₃-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C3 alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C3 alkyl), -0-(Ci-C3 haloalkyl), and -S-( C1-C₃ alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C18 heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C3-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

51. A method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have a mutation in at least one of the following genes ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, and NOTCH3; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I)

wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C₃ alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl; R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^r)-N(R^5’)(R^6’), and C5-C18 heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C3-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

52. A method of treating a patient suffering from a multiple myeloma, comprising the steps of: receiving information about a mutation in one or genes present in the patient: ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, andNOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I)

to the patient only if the subject has a mutation in one or more of the genes, wherein: ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-Ci-C3 alkyl, -CN, halo, - OH, Ci- C3 alkyl, C3-C6 cycloalkyl, C3-C12 heterocycloalkyl, -NH2, -NO2, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)(Ci-C₃ alkyl), -C(0)0H, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C₃ alkyl), -0-(Ci-C₃ alkyl), -0-(Ci-C₃ haloalkyl), and -S-( C1-C3 alkyl);

R² is selected from optionally substituted C5-C18 heteroaryl, -C(0)-0-R³, -C(0)-N(R⁵)(R⁶), -C(0)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF3, -S(0)i- 2(Ci-C4 alkyl), and optionally substituted C6-C18 aryl;

R^a is hydrogen and R^b is selected from -C(0)-N(R⁵ )(R⁶ ), hydrogen, -C(0)-0-R³, -C(0)-N(R^r)-N(R^5’)(R^6’),

-CN, -C(S)-0-R³ , -C(S)-N(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C5-C1₈ heteroaryl, wherein:

R³ and R³ are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₃-C18 carbocyclyl, C₆-C18 aryl, C₃-C18 heterocyclyl and C5-C18 heteroaryl;

R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, Ci- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C18 carbocyclyl, C6-C18 aryl, C3-C18 heterocyclyl and C5-C18 heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C18 heterocyclyl or C5-C18 heteroaryl; each R⁷ and R⁷ are each independently hydrogen or C1-C4 alkyl; and n is 0, 1, 2, 3, 4 or 5, wherein each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

53. The method of any one of Claims 49-52, further comprising: collecting a bone marrow sample from the subject; separating CD131+ cells in the bone marrow sample; identifying the activity pattern of the MR proteins in the CD131+ cells.

54. The method of any one of Claims 49-53, wherein the multiple myeloma is a relapsed or refractory multiple myeloma. 55. The method of any one of Claims 49-54, wherein the subject has received from 1 to 7 prior therapies.

56. The method of Claim 55, wherein the subject has received at least two prior therapies.

57. The method of Claim 55, wherein the subject has received at least three prior therapies.

58. The method of Claim 55, wherein the subject has received at least four prior therapies.

59. The method of any one of Claims 49-58, wherein the subject is a human.

60. The method of Claim 59, wherein the human is an adult.

61. The method of any one of Claim 49-60, wherein the compound represented by formula (I) is administered orally.

62. The method of Claim 61, wherein the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

63. The method of any one of Claims 49-62further comprising administering at least one additional therapeutic agent.

64. The method of Claim 63, wherein the additional therapeutic agent is dexamethasone.

65. The method of Claim 64, wherein the dexamethasone is orally administered at an amount of 20 mg/day.

66. The method of any one of Claims 64 or 65, further comprising administering bortezomib. 67. The method of any one of Claims 49-53, wherein the multiple myeloma is relapsed or refractory multiple myeloma, the subject is an adult human who has received at least four prior therapies and the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

68. The method of Claim 67, wherein the compound of formula (I) is administered at 80 mg/per day on days 1 and 3 of each week of treatment.

69. The method of Claim 68, wherein an additional therapeutic agent is administered.

70. The method of Claim 69, wherein the additional therapeutic agent is dexamethasone.

71. The method of Claim 70, wherein the dexamethasone is administered at 20 mg/day on days 1 and 3 of each week of treatment.

72. The method of any one of Claims 49-53, wherein the multiple myeloma is relapsed or refractory multiple myeloma, the subject is an adult human who has received from 1 to 3 prior therapies.

73. The method of Claim 72, wherein the compound of formula (I) is administered at 100 mg once a week.

74. The method of Claim 72 or Claim 73, wherein at least one additional therapeutic agent is administered.

75. The method of Claim 74, wherein the additional therapeutic agents are bortezomib administered at 1.3 mg/m2 once a week and dexamethasone administered twice a week at 20 mg per administration.