Selinexor and Backbone Treatments of Multiple Myeloma Patients (STOMP)

A Phase 1b/2 Study of Selinexor (KPT-330) in Combination With Backbone Treatments for Relapsed/Refractory Multiple Myeloma and Newly Diagnosed Multiple Myeloma

This study will independently assess the efficacy and safety of 11 combination therapies in 12 arms, in dose-escalation/-evaluation and expansion phases, for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM). The combinations to be evaluated are:

• Arm 1: Selinexor + dexamethasone + pomalidomide (SPd)
• Arm 2: Selinexor + dexamethasone + bortezomib (SVd); enrollment complete
• Arm 3: Selinexor + dexamethasone + lenalidomide (SRd) in RRMM; enrollment complete
• Arm 4: Selinexor + dexamethasone + pomalidomide + bortezomib (SPVd)
• Arm 5: Selinexor + dexamethasone + daratumumab (SDd); enrollment complete
• Arm 6: Selinexor + dexamethasone + carfilzomib (SKd)
• Arm 7: Selinexor + dexamethasone + lenalidomide (SRd) in NDMM
• Arm 8: Selinexor + dexamethasone + ixazomib (SNd)
• Arm 9: Selinexor + dexamethasone + pomalidomide + elotuzumab (SPEd)
• Arm 10: Selinexor + dexamethasone + belantamab mafodotin (SBd)
• Arm 11: Selinexor + dexamethasone + pomalidomide + daratumumab (SDPd)
• Arm 12: Selinexor + dexamethasone + mezigdomide (SMd)

Selinexor pharmacokinetics:

• PK Run-in (Days 1-14):

Starting in protocol version 8.0, patients enrolled to any arm in the Dose Escalation Phase (i.e., Arm 4 [SPVd], Arm 6 [SKd], Arm 8 [SNd], Arm 9 [SPEd], Arm 10 [SBd], and Arm 11 [SDPd]) will also first be enrolled to a pharmacokinetics (PK) Run-in period until 9 patients have been enrolled to this period to evaluate the PK of selinexor before and after co-administration with a strong CYP3A4 inhibitor. This run-in period does not apply to Arm 12 (SMd).

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: Selinexor; Drug: Pomalidomide; Drug: Bortezomib; Drug: Lenalidomide; Drug: Clarithromycin; Drug: Daratumumab; Drug: Carfilzomib; Drug: Ixazomib; Drug: Elotuzumab; Drug: Belantamab Mafodotin; Drug: Mezigdomide

Detailed Description

This is a multi-center, open-label, clinical study with Dose Escalation (Phase 1) and Expansion (Phase 2) to independently assess the MTD, efficacy , and safety of 11 combination therapies in 12 arms in patients with RRMM and NDMM. Patients will be assigned to treatment arms based on their diagnoses and treatment histories. For 9 patients, a PK Run-in period will precede Cycle 1 (DLT evaluation) to assess selinexor PK when co-administered with a strong CYP3A4 inhibitor. In the Dose Escalation Phase (Phase 1): (a) in Arm 1 (SPd), Arm 2 (SVd), and Arm 3 (SRd in RRMM), patients will be randomized to either QW or BIW selinexor dosing cohorts; (b) in Arm 5 (SDd), patients will be sequentially assigned in blocks of 3 to either QW or BIW selinexor dosing; (c) in Arm 4 (SPVd), Arm 6 (SKd), Arm 7 (Srd in NDMM), Arm 8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), Arm 11 (SDPd), and Arm 12 (SMd) patients will be assigned to QW selinexor dosing.

Cohort 1.4 is included from Version 10 to study safety and tolerability of SPd with selinexor 40 mg QW, is lower than RP2D (ie, selinexor 60 mg QW) in combination with pomalidomide 4 mg. Cohort 1.4 is a different expansion cohort from the one with RP2D (ie, Cohort 1.3). In Cohort 1.4, 20 patients will be enrolled in total.

Starting in protocol Version 8.0, patients enrolled to the Dose Escalation Phase of Arm 4 (SPVd), Arm 6 (SKd), Arm 8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), and Arm 11 (SDPd) will first be enrolled to a 14-day PK Run-in period (selinexor +/- clarithromycin) until 9 patients have been enrolled. During this 14-day PK Run-in period, selinexor 40 milligrams (mg) will be administered alone on Day 1, clarithromycin 500 mg twice daily (BID) will be administered on Days 2-8, and selinexor 40 mg will again be administered on Day 8 with the morning clarithromycin dose. Blood samples for PK analysis will be collected pre-dose and 1 (± 10 min), 1.5 (± 10 min), 2 (± 10 min), 3 (± 10 min), 4 (± 10 min), 5 (± 10 min), 6 (± 10 min), 8 (± 10 min), and 24 h (± 30 min) hours after selinexor is dosed on Day 1 (without clarithromycin) and Day 8 (with clarithromycin). Patients will then proceed to the DLT evaluation period that will begin after the completion of the 14-day PK Run-in period; this day will be designated as Cycle 1 Day 1 (C1D1) in the Dose Escalation Phase.

Starting in protocol v12, in Arm 12 (SMd) additional PK sampling for mezigdomide will be collected concurrently with selinexor on Cycle 1 Day 1 (C1D1) at 2,4, and 6 hrs post-mezigdomide/selinexor dose; additional mezigdomide PK samples will be collected pre-mezigdomide dose on Days 8 and 15 of Cycles 1 and 2.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Eric Sbar, DO; Email: eric.sbar@karyopharm.com
• Study Contact Backup: Name: Sharon Shacham, PhD; Email: SShacham@karyopharm.com

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • Cancer Care Manitoba
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Memorial Hospital of Newfoundland
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II Health Sciences Center
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital / McGill University
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Los Angeles, California, United States, 0095
      • Jonnsson Comprehensive Cancer Center / University of Los Angeles
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center - John Theurer Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
    • Rochester, New York, United States
      • Wilmot Cancer Center/ University of Rochester
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Chapel Hill Comprehensive Cancer Center
    • Durham, North Carolina, United States, 27710
      • Duke Institute of Cancer/ Duke University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon- Tennessee Oncology Nashville
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin School of Medicine and Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent signed in accordance with federal, local, and institutional guidelines.
2. Age greater than or equal to (≥) 18 years at the time of informed consent.
3. Histologically confirmed diagnosis with measurable disease for relapsed/refractory myeloma.
4. Symptomatic MM, based on IMWG guidelines.

5. Patients must have measurable disease as defined by at least one of the following:

   1. Serum M-protein ≥ 0.5 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitative IgA
   2. Urinary M-protein excretion at least 200 mg/24 hours
   3. Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided that FLC ratio is abnormal
   4. If SPEP is felt to be unreliable for routine M-protein measurement (example, for IgA MM), then quantitative immunoglobulin (Ig) levels by nephelometry or turbidometry are acceptable
6. Any non-hematological toxicities (except for peripheral neuropathy as described in exclusion criterion #22) that patients had from treatments in previous clinical studies must have resolved to less than or equal (≤) Grade 2 by C1D1.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

8. Adequate hepatic function within 28 days prior to C1D1:

   • For SPd, SRd, and SPEd: Total bilirubin < 2* upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5* ULN
   • For SVd, SPVd, SDd, SNd, SBd and SDPd: Total bilirubin of < 1.5* ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and both AST and ALT < 2.0* ULN
   • For SKd and SMd: Total bilirubin < 2x ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x ULN) and both AST and ALT < 3.0x ULN

9. Adequate renal function within 28 days prior to C1D1. For Arms 1-11, estimated creatinine clearance (CrCl) calculated using the formula of Cockroft and Gault (1976).

   • ≥ 20 milliliter per minute (mL/min) for SVd, SDd, and SKd arms
   • ≥ 30 mL/min for SNd, SBd, and SMd arms
   • ≥ 45 mL/min for SPd, SPVd, SPEd and SDPd arms
   • > 60 mL/min for SRd arm

10. Adequate hematopoietic function within 28 days prior to C1D1: absolute neutrophil count (ANC) ≥ 1,000/mm^3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet count ≥ 100,000/mm^3.

    • SPVd (Arm 4) and SKd (Arm 6) only: platelet count ≥150,000.
    • SMd (Arm 12) only: platelet count ≥75,000 for subjects in whom <50% of bone marrow nucleated cells are plasma cells; or platelet count <50,000 for subjects in whom ≥50% of bone marrow nucleated cells are plasma cells.

11. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients must use highly effective methods of contraception throughout the study and for 90 days following the last dose of study treatment. For Arm 12 (SMd), all study subjects must agree and adhere to all testing and contraception requirements as specified in the mezigdomide Global Pregnancy Prevention Plan (PPP)

    SPd (Arm 1) Only.

12. Relapsed or refractory MM with:

    1. Documented evidence of progressive disease (PD) after achieving at least stable disease (SD) for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)
    2. ≤ 25 percent (%) response (i.e., patients never achieved ≥ MR) or PD during or within 60 days from the end of the most recent MM regimen (i.e., refractory MM)
    3. Previously undergone ≥ 2 cycles of lenalidomide and a PI (in separate therapeutic regimens [not for maintenance] or in combination)
    4. In the expansion arm at RP2D, patients must not be pomalidomide refractory

    SVd (Arm 2) Only:

13. Relapsed or refractory MM with:

    1. Documented evidence of relapse after ≥ 1 previous line of therapy
    2. Not refractory to bortezomib in their most recent line of therapy

    SRd in RRMM (Arm 3) Only:

14. Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowed as long as patient's MM was not refractory to prior lenalidomide; patients whose MM was refractory to lenalidomide maintenance regimens will be allowed in this cohort).

    SPVd (Arm 4) Only:

15. Patients who received 1- 3 prior lines of therapy, including ≥ 2 cycles of lenalidomide and have demonstrated disease progression on their last therapy (may include prior bortezomib, as long as the patient's MM was not refractory to bortezomib therapy), but patients must be pomalidomide-naïve in the Dose Expansion at RP2D (Cohort 4.3 ONLY).

    SDd (Arm 5) Only:

16. Patients who received ≥ 3 prior lines of therapy, including a PI and an immunomodulatory agent (IMiD), or patients with MM refractory to both a PI and an IMiD.

17. Patients must not have received prior anti-cluster of differentiation 38 (anti-CD38) monoclonal antibodies (Cohort 5.3 ONLY - Dose Expansion at RP2D).

    SKd (Arm 6) Only:

18. Patients may have received prior PIs; however, their MM must NOT be refractory to carfilzomib.

    SRd in NDMM (Arm 7) Only:

19. Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria (calcium elevation, renal failure, anemia, lytic bone lesions) or myeloma-defining events and need systemic therapy. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone (maximum dose of 160 mg) or corticosteroid equivalent.

    SNd (Arm 8) Only:

20. Patients must have MM that relapsed after 1 - 3 prior lines of therapy (may not include those with MM refractory to bortezomib or carfilzomib but patients must be ixazomib-naïve).

    SPEd (Arm 9) Only:

21. Patients who received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimens), but patients must be pomalidomide-naive and elotuzumab-naive in the Dose Expansion at RP2D (Cohort 9.3 ONLY).

    SBd (Arm 10) Only:

22. Patients who have MM that was refractory to an IMiD, a proteasome inhibitor, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody. Patients must be belantamab mafodotin-naive in the Dose Expansion cohort at RP2D (Cohort 10.3 ONLY).

    SDPd (Arm 11) Only:

23. Patients who received 1-3 prior therapies, including lenalidomide and a proteasome inhibitor (in separate or the same regimen), but patients must be pomalidomide-naive and daratumumab-naive in the Dose Expansion cohort at RP2D (Cohort 11.3 ONLY).

    SMd (Arm 12) only:

24. Patients with RRMM who have received at least 2 prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody. Patients must have either failed a T-cell redirecting treatment (eg, CAR-T or bispecific antibody) or otherwise cannot receive such therapy due to either medical or logistic reasons.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:

1. Smoldering MM.
2. MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and quantitative immunoglobulin levels cannot be used instead.
3. Documented active systemic amyloid light chain amyloidosis.
4. Active plasma cell leukemia.
5. Red Blood Cell (RBC) and platelet transfusions and blood growth factors within 14 days of C1D1 (Arms 1-11 only). Red blood cells and platelet transfusions and blood growth factors within 7 days of C1D1 (Arm 12).
6. Platelet transfusion or G-CSF within 7 days or pegfilgastrim within 14 days prior to the complete blood count (CBC) used to determine eligibility.
7. Radiation, chemotherapy, or immunotherapy or any other tumor-directed therapy ≤ 2 weeks prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patients on long-term glucocorticoids during Screening do not require a washout period. Spot radiation is permitted at any time for treatment of fractures or to prevent fractures as well as for pain management.
8. Patients with history of spinal cord compression with residual paraplegia (Dose Escalation Phase only).
9. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1.
10. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell transplantation < 3 months prior to C1D1.
11. Active graft versus host disease after allogeneic stem cell transplantation.
12. Life expectancy < 3 months.
13. Major surgery within 4 weeks prior to C1D1.

14. Active, unstable cardiovascular function:

    1. Symptomatic ischemia, or
    2. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or
    3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
    4. Myocardial infarction (MI) within 3 months prior to C1D1
    5. Ejection fraction (EF) < 50% at Screening (Arms 1-11 only, screening echocardiogram not required for Arm 12, SMd)
15. Uncontrolled active hypertension (Arms 1-11 only).
16. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose.
17. Known active hepatitis A, B or C.
18. Known human immunodeficiency virus (HIV) infection or HIV seropositivity.
19. Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment.
20. Currently pregnant or breastfeeding.
21. A serious active psychiatric or active medical condition which, in the opinion of the Investigator, could interfere with treatment.
22. Hypersensitivity to any of the treatments for the arm in which the patient is enrolled.
23. SVd Arm (Arm 2), SPVd (Arm 4), and SNd Arm (Arm 8) only: Prior history of neuropathy Grade > 2, or Grade ≥ 2 neuropathy with pain at Screening (within 28 days prior to C1D1).
24. Patients who are eligible for the selinexor PK Run-in only: Treatment with moderate or strong inhibitors/inducers of CYP3A within 7 days prior to Day 1 of the PK Run-in period.
25. Patients who are eligible for the selinexor PK Run-in only: Not able to receive a strong CYP3A4 inhibitor due to concomitant medications.
26. SKd arm only: HBs Ag + plus HBc Ab + even though no active hepatitis B virus (HBV) hepatitis. If HBs Ag - plus HBc Ab +, treating physician needs to contact the medical monitor.

27. Prior exposure to a selective inhibitor of nuclear export (SINE) compound, including selinexor.

    SBd (Arm 10): Only:

28. Current corneal epithelial disease except mild punctate keratopathy.

    SMd (Arm 12 only):

29. History of allogeneic stem cell or solid organ transplant at any time.
30. History of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide (including ≥Grade 3 rash during prior thalidomide, lenalidomide, or pomalidomide therapy), carfilzomib or dexamethasone, any CELMoD agents, or the excipients contained in the formulations, or subject has any contraindications per local prescribing information.
31. Subject is unable or unwilling to agree to refrain from donating blood while on study intervention, during dose interruptions, and for at least 28 days following the last dose of study intervention.
32. Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis.
33. Use of strong CYP3A4 modulator or proton-pump inhibitors (eg, omeprazole, lansoprazole), within 2 weeks of starting study intervention.
34. Active concomitant malignancies or history of another malignancy within 3 years prior to C1D1 except for adequately treated early-stage basal cell or squamous cell carcinoma of skin, adequately treated carcinoma in situ of breast or cervix, or organ confined prostate cancer.
35. History of chronic hepatitis B with detectable viral load.
36. Subject is unable or unwilling to receive protocol-required dual antiemetic prophylaxis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: Selinexor, Low-dose Dexamethasone and Pomalidomide (SPd); Each cycle is of 28 days Cohort 1.1: Selinexor (SEL) 60/80/100 mg orally (PO) once weekly (QW); Dexamethasone (DEX) 40 mg PO once weekly; Pomalidomide (POM) 2/3/4 mg PO Days 1-21. Cohort 1.2: SEL 40/60/80 mg PO twice weekly (BIW); DEX 20 mg PO twice weekly; POM 3/4 mg PO Days 1-21. Cohort 1.3: Selinexor, Dexamethasone and Pomalidomide will be dosed at RP2D-1. Cohort 1.4: SEL 40 mg PO QW; DEX 40 mg PO QW; POM 4mg PO once daily (QD) Days 1-21.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Pomalidomide; Oral tablets; Other Names: Pomalyst®
Experimental: 2: Selinexor, Low-dose Dexamethasone and Bortezomib (SVd); Each cycle is of 35 days Cohort 2.1: SEL 60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Bortezomib (BOR) 1.3 milligram per meter square (mg/m^2) subcutaneous (SC) once weekly. Cohort 2.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; BOR 1.3 mg/m^2 subcutaneous (SC) once weekly. Cohort 2.3: Selinexor, Dexamethasone and Bortezomib will be dosed at RP2D-2.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Bortezomib; Subcutaneous Injection (single use vial); Other Names: Velcade®
Experimental: 3: Selinexor, Low-dose DEX, and Lenalidomide (SRd) in RRMM; Each cycle is of 28 days Cohort 3.1: SEL 40/60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Lenalidomide (LEN) 15/25 mg PO Days 1-21. Cohort 3.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; LEN 15/25 mg PO Days 1-21. Cohort 3.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-3.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Lenalidomide; Oral capsule; Other Names: Revlimid®
Experimental: 4:Selinexor, Low-dose dexamethasone, Pomalidomide, Velcade (SPVd); PK Run-in Period: Selinexor and Clarithromycin: For the first 9 patients enrolled into this dose escalation arm; 14 day run-in period after which patients will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-escalation Phase: All patients enrolled into this Arm; Each cycle is of 28 days. Cohort 4.1: SEL 40/60 mg PO once weekly; DEX 40 mg PO once weekly; POM 4 mg PO Days 1-21; BOR 1.3 mg/m^2 subcutaneous (SC) once weekly. Cohort 4.3: Selinexor, Dexamethasone, Pomalidomide, Velcade (Bortezomib) will be dosed at RP2D-4.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Pomalidomide; Oral tablets; Other Names: Pomalyst®; Drug: Bortezomib; Subcutaneous Injection (single use vial); Other Names: Velcade®; Drug: Clarithromycin; Tablets; Other Names: Biaxin
Experimental: 5: Selinexor, Low-dose dexamethasone, and Daratumumab (SDd); Each cycle is of 28 days Cohort 5.1: SEL 80/100 mg PO once weekly; DEX 40 mg once weekly (IV or PO); DARA: 16 mg/kg IV infusion Cycle 1-2: Once weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month. Cohort 5.2: SEL: 60 mg PO twice weekly; DEX: 40 mg weekly (IV or PO); DARA: 16 milligram per kilogram (mg/kg) IV infusion Cycle 1-2: Once. weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month. Cohort 5.3: Selinexor, Dexamethasone and Daratumumab will be dosed at RP2D-5.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Daratumumab; Intravenous Infusion; Other Names: Darzalex®
Experimental: 6: Selinexor, Low-dose dexamethasone, and Carfilzomib (SKd); PK Run-in Period: Selinexor and Clarithromycin: For the first 9 patients enrolled into this dose escalation arm; 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: All patients enrolled into this Arm; Each cycle is of 28 days Cohort 6.1: SEL 40/60/80/100 mg PO once weekly on days 1, 8, 15, and 22; DEX 40 mg IV or PO once weekly; Carfilzomib (CAR) 56 or 70 mg/m^2 IV infusion once weekly on days 1, 8, and 15. Cohort 6.2: SEL 60/80/100 mg PO once weekly on days 1, 8, and 15; DEX 40 mg IV or PO once weekly; CAR 56 or 70 mg/m^2 IV infusion once weekly on days 1, 8, and 15. Cohort 6.3: Selinexor, Dexamethasone and Carfilzomib will be dosed at RP2D-6.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Clarithromycin; Tablets; Other Names: Biaxin; Drug: Carfilzomib; Intravenous infusion; Other Names: Kyprolis®
Experimental: 7: Selinexor, Low-dose DEX and Lenalidomide (SRd) in NDMM; Each cycle is of 28 days Cohort 7.1: SEL 40/60/80 mg PO once weekly; DEX 40 mg PO once weekly; LEN 25 mg PO Days 1-21. Cohort 7.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-7.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Lenalidomide; Oral capsule; Other Names: Revlimid®
Experimental: 8: Selinexor, Low-dose dexamethasone, and Ixazomib (SNd); PK Run-in Period: Selinexor & Clarithromycin: For the first 9 patients enrolled into this dose escalation arm; 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: All patients enrolled into this Arm; Each cycle is of 28 days Cohort 8.1: SEL 40/60/80/100 mg PO once weekly; DEX 20 mg PO twice weekly; IXA 3/4 mg PO once weekly. Cohort 8.3: Selinexor, Dexamethasone and Ixazomib will be dosed at RP2D-8.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Clarithromycin; Tablets; Other Names: Biaxin; Drug: Ixazomib; Oral capsule; Other Names: Ninlaro®
Experimental: 9: Selinexor, Low-dose DEX, Pomalidomide and Elotuzumab (SPEd); PK Run-in Period: Selinexor and Clarithromycin: For the first 9 patients enrolled into this dose escalation arm; 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: All patients enrolled into this Arm; Each cycle is of 28 days Cohort 9.1: SEL 20/40/60 mg PO once weekly; DEX 28/20 mg PO twice weekly; POM 4 mg PO QD Days 1-21; Elotuzumab (ELO) 10/20 mg/kg IV will be given once weekly on Days 1,8, 15 and 22 of Cycles 1-2. Starting on Cycle 3 and continuing for future cycles, elotuzumab will be dosed at 20 mg/kg on Day 1 of each cycle only. Cohort 9.3: Selinexor, Dexamethasone, Pomalidomide and Elotuzumab will be dosed at RP2D-9.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Pomalidomide; Oral tablets; Other Names: Pomalyst®; Drug: Elotuzumab; Intravenous infusion; Other Names: Empliciti®
Experimental: 10. Selinexor, Dexamethasone, and Belantamab Mafodotin (SBd); Each cycle is of 21 days Cohort 10.1: SEL 40/60/80 mg PO once weekly on Days 1, 8, and 15; DEX 40 mg PO QW on Days 1, 8, and 15; Belantamab Mafodotin (BEL) 2.5 mg/kg IV infusion every 3 weeks (Q3W) Day 1 of each cycle. Cohort 10.3: Selinexor, Dexamethasone, and Belantamab Mafodotin will be dosed at RP2D-10.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Belantamab Mafodotin; Intravenous infusion; Other Names: BLENREP
Experimental: 11. Selinexor, Dexamethasone, Pomalidomide, and Daratumumab (SDPd); Each Cycle is of 28 days Cohort 11.1 SEL 40/60 mg PO once weekly on Days 1, 8, and 15; DEX total 40 mg weekly (IV or PO) single or divided doses on Days 1, 8, 15, and 22; POM 4 mg PO QW Days 1-21; DARA 16 mg/kg IV or SC QW on Days 1, 8, 15 and 22 of Cycles 1-2 and on Days 1 and 15 of Cycles 3-6, Day 1 of every Cycle greater than (>6). Cohort 11.3 Selinexor, Dexamethasone, Pomalidomide, and Daratumumab will be dosed at RP2D-11.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Pomalidomide; Oral tablets; Other Names: Pomalyst®; Drug: Daratumumab; Intravenous Infusion; Other Names: Darzalex®
Experimental: 12. Selinexor + dexamethasone + mezigdomide (SMd); The dose of selinexor will be formally escalated from 40 mg QW to 60 mg QW in combination with mezigdomide 0.6 mg daily. Mezigdomide dosing may be de-escalated as per 3+3 criteria to 0.3 mg or escalated to 1.0 mg. The dose level that passes DLT evaluation will be considered the MTD for the cohort.	Drug: Dexamethasone; Oral tablets; Other Names: Decadron®; Drug: Selinexor; Oral tablets; Other Names: KPT-330; XPOVIO®; Drug: Mezigdomide; Oral Capsules; Other Names: BMS-986348; CC-92480

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 (Dose-escalation): Maximum Tolerated Dose (MTD)	MTD for once weekly and twice weekly selinexor dose cohorts in the 11 Arms will be evaluated.	12 months
Phase 1 (Dose-escalation): Recommended Phase-2 dose (RP2D)	RP2D for each Arm will be determined.	12 months
Phase 1 (Dose-escalation): Maximum Plasma Concentration (Cmax) of Selinexor	Cmax of selinexor over a dosing interval when given with and without clarithromycin.	Pre-dose, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin)
Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Selinexor	Total exposure of selinexor in the blood (AUC0-last) from the time of dosing to the last measurable concentration collected when given with and without clarithromycin.	Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin)
Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated) (AUC0-inf)		Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post-dose on Day 1 (without clarithromycin) and Day 8 (with clarithromycin)
Phase 2 (Expansion): Overall response rate (ORR)	ORR for each Arm independently. ORR to include stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), according to the International Myeloma Working Group (IMWG) criteria.	12 months
Phase 2 (Expansion): Duration of response (DOR)	Duration of response for each Arm. DOR is defined as the number of days from the date of the first evidence of objective response until progression.	12 months
Phase 2 (Expansion): Clinical Benefit Rate (CBR)	CBR is defined the point estimate of the percentage of patients in that arm who have a response of sCR, CR, VGPR, PR or Minimal response (MR), as assessed by IMWG criteria.	12 months

Collaborators and Investigators

• Sponsor: Karyopharm Therapeutics Inc
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Michael Kauffman, MD, Ph.D, Karyopharm Therapeutics Inc

Publications and helpful links

General Publications

• Bahlis NJ, Sutherland H, White D, Sebag M, Lentzsch S, Kotb R, Venner CP, Gasparetto C, Del Col A, Neri P, Reece D, Kauffman M, Shacham S, Unger TJ, Jeha J, Saint-Martin JR, Shah J, Chen C. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018 Dec 13;132(24):2546-2554. doi: 10.1182/blood-2018-06-858852. Epub 2018 Oct 23.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: January 13, 2015
• First Submitted That Met QC Criteria: January 15, 2015
• First Posted (Estimated): January 21, 2015

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pomalidomide; Multiple Myeloma; Daratumumab; Lenalidomide; Dexamethasone; Carfilzomib; Bortezomib; Newly Diagnosed; Clarithromycin; Relapsed/Refractory; STOMP; Karyopharm; CC-92480; Selinexor; Ixazomib; Belantamab mafodotin; BMS-986348; KCP-330; Elotuzumab; Mezigdomide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Dexamethasone; Pomalidomide; Lenalidomide; Daratumumab; Ixazomib; Bortezomib; Clarithromycin; Elotuzumab
• Other Study ID Numbers: KCP-330-017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No