| Eligibility |
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
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