Study of Selinexor With Carfilzomib, Isatuximab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma

Inclusion Criteria33

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of ≤2 within 28 days prior to registration. A performance status of >2 will be allowed only if it is related to bone pain that is expected to improve with treatment.
• Patients with a diagnosis of relapsed or relapsed/refractory MM who have received at least 1 line of prior therapy. In the phase 2 component, we will specifically enrich for patients with 1q gain or amplification as well as other IMWG high-risk features with the aim of including ≥50% of the enrolled population (a minimum of 25 patients) with high risk disease. High risk disease is defined as the presence of:
• del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation
• an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32)
• monoallelic del(1p32) along with 1q+ or biallelic del(1p32)
• β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL) For purposes of the study, patients with 2 or more of these high risk cytogenetic abnormalities. Patients known to carry such abnormalities on previous FISH analysis and/or cytogenetic testing will also be eligible, if results from on-study marrow are unavailable or not obtainable. Therefore, enrollment of patients without these feature(s) will halt once 25 standard risk, non-mutated patients are enrolled and treated. Refractory is defined as patients relapsing on or within 60 days of therapy, per IMWG.
• Patients must have measurable disease as defined by at least one of the following:
• A monoclonal protein (M-protein): ≥ 0.5g/dL on serum protein electrophoresis or ≥ 200 mg of monoclonal protein on a 24-hour urine protein or involved serum light chain ≥ 10 mg/dl at time of relapse, or
• Biopsy proven plasmacytoma that can be assessed by physical exam or imaging, or
• If non- or oligo secretory, ≥10% plasma cells on BM biopsy/aspirate at time of relapse or plasmacytoma as described and/or evaluable disease by positron emission tomography, either MR or CT. Patients must be willing to undergo repeat BM aspirate and biopsy to assess response.
• Due to the difficulty of quantitation using conventional SPEP of IgA and IgD monoclonal proteins, an absolute increase of > 25 % over previous nadir of the total values in mg/dl (or adjusted units) will meet eligibility requirements for progression and study eligibility.
• NOTE: Urine protein electrophoresis (UPEP) (on a 24-h collection) is required at baseline; no substitute method is acceptable. Urine must be assessed to establish response if the baseline urine M-spike is ≥ 200 mg/24 h. Please note that if both serum and urine M-components are present at the time of enrollment, both should be assessed in order to evaluate response for CR but monthly 24 hour urine tests outside of this response testing are not necessary. For patients without a monoclonal urine protein ≥200mg/24 hours, the test only needs to be repeated to corroborate CR.
• Patients may have received any number and type of previous treatments for myeloma including carfilzomib and an anti-CD38 antibody but cannot be refractory to the combination of daratumumab and carfilzomib.
• Patients may not have received any anti-CD38 therapy within 6 months of start of study treatment (not enrollment).
• Previous allogeneic transplant is allowed provided the patient is not receiving ongoing systemic therapy for graft-versus-host disease (GVHD).
• Previous B-cell maturation antigen (BCMA)-directed therapy, including chimeric antigen receptor T-cell therapy (CAR-T) transplantation, antibody drug conjugates, or bispecific engagers is also allowed, provided there is no evidence of residual cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. In addition, other T cell redirecting therapy exposure is permitted as well.
• Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
• White blood cell (WBC): ≥ 1,500/mm3
• Absolute Neutrophil Count (ANC): ≥ 1,000/mm3 a (For subjects with known Duffy null phenotype (benign ethnic neutropenia), the lowest acceptable ANC will be 750/mm3)
• Platelet Count: ≥75,000/mm3
• Hemoglobin (Hgb): ≥ 8 g/dL
• Calculated creatinine clearance: ≥ 20 cc/min using the Cockcroft-Gault formula
• Total Bilirubin: ≤ 2 × upper limit of normal (ULN) (except patients with suspected Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\] who must have a total bilirubin of ≤ 3x ULN)
• Aspartate aminotransferase (AST): ≤ 3 × ULN
• Alanine aminotransferase (ALT): ≤ 3 × ULN
• Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 7 days prior to registration.
• Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual activity or use an effective method(s) of contraception from the time of informed consent, during the study and for 6 months after the last dose of study drug(s). Males able to father a child must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception from initiation of treatment, during the study and for 3 months after the last dose of study drug(s). Male participants must agree not to donate sperm during this same time period.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
• Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment and absolute lymphocyte count is ≥ 350/ul. Such subjects may stay on antiviral therapy during study treatment.
• Patients with a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection may be enrolled if the viral load by PCR is undetectable with/without active treatment. Such patients may stay on viral therapy while on treatment. Due to a potential HBV and HepC reactivation risk with carfilzomib, the subjects are required to have HBs Ag and HBc Ab screening.
• Subject willing to provide mandatory bone marrow biopsy and peripheral blood laboratory testing for research purposes only.