Isatuximab Plus Pomalidomide and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma at Risk for Toxicity

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information (PHI). Consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Age >= 18 years at the time of consent
• Documented symptomatic multiple myeloma that has previously responded to therapy (partial response or better) and is relapsed or relapsed and refractory to the last line of therapy. Refractory disease is defined as less than a minimal response or confirmed progressive disease per International Myeloma Working Group (IMWG) criteria within 60 days (measured from the end of the last cycle) after cessation of treatment. Relapsed disease is defined as previously treated disease that progresses and requires initiation of therapy but does not meet criteria for refractory disease
• Subjects must also be refractory to at least 1 prior line of therapy that includes an immunomodulators (IMiD) and/or a proteasome inhibitor (PI) and should have received at least 2 cycles of that regimen
• If previously treated with at least 2 consecutive cycles of an anti-CD38 containing regimen, and if refractory to that regimen, the subject must have achieved at least a PR to that line of therapy and must not have received an anti-CD38 mAb for at least 6 months prior to enrollment
• Willing and able to adhere to the study visit schedule and other protocol requirements based on the judgement of the investigator
• Predicted high risk for severe toxicity from intensive regimens for RRMM, such as standard (full-dose) daratumumab-dexamethasone-pomalidomide (DPD), daratumumab-bortezomib-dexamethasone (DVD), carfilzomib-pomalidomide-dexamethasone (KPD), carfilzomib-lenalidomide-dexamethasone (KRD), isatuximab-pomalidomide-dexamethasone (Ixa-PD), or dexamethasone-elotuzumab-pomalidomide (Elo-PD) as each regimen was published (such regimens often use, for example, twice-weekly bortezomib at 1.3 mg/m^2, lenalidomide at 25 mg, or pomalidomide 4 mg). High-risk is defined as one of the following: * A. Score >= 2 (indicating "frail") on the International Myeloma Working Group instrument * B. Karnofsky performance status (KPS) =< 70 * C. Not meeting criteria A or B above but felt by treating clinician to not be candidate for a standard full-dose regimen on account of one of the following: ** History of requiring clinically significant non-hematologic grade >= 3 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 5.0) toxicity attributed to prior anticancer therapy ** History of dose-reduction of at least two separate anticancer drugs during prior therapy for multiple myeloma Subjects qualifying for enrollment by criteria (C) should be discussed with study principal investigator (PI) before enrollment, to ensure uniform application of this criterion across participating sites
• Measurable disease as defined by one or more of the following: * Monoclonal protein (M-protein) present in serum and/or urine, defined as serum M-protein of >= 0.5 g/dL * Urine M-protein of >= 200 mg/24 hours * Involved light chain >= 10 mg/dL (100 mg/L) AND abnormal serum free light chain ratio
• Subjects who require radiotherapy (which must be localized in its field size) may be enrolled but initiating study therapy should be deferred until the radiotherapy is completed and 14 days have elapsed since the last date of radiotherapy
• Hemoglobin (Hgb) >= 8 g/dL (Obtained within 72 hours prior to initiating study treatment) (Transfusion of packed red blood cells or use of erythropoietin or analogs is permitted, if clinically appropriate, to achieve this threshold)
• Absolute Neutrophil Count (ANC) >= 1.0 x 10^9/L (Obtained within 72 hours prior to initiating study treatment) (Use of growth factors is permitted to fulfill this criterion if neutropenia is felt to be due to MM or due to prior therapy for MM)
• Platelets >= 50 x 10^9/L if < 50% of bone marrow nucleated cells are plasma cells, >= 30 x 10^9/L if >= 50% of BM nucleated cells are plasma cells (Obtained within 72 hours prior to initiating study treatment) (Platelet transfusions are permitted to reach entry criteria if thrombocytopenia is felt to be due to MM or due to prior therapy for MM)
• Calculated creatinine clearance - any GFR as long as not currently dialysis-dependent (Obtained within 72 hours prior to initiating study treatment)
• Bilirubin =< 2 x upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level > 2 x ULN if their conjugated bilirubin is < 2 x ULN) (Obtained within 72 hours prior to initiating study treatment)
• Aspartate aminotransferase (AST) =< 3 x ULN (Obtained within 72 hours prior to initiating study treatment)
• Alanine aminotransferase (ALT) =< 3 x ULN (Obtained within 72 hours prior to initiating study treatment)
• Hematology and other lab parameters that are =< grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Male or female contraceptive requirements * Male participants **Men must agree to use a latex or synthetic condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a vasectomy from the time of signing the informed consent form through 90 days after the last dose of pomalidomide and 5 months after the last dose of isatuximab. These same patients must not donate sperm * Female participants ** A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: ***Not a Female of childbearing potential (FCBP). A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), OR *** If an FCBP, participant must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME (male or female contraceptive requirements), at least 28 days before she starts taking pomalidomide through 90 days after the last dose of pomalidomide and 5 months after the last dose of isatuximab. FCBP must also agree to ongoing pregnancy testing during the entire duration of treatment and monthly for 5 months after the last dose of isatuximab. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. All patients enrolled into this trial, must be registered in and must comply with all requirements of the Pomalyst REMS program
• Subject may be human immunodeficiency virus positive (HIV+) if the following criterion are met: * CD4+ T-cell counts >= 350 cells/uL * No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections * Subject is on an established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study treatment. * Absence of known, clinically significant drug-drug interactions with isatuximab, pomalidomide, and dexamethasone
• Subjects is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee

Exclusion Criteria

• Anti-myeloma treatment within 2 weeks of cycle 1 day 1
• Subject is refractory to pomalidomide and/or known to be intolerant of pomalidomide at a dose of 3 mg or less
• Any monoclonal antibody therapy within the previous 28-days
• Autologous stem cell transplantation within 12 weeks of day 1 of cycle 1
• Subjects felt to not be candidates by treating physician for ANY systemic therapy due to excessive comorbidities, frailty, impaired performance status, or other severe limitations. Such limitations can be conceptualized generally as making subjects exceedingly high-risk for ANY systemic treatment. These limitations often stem from medical comorbidities unrelated to MM and they are hence unlikely to improve with MM therapy
• Light-chain (AL) amyloidosis. Subjects with secondary amyloidosis due to MM are eligible, providing amyloidosis is not felt to be a clinically significant issue (e.g., amyloid found incidentally on bone marrow core biopsy without evidence of amyloid-mediated organ compromise)
• Myocardial infarction within 3 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Evidence of active bleeding requiring intervention within the last four weeks
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if patient otherwise meets entry criteria
• Any major surgery within the last four weeks
• Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy. Diagnosis of other prior malignancy within 2 years of enrollment also permissible if no evidence of disease, previously treated with curative intent, and if felt to be unlikely to impact survival during the duration of the study. Other low-risk malignancies may also be permissible if natural history or treatment is unlikely to interfere with efficacy or safety endpoints
• Concurrent use of other anti-cancer agents or treatments (with the exception of adjuvant/maintenance hormonal therapy for participants with a history of breast or prostate cancer and other similar agents deemed to have a low likelihood of affecting the outcome of this study (per discretion of treating physician)
• Known to have hepatitis A, B, or C active infection. * Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positive hepatitis B surface protein antigen (HBsAg) and/or HBV deoxyribonucleic acid (DNA) Of note: * Patient can be eligible if anti-HBc IgG positive (with or without positive anti- HBs) but HBsAg and HBV DNA are negative. * If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. * Patients with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment. If HBV DNA becomes negative and all the other study criteria are still met the subject will be eligible. * Active hepatitis C virus (HCV) infection: positive HCV ribonucleic acid (RNA) and negative anti-HCV Of note: * Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. * Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible
• Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
• Any clinically significant, uncontrolled medical or psychiatric conditions that, in the investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and histamine-2 (H2) blockers or would prohibit further treatment with these agents
• Received any investigational drug within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer
• Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy
• Subject does not currently use tobacco products including cigarettes, chew, or smokeless tobacco