Isatuximab, Bela Maf, Pom, and Dex in Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

* Participant has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to their future medical care.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix A).
* Age ≥ 18 years
* Measurable disease of multiple myeloma as defined by at least one of the following:

  * Serum monoclonal protein ≥ 0.5 g/dL. Patients with IgD disease and lower amounts of monoclonal protein may be permitted to enroll with PI approval
  * ≥ 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
  * Involved serum free light chain ≥ 100 mg/L (10 mg/dL) and abnormal serum free light chain ratio
* Previously treated relapsed and refractory multiple myeloma:
* Patients must have received at least one prior line of therapy;
* Prior therapy must include at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen); and
* Disease progression on or within 60 days of completion of last therapy.
* ANC ≥ 1000/μL. G-CSF is not permitted within 14 days of screening. Patients with ANC \<1000/µL can be considered for screening on a case-by-case basis with additional monitoring, after discussion with and approval from the PI.
* Platelet count ≥ 75,000/µL. Platelet transfusion is not permitted within 7 days of screening.
* Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria.
* Calculated creatinine clearance of ≥ 30 mL/min by Modified Diet in Renal Disease (MDRD) formula or Cockcroft-Gault formula
* Spot urine (albumin/creatinine ratios (spot urine) \< 500 mg/g or urine dipstick negative/trace.
* Patient has adequate hepatic function, as evidenced by each of the following:
* Serum bilirubin values \< 1.5 × ULN. Isolated bilirubin ≥ 1.5 × ULN is acceptable if bilirubin is fractionated and direction bilirubin \<35%. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. total bilirubin \<3 mg/dL and normal direct bilirubin); and
* Serum aspartate transaminase (ALT) and/or aspartate transaminase (AST) values \< 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. total bilirubin \<3 mg/dL and normal direct bilirubin).
* Must be able to take acetylsalicylic acid (ASA) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin, apixaban, rivaroxaban, or equivalent.
* All study participants must be registered into the mandatory Pomalyst REMS program and be willing and able to comply with the requirements of the Pomalyst REMS program.
* Women of childbearing potential (WOCBP) must adhere to the scheduled pregnancy testing as required in the Pomalyst REMS program and agree to use a highly effective method of contraception during the study for 4 months after the last dose of treatment in the study (see Appendix) and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period). A WOCBP must have a negative highly sensitive serum pregnancy test within 72 hours before the first dose of study intervention and agree to use a highly effective method of contraception during the study and for 4 months after the last dose of belantamab mafodotin. Note: non childbearing potential defined as follows (by other than medical reasons):

  * ≥ 45 years of age and has not had menses for \> 1 year
  * Patients who have been amenorrhoeic for \< 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
  * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
* A man who is sexually active with a WOCBP (even if they have undergone a successful vasectomy) must agree to use a barrier method of birth control e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for 6 months after receiving the last dose of study drug.
* Male participants must refrain from donating sperm for 6 months after the last dose of study drug.
* Able to swallow capsules whole (pomalidomide capsules cannot be crushed, dissolved or broken).

Exclusion Criteria:

* Participant must not have had current corneal epithelial disease except mild changes in corneal epithelium.
* Participant must not use contact lenses while participating in this study.
* Participants who have had myeloma therapy or investigational drug within 2 weeks prior to start of treatment or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
* Participants who are receiving any investigational agents.
* Prior therapy with anti-CD38 monoclonal antibody within six months. No other multiple myeloma monoclonal antibody therapy within 30 days of start of study treatment.
* Prior therapy with anti-BCMA therapy.
* Plasmapheresis within seven days prior to start of study treatment.
* Primary refractory disease.
* Concomitant high dose corticosteroids. Low dose corticosteroids (maximum dose prednisone 10 mg/day or equivalent) are permitted if given for disorders other than myeloma, e.g. adrenal insufficiency, rheumatoid arthritis, etc.
* Pregnancy or lactation or planned lactation (breastfeeding).
* Prior history of malignancies, other than MM, unless the patient has completed definitive treatment and has been free of the disease for ≥ 3 years. Patients who are free of disease \< 3 years may enroll after discussion with and approval of the PI. Exceptions include the following (i.e. the following are eligible to participate):

  * Basal or squamous cell carcinoma of the skin
  * Carcinoma in situ of the cervix
  * Ductal carcinoma in situ of the breast
  * Incidental histologic finding of prostate cancer (T1a or T1b) managed with surveillance
* Patients with active plasma cell leukemia at time of screening, POEMS syndrome, or primary AL amyloidosis are excluded from this trial.
* Seropositive for HIV infection
* Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]; see exception below). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened for hepatitis B virus (HBV) DNA levels. Those with positive HBV viral load will be excluded. Exception: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need testing for HBV DNA.
* Seropositive for hepatitis C (except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy).
* Peripheral neuropathy ≥ grade 2 despite supportive therapy.
* Hypersensitivity to isatuximab, belantamab mafodotin, pomalidomide, or dexamethasone, such as Stevens-Johnson syndrome. Rash to immunomodulatory drug that can be medically managed is allowed.
* Allogeneic stem cell transplant \<12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least four weeks prior to initiation of study treatment and who are currently dependent on such treatment. Patients may also not have active graft v. host disease (GVHD).
* Autologous stem cell transplant \<6 months prior to start of treatment
* Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to:

  * Congestive heart failure (New York Heart Association \[NYHA\] Class 3 or 4)
  * Unstable angina
  * Clinically significant, uncontrolled cardiac arrhythmia such a 2nd degree or 3rd degree atrioventricular block
  * Recent (within the preceding 6 months) myocardial infarction or stroke
  * Uncontrolled hypertension
  * Diabetes mellitus with \> 2 episodes of ketoacidosis in the preceding 12 months
  * Chronic obstructive pulmonary disease (COPD) requiring \> 2 hospitalizations in the preceding 12 months.
  * Unstable liver or biliary disease
  * Active bacterial, viral, or fungal infection
* Patient has any other medical, psychiatric, or social condition that would preclude participation in the study, pose an undue medical hazard, interfere with the conduct of the study, or interfere with interpretation of the study results.
* Major surgery within 4 weeks prior to C1D1.
* Live or live-attenuated vaccine within 30 days prior to C1D1.
* Toxicity from previous anticancer therapy must resolve to baseline levels or to grade ≤1, except for alopecia and peripheral neuropathy.