Post-Autologous Transplant Maintenance With Isatuximab and Lenalidomide in Minimal Residual Disease Positive Multiple Myeloma

NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

12. Patients must be willing to take appropriate DVT prophylaxis, either aspirin, lowmolecular weight heparin, direct oral anticoagulants, or warfarin while receivinglenalidomide.

Inclusion Criteria:

1. Age > 18 years

2. Patients must have a confirmed diagnosis of multiple myeloma according to IMWGcriteria. Patients with smoldering multiple myeloma, or plasma cell leukemia are noteligible. Patients must not have significant amyloid organ dysfunction per the studychair.

3. R-ISS stage 1, 2 or 3 at diagnosis. If stage at diagnosis is not known, patient maybe enrolled if the intent is to treat with post -ASCT maintenance therapy.

4. Received up to or less than 2 lines of therapy prior to ASCT (as long as they didnot meet IMWG refractory disease for CD38 monoclonal antibody or lenalidomidetherapies as defined in exclusion).

5. Patients are planned to undergo ASCT with high dose melphalan, or have completedASCT with high dose melphalan within the last 180 days and have not yet initiatedpost-ASCT maintenance.

6. Obtain at least partial response according to IMWG criteria prior to autologous stemcell transplant

7. ECOG performance status of 0, 1, or 2 within 30 days prior to enrollment.

8. Demonstrate adequate organ function as defined in the table below; all screeninglabs are to be obtained within 30 days prior enrollment. Hematologic White blood cell (WBC) ≥ 1500/mm3 Absolute Neutrophil Count (ANC) ≥ 1000/mm3 Platelets ≥ 50,000/mm3 Renal Calculated creatinine clearance ≥ 30 mL/minusing either the Cockcroft-Gault formula or estimated GFR, and not requiringcontinuous or intermittent dialysis Hepatic Bilirubin ≤ 2.5 × upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)Activated Partial Thromboplastin Time (aPTT)1 ≤ 2 × ULN Note: Patients onanticoagulation are exempt from meeting this criterion

9. Standard of care lenalidomide will not be provided by the sponsor or study andtherefore study subjects must have confirmed access to lenalidomide for use duringthe study at the time of enrollment.

10. Must be able to take and swallow oral medication (capsules) whole. Patients may nothave any known impairment of gastrointestinal function or gastrointestinal diseasethat may significantly alter the absorption of study drug (e.g. ulcerative disease,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowelresection).

11. Females of childbearing potential and males must be willing to abstain fromheterosexual activity or to use 2 forms of effective methods of contraception fromthe time of informed consent until 5 months for females, and 1 month for males aftertreatment discontinuation. The two contraception methods can be comprised of twobarrier methods, or a barrier method plus a hormonal method. Interventions such asIUD, tubal ligation, hormonal (birth control pills, injections, hormonal patches,vaginal rings, or implants), or partner's vasectomy, all count as one method. Forwomen of childbearing potential (WOCBP), a second form must also be used. Men mustagree to use a latex condom during sexual activity with a female of childbearingpotential, irrespective of a prior vasectomy, during the study treatment and for 1month after the end of treatment. Females of childbearing potential agree to notplan a pregnancy for 1 month after the last dose of study medication. Females ofchildbearing potential must agree to ongoing pregnancy testing during the treatmentperiod. NOTE: Females are considered of childbearing potential unless they are surgicallysterile (have undergone a hysterectomy or bilateral oophorectomy) or they arenaturally postmenopausal for at least 12 consecutive months.

12. Patients must be willing to take appropriate DVT prophylaxis, either aspirin, lowmolecular weight heparin, direct oral anticoagulants, or warfarin while receivinglenalidomide.

Exclusion Criteria:

1. Refractory to anti-CD38 monoclonal antibody therapy OR lenalidomide as defined bythe IMWG (defined as non-responsive or progressive disease on therapy or within 60days of last treatment).

2. Prior intolerance to isatuximab or lenalidomide.

3. Prior allogeneic stem cell transplant.

4. Prior solid organ transplant requiring immunosuppressive therapy.

5. Known additional malignancy that is active and/or progressive requiring treatment;exceptions include adequately treated basal cell or squamous cell skin cancer, insitu cervical cancer, adequately treated Stage I or II cancer from which the patientis currently in complete remission, or any other cancer from which the patient hasbeen disease free for three years.

6. Known CNS involvement by multiple myeloma, defined by positive CSF cytology forplasma cells, leptomeningeal involvement, or parenchymal CNS plasmacytoma at time ofenrollment. Lumbar puncture is not required.

7. Treatment with any investigational drug within 30 days prior to enrollment.

8. Planned transplant is considered part of tandem autologous transplant approach fornewly diagnosed MM.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris orcoronary angioplasty, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias ofNCI Common Terminology Criteria for Adverse Events [CTCAE] v5.0 Grade ≥ 2),intracardiac defibrillators, known cardiac metastases, or abnormal cardiac valvemorphology (≥ Grade 3), or known psychiatric illness/social situations that wouldlimit compliance with study requirements.

10. Pregnant women are excluded from this study because lenalidomide is an agent withthe potential for teratogenic or abortifacient effects. Because there is an unknownbut potential risk for adverse events in nursing infants secondary to treatment ofthe mother with lenalidomide, breastfeeding should be discontinued if the mother istreated with lenalidomide.

11. Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) may be enrolled if theviral load by polymerase chain reaction (PCR) is undetectable with active treatmentand absolute lymphocyte count ≥ 350/ul. Antiviral therapy for HIV should continuethroughout the study.

12. Patients with a positive test for hepatitis B virus surface antigen (HBsAg) and/orHBV DNA indicating uncontrolled or active HBV infection. Patients with negativeHBsAg and positive HBV viral load can be evaluated by a specialist for start ofanti-viral therapy and study treatment can be proposed if HBV viral load becomesnegative and other study criteria are met. Participants can be eligible if anti-HBcIgG is positive, but HBsAg and HBV viral load is negative (i.e., cleared infection).

13. Patients with known hepatitis C virus (HCV) viral load indicating acute or chronicinfection might be enrolled if the viral load by PCR is undetectable with/withoutactive treatment. If a patient was started on antiviral therapy prior to studyenrollment, antiviral therapy should continue throughout the study.

NOTE: HIV, Hep B, and Hep C viral testing is not required and this criterion apply only to patients with a known history of HCV infection.