The purpose of this study is to find out whether the combination of elranatamab and cyclophosphamide is an effective treatment for people with relapsed/refractory multiple myeloma (MM) who have risk factors that may affect how well their disease would respond to elranatamab alone.

Inclusion Criteria:

• Documentation of Disease:

  • Patients must have pathologically confirmed diagnosis of multiple myeloma (MM) as defined according to 2014 IMWG criteria.
  • Measurable disease defined by at least 1 of the following:
  • Serum M-protein ≥0.5 g/dL by SPEP
  • Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65)
  • Urinary M-protein excretion ≥200 mg/24 hours by UPEP
  • Bone marrow plasma cell percentage (in aspirate or biopsy, whichever is higher) of ≥30%
  • Myeloma bone lesion or plasmacytoma lesion with a single diameter of ≥2 cm

• Adverse risk features defined as having ≥1 of the following:

  • Presence of extramedullary myeloma identifiable by 18F-FDG PET/CT
  • Serum beta-2-microglobulin (B2M) level ≥5.5 mg/dL
  • Bone marrow plasma cell percentage (in aspirate or biopsy, whichever is higher) of ≥50%

• Prior Treatment Exposure:

  • Participants have received at least 1 prior lines of therapy for MM including:

• At least 1 IMiD (thalidomide, lenalidomide or pomalidomide)

• At least 1 PI (bortezomib, carfilzomib or ixazomib)

• At least 1 anti-CD38 monoclonal antibody (daratumumab or isatuximab)

• Age ≥ 18

• ECOG Performance Status ≤ 2 (See Appendix I for performance status criteria)

• Not Pregnant and Not Nursing

  • The effects of elranatamab and cyclophosphamide on the developing human fetus are unknown. For this reason and because cyclophosphamide as well as other therapeutic agents used in this trial are known to be teratogenic, participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 6 months following the completion of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately.

• Required Organ Function:

  • Adequate hematologic function defined as follows:

• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3(use of G-CSF is permitted if completed at ≥7 days prior to planned start of study treatment)

• Platelets ≥ 25,000 cells/mm3 (transfusion support is permitted)

• Hemoglobin ≥ 8 g/dl (transfusion support is permitted)

  • Adequate renal function defined as follows:

• Creatinine clearance (CrCL) of ≥15 mL/min by the CKD-EPI formula, Cockcroft-Gault formula, or with direct measurement.

  • Adequate hepatic function defined as follows:

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled)

• AST and ALT ≤3 x institutional ULN

  • Adequate cardiac function defined as follows:

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function (see exclusionary cardiac conditions below)

Exclusion Criteria:

• Exclusionary Prior Treatments, Diagnoses and Comorbid Conditions

  • Previous treatment with a CD3 redirecting bispecific or trispecific antibody for multiple myeloma.
  • Plasma cell leukemia (as defined by the IMWG49), smoldering multiple myeloma, Waldenström's macroglobulinemia, amyloidosis, or POEMS syndrome.
  • Active central nervous system involvement or clinical signs of myelomatous meningeal involvement.
  • History of autologous stem cell transplant within 8 weeks prior to enrollment.
  • Active graft-versus-host disease or history of allogeneic stem cell transplant within 12 weeks prior to enrollment.
  • Clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment:

• Acute myocardial infarction, acute coronary syndromes (e.g., unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, pericardial effusion)

• Clinically significant cardiac arrhythmias (e.g., uncontrolled atrial fibrillation, uncontrolled paroxysmal supraventricular tachycardia, or ventricular tachycardia)

• Decompensated heart failure syndrome. To be eligible for this trial, patients should be class 2B or better (see Appendix II: New York Heart Association (NYHA) Functional Classification).

• Thromboembolic or cerebrovascular events (e.g., transient ischemic attack, cerebrovascular accident, or pulmonary embolism with evidence of right heart strain)

• Prolonged QT syndrome (or QTcF >470 msec at screening).

• Active or uncontrolled bacterial, HIV, HBV, HCV, SARS-CoV-2, other viral, or fungal infections. Acute bacterial, viral, or fungal infections must be resolved prior to enrollment. Specific considerations for certain infections listed below:

  • HIV
  • HIV seropositive participants who are otherwise healthy and at low risk for AIDS-related outcomes could be considered eligible. Potential eligibility for a specific HIV-positive protocol candidate should be evaluated and discussed with the investigator prior to any screening, based on current and past CD4 and T-cell counts, history (if any) of AIDS defining conditions (e.g., opportunistic infections), and status of HIV treatment.
  • HBV
  • Participants with positive HBsAg or detectable HBV DNA may be permitted provided they have been taking appropriate anti-viral medication (e.g. entecavir, tenofovir) for at least 28 days prior to enrollment, willing to continue therapy, and with screening HBV DNA is <2 × 10³ IU/mL, without evidence of hepatic decompensation. Participants with negative HBsAg but positive anti-HBc antibody, indicating immunity from prior natural infection, are eligible provided their screening HBV DNA is <2 × 10³ IU/mL, they are willing to take an appropriate anti-viral medication and undergo HBV DNA monitoring during the study.
  • HCV
  • Positive HCV antibody is indicative of prior infection but may not necessarily render a potential participant ineligible. If exposure to HCV is recent, the HCV antibody test may not yet be positive. In this case, testing for HCV RNA is recommended. Patients with a positive HCV antibody must undergo HCV RNA PCR, and those with detectable HCV RNA will be excluded.
  • COVID-19/SARS-CoV-2
  • COVID-19/SARS-CoV-2: COVID-19/SARS-CoV-2 PCR testing of nasopharyngynx is mandated at the screening visit. Participants with a positive PCR test result within 7 days prior to enrollment or those suspected of having an active COVID-19/SARS-CoV-2 infection will be excluded from study enrollment.

• Any other active malignancy within 2 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, Stage 0/1 malignancy with minimal risk of recurrence, or low risk neoplasm that does not require active therapy and has demonstrated stability over a 2-year surveillance period.

• History of Guillain-Barré syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.

• History of organ transplant requiring immunosuppressive therapy.

• Gastrointestinal conditions that would alter the absorption of cyclophosphamide.

• Other surgical (including major surgery within 14 days prior to enrollment), medical or psychiatric conditions including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.

• History of anaphylaxis or severe hypersensitivity to cyclophosphamide.

• Receipt of a live attenuated vaccine within 4 weeks of the first dose of study intervention.

• Receipt of a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the first dose of study intervention.

• Participant unable or unwilling to undergo protocol required anti-infection prophylaxis.

• Previous administration with an investigational product (drug or vaccine) within 28 days or 5 half-lives preceding the first dose of study intervention used in this study (whichever is shorter). A participant may be eligible even if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of investigational product. Cases must be discussed with the investigator to judge eligibility.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.