Elranatamab With Mezigdomide and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma

Prior treatment

• Prior therapy with mezigdomide or any BCMA bispecific agent. Prior therapy with a BCMA-targeted CAR T-cell therapy or ADC are allowed if \>6 months have elapsed from the last dose.
• The following relevant diseases or adverse clinical conditions:
  • Uncontrolled cardiac arrhythmias (i.e., requiring a change in medication within the last 3 months or a hospital admission within the past 6 months) or clinically significant electrocardiogram abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block.
  • History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 12 months before screening.
  • Class III or IV heart failure as defined by the New York Heart Association functional classification system \[NYHA, 1994\].
  • Uncontrolled arterial hypertension (defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment).
  • History of significant neurological or psychiatric disorders.
  • Ongoing Grade 2 or higher peripheral sensory or motor neuropathy, history of Guillain Barre Syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
  • Active infection requiring antibiotic, antiviral, or antifungal treatment.
  • Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis)
  • Uncontrolled endocrine diseases (i.e., diabetes mellitus, hypothyroidism, or hyperthyroidism) (i.e., requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
• Administration of live or live-attenuated vaccines within 30 days prior to the day 1 of cycle 1.
• Prior history of neoplastic disease/malignancies other than MM in the last 5 years (except for basal cell carcinoma, skin epithelioma or carcinoma in situ of any site \[i.e., breast, cervix\]).
• Use of any antimyeloma therapy within 14 days prior to day 1 of cycle 1.
• Stem cell transplant within 12 weeks prior to enrolment, active GVHD or active immunosuppressive therapy for GVHD.
• Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days prior to day 1 of cycle 1.
• Major surgery 14 days prior to initiating study therapy / prior to day 1 of cycle 1.

Other illness

• Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
• Other plasma cell disorders/associated syndromes, e.g. plasma cell leukemia, POEMS, amyloidosis
• Patient is known to be positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C. In case of doubt, viral load must be negative.
• Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to mezigdomide or drugs chemically related to mezigdomide, or any of the excipients contained in the formulation of the study treatment.
• Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other bispecific antibodies.
• Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study;
• Subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.

Lab values

• Patients with non-adequate hematological and/or non-hematological parameters defined as the following laboratory abnormalities:
  • Absolute neutrophil count (ANC) \<1 x109/L without previous granulocyte colony-stimulating factor G-CSF support in the last 7 days prior to screening blood count.
  • Platelet count \<75 x109/L without previous platelet transfusions in the last 7 days prior to screening blood count.
  • Hemoglobin \<8.0 g/dl (Erythropoietin or RBC transfusions allowed).
  • Calculated or measured creatinine clearance / estimated glomerular filtration rate (eGFR) \<30 mL/min (calculated from the Cockcroft and Gault formula) (APPENDIX 5) or requiring dialysis.
  • Serum aspartate transaminase (AST): \> 2.5 x the upper limit of normal (ULN).
  • Serum alanine transaminase (ALT): \> 2.5 x ULN.
  • Serum total bilirubin: \> 2 x ULN
  • Corrected serum calcium \> 13.5 mg/dL (\> 3.4 mmol/L).
• Left ventricular ejection fraction (LVEF) \<50%.

Other

• Women who are pregnant or breastfeeding, or who intends to become pregnant during participation in the study, and men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, oral contraception).
• Patient is simultaneously enrolled in other interventional clinical trial.

• Patient is, in the investigator's opinion, willing and able to adhere/comply with visit schedule and other protocol requirements.
• Patient must be able to understand the study procedures. c. Patients aged ≥18 years at the time of signing the informed consent form. d. Patients have documented diagnosis of MM according to the IMWG criteria (Lancet Oncol 2014).
• Patients have a relapsed MM who have previously received treatment with at least one line of antimyeloma therapy.
• Patients must have documented disease progression during or after their last antimyeloma regimen.
• Patients must have received prior treatment with a lenalidomide-containing regimen and must be intolerant or refractory to it, defined as occurrence of disease progression on lenalidomide or within 60 days after the last dose of treatment to lenalidomide.
• Patient must have a measurable disease, defined as follows:
• Serum monoclonal protein (M-protein) ≥0,5 g/dl by serum protein electrophoresis (sPEP) or
• Urine light-chain excretion ≥200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or
• Serum free light-chain (sFLC) levels \>100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambdda FLC ratio (for patients whose disease is only measurable by serum FLC) i. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
  • All prior relevant treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be ≤grade 1 at the time of enrolment.
  • Reproductive Status
• Individuals of childbearing potential (IOCBP) must agree and adhere to all testing and contraception requirements for elranatamab based on SmPC and/or IB, and in the mezigdomide Clinical Trial Pregnancy Risk Awareness Checklist. IOCBPs must either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with 2 effective forms of contraception without interruption: 28 days prior to starting study intervention, during treatment (including dose interruptions), and for at least 28 days after the last dose of mezigdomide\*\* or for at least 4 months (or 150 days) following last elranatamab dose whichever is longer.
• Male participants must practice true abstinence\* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant individual or an IOCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of mezigdomide, or for at least 4 months (or 150 days) following last elranatamab dose whichever is longer, even if he has undergone a successful vasectomy.
  • \*True Abstinence is acceptable when this is in line with the preferred and usual lifestyle of the individual. Periodic abstinence (eg, calendar, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• Male participants must agree to refrain from donating semen or sperm while taking mezigdomide or during dose interruptions and that they will not donate semen or sperm for at least 28 days after the last dose of mezigdomide.
• Females must agree to refrain from donating eggs and breastfeeding a baby while taking mezigdomide, during dose interruptions and for 28 days after the last dose of mezigdomide.
  • Participants must agree to refrain from donating blood while on study treatment, during dose interruptions, and for at least 28 days following the last dose of Mezigdomide or for 4 months (or 150 days) following last dose of elranatamab, whatever happens later.