Mezigdomide, Talquetamab and Dexamethasone for the Treatment of Relapsed and 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of any study related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to their future medical care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
• 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 immunoglobulin D (IgD) disease and lower amounts of monoclonal protein may be permitted to enroll with principal investigator (PI) approval * ≥ 200 mg of monoclonal protein in the urine on 24-hour urine protein electrophoresis * Serum free light chain (FLC) ≥ 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 three prior lines of therapy; * Prior therapy including an immunomodulatory drug, proteasome inhibitor, and anti CD38 antibody (either in separate regimens or within the same regimen); and * Disease progression on, or within 60 days of completion of last therapy.
• Absolute neutrophil count (ANC) ≥ 1000/μL. Granulocyte colony-stimulating factor (G-CSF) is not permitted within 14 days of screening
• Platelet count ≥ 50,000/µL. Platelet transfusion and thrombopoietin receptor agonists are 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
• Serum bilirubin values < 1.5 x upper limit of normal (ULN). Isolated bilirubin ≥ 1.5 x ULN is acceptable if bilirubin is fractionated and direct 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 aspartate transaminase (AST) values < 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range
• Must be able to comply with thromboembolism prophylaxis with e.g. acetylsalicylic acid (ASA), apixaban, rivaroxaban, lower molecular weight heparin, or equivalent
• Females of childbearing potential (FCBP)** must: * Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. The subject must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. * 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 two reliable forms of contraception as defined by the Pregnancy Prevention Plan ** A female of childbearing potential (FCBP) is a female who: *** has achieved menarche at some point, *** has not undergone a hysterectomy or bilateral oophorectomy, or bilateral salpingectomy, or *** has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Male subjects must follow the mezigdomide Pregnancy Prevention Plan
• Agree to follow the lifestyle considerations regarding blood donation, hospitalization and being in proximity to the hospital, and driving or operating heavy machinery

Exclusion Criteria

• 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 mezigdomide or iberdomide
• Prior therapy with anti-GPRC5D therapy (e.g. talquetamab)
• Prior therapy with bispecific antibody therapy within three months
• Prior therapy with gene-modified adoptive cell therapy (e.g. chimeric antigen receptor [CAR] T-cells, natural killer [NK] cells) within three months
• 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)
• Participant plans to father a child while enrolled in the study or within 100 days after last dose of study treatment
• Prior history of malignancies, other than multiple myeloma (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 approval of the PI (e.g. localized breast cancer considered to have very low risk of recurrence). 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 * Other malignancies of clinically localized disease may be permitted to enroll after discussion with Principal Investigator
• 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
• Hepatitis B viral load positive
• Hepatitis C viral load positive
• Peripheral neuropathy ≥ grade 2 despite supportive therapy
• Autologous stem cell transplant < 6 months prior to start of treatment
• Allogeneic stem cell transplant < 6 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 versus (v.) host disease (GVHD)
• 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 * Severe non-ischemic cardiomyopathy * 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. * Acute diffuse infiltrative pulmonary disease
• Active bacterial, viral, or fungal infection
• Stroke, transient ischemic attack, or seizure within six months of starting treatment
• 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 cycle (C) 1 day (D) 1. Kyphoplasty or vertebroplasty are not considered major surgery
• Live or live-attenuated vaccine within 30 days prior to C1D1
• Concurrent administration of strong CYP3A4/5 modulators
• Toxicity from previous anticancer therapy must resolve to baseline levels or to grade ≤ 1, except for alopecia and peripheral neuropathy