ELDORADO: Elranatamab Versus Daratumumab in Combination With RVd Lite for Newly Diagnosed Transplant Ineligible/Deferred Multiple Myeloma

Inclusion Criteria:

• Participants must be at least 18 years of age

• Newly diagnosed multiple myeloma, with monoclonal plasma cells in the bone marrow ≥10% or a biopsy proven plasmacytoma and either CRAB criteria or biomarker ofmalignancy a. CRAB criteria, one or more of the following: i. Hypercalcemia: serum calcium (>1mg/dL) higher than the upper limit of normal or >11 mg/dL ii. Renal insufficiency:creatinine clearance <40 mL/min (calculated per local practice) or serum creatinine >2 mg/dL iii. Anemia: hemoglobin value >2 g/dL below the lower limit of normal orhemoglobin <10 g/dL iv. Bone lesions: one or more lytic lesions on skeletalradiography, CT, or PET CT b. Biomarker of malignancy (one or more of thefollowing): i. Clonal bone marrow plasma cells ≥60% ii. Involved:uninvolved serumfree light chain ratio ≥100 iii. >1 focal lesion on magnetic resonance imaging (MRI)

• Measurable disease as defined by one of the following:

1. Serum monoclonal protein ≥0.5 g/dL. For IgA monoclonal protein, total IgA >500mg/dL is allowable.

2. Urine monoclonal protein ≥200 mg/24 hours

3. Involved serum free light chain ≥100 mg/L with abnormal free light chain ratio

• Not considered eligible for high dose melphalan and autologous stem cell transplantper treating investigator or plan for deferred high dose melphalan and autologousstem transplant

• ECOG performance status of 0-2

• ANC ≥1000/μL. G-CSF is not permitted within 14 days of screening.

• Platelet count ≥75,000/µL. Platelet count ≥50,000/µL is permitted if bone marrow is >50% involved. Platelet transfusion and thrombopoietin receptor agonists are notpermitted within 7 days of screening.

• Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibilitycriteria.

• Calculated creatinine clearance of ≥ 30 mL/min, not requiring dialysis, withcalculation per local practice.

• Serum bilirubin values < 1.5 x ULN. Isolated bilirubin x 1.5 x ULN is acceptable ifbilirubin is fractionated and direct bilirubin <35%. Patients with elevatedbilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. totalbilirubin <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. acetylsalicylicacid (ASA), apixaban, rivaroxaban, lower molecular weight heparin, or equivalent.

• Females of childbearing potential (FCBP) must:

1. Have 2 negative pregnancy tests as verified by the Investigator prior tostarting study therapy within 10-14 days, with the second test within 24 hoursof starting lenalidomide. She must agree to ongoing pregnancy testing duringthe course of the study, and after end of study treatment. This applies even ifthe subject practices true abstinence from heterosexual contact.

2. Either commit to true abstinence from heterosexual contact (which must bereviewed on a monthly basis and source documented) or agree to use and be ableto comply with two reliable forms of contraception as defined by lenalidomideRisk Evaluation and Mitigation Strategy (REMS) program.

• Male subjects must follow the lenalidomide REMS.

• Ability and the willingness to undergo repeat bone marrow biopsy assessments.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Prior or current systemic therapy for any plasma cell disorder. An exception isemergency use of corticosteroids (equivalent to dexamethasone 40 mg daily for fourdays). After discussion with the principal investigator. one cycle of standard ofcare myeloma therapy (without anti-CD38 monoclonal antibody) is permissible to allowfor stabilization of disease, during screening/prior to enrollment.

• Pregnancy, currently breastfeeding, or planned breastfeeding.

• Participant plans to father a child while enrolled in the study or within 100 daysafter last dose of study treatment.

• Prior history of malignancies, other than MM, unless the patient has completeddefinitive treatment and has been free of the disease for ≥3 years. Patients who arefree of disease <3 years may enroll after approval of the PI (e.g. localized breastcancer considered to have very low risk of recurrence). Exceptions include thefollowing (i.e. the following are eligible to participate):

1. Basal or squamous cell carcinoma of the skin

2. Carcinoma in situ of the cervix

3. Ductal carcinoma in situ of the breast

4. Incidental histologic finding of prostate cancer (T1a or T1b) managed withsurveillance

5. Other malignancies of clinically localized disease may be permitted to enrollafter discussion with the Sponsor-Investigator

• Patients with plasma cell leukemia at time of screening, POEMS syndrome, or primaryAL amyloidosis are excluded from this trial.

• Seropositive for HIV infection.

• Hepatitis B viral load positive.

• Hepatitis C viral load positive.

• Peripheral neuropathy ≥grade 2.

• Patient has a history of significant cardiovascular, neurological, endocrine,gastrointestinal, respiratory, or inflammatory illness that could preclude studyparticipation, pose an undue medical hazard, or interfere with the interpretation ofthe study results, including, but not limited to:

1. Congestive heart failure (New York Heart Association [NYHA] Class 3 or 4)

2. Unstable angina

3. Clinically significant, uncontrolled cardiac arrhythmia such a 2nd degree or 3rd degree atrioventricular block

4. Recent (within the preceding 6 months) myocardial infarction or stroke

5. Severe non-ischemic cardiomyopathy.

6. Uncontrolled hypertension

7. Diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months

8. Chronic obstructive pulmonary disease (COPD) requiring >2 hospitalizations inthe preceding 12 months.

9. Acute diffuse infiltrative pulmonary disease.

10. Active bacterial, viral, or fungal infection

11. Stroke, transient ischemic attack, or seizure within six months of startingtreatment.

• Patient has any other medical, psychiatric, or social condition that would precludeparticipation in the study, pose an undue medical hazard, interfere with the conductof the study, or interfere with interpretation of the study results.

• Major surgery within 4 weeks prior to C1D1. Kyphoplasty or vertebroplasty are notconsidered major surgery.

• Received an investigational drug (or vaccine) or used an invasive investigationalmedical device within four weeks before screening or is currently enrolled in aninterventional investigational study.

• Live or live-attenuated vaccine within 30 days prior to C1D1.