Comparison of Elranatamab and Lenalidomide Versus Daratumumab and Lenalidomide as Post-transplant Maintenance Therapy in Patients With Newly Diagnosed Myeloma (ElMMA)

Inclusion Criteria:

1.

• Male or female subjects, 18 years of age or older

2.

• Voluntary written informed consent must be given before performance of anystudy-related procedure not part of normal medical care, with the understandingthat the subject may withdraw consent at any time without prejudice to futuremedical care.

3.

• Subject must have documented multiple myeloma according to InternationalMyeloma Working Group (IMWG) criteria and have received 4 to 6 cycles ofquadruplet-based therapy including proteasome inhibitor, IMID and anti CD38monoclonal antibody.

4.

• Subject must have received only one line of therapy and achieved at least apartial response as per IMWG 2016 criteria.

5.

• Subject must have received high-dose melphalan and ASCT within 12 months of thestart of induction therapy and be within 6 months of the last ASCT at the timeof first treatment dose.

6.

• Subject must have NGS analysis performed at time of MM diagnosis and/oradequate stored bone marrow material allowing NGS analysis (IUCT-Oncopole,Toulouse, France) in order to calibrate MRD analysis.

7.

• Karnofsky performance status score ≥ 50% (eastern cooperative oncology groupperformance status ECOG score ≤ 2).

8.

• Subject must have clinical laboratory values meeting the following criteriaduring the Screening Phase:

• Hematology : Hemoglobin >8.0 g/dL without prior RBC transfusion within 7 daysbefore the laboratory test; recombinant human erythropoietin use is permitted)

• Platelets ≥75×109/L (without transfusion support or thrombopoietin receptoragonist within 7 days before the laboratory test) + Absolute neutrophil count ≥1.0×109/L (prior growth factor support is permitted but must be withoutsupport for 7 days for G-CSF or 14 days for pegylated-G-CSF)

• Chemistry : AST and ALT ≤2.5× upper limit of normal (ULN) + CrCl ≥30 mL/minbased on Cockroft-Gault formula calculation or a 24-hour urine collection +Total bilirubin ≤1.5×ULN; except in participants with congenital bilirubinemia,such as Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required)

• Serum calcium corrected for albumin ≤14 mg/dL (≤3.5 mmol/L)

9.

• Women of childbearing potential must have a negative serum or urine pregnancytest within 10 to 14 days prior to therapy and repeated within 24 hours beforestarting study drug. They must commit to continued abstinence from heterosexualintercourse or begin 2 acceptable methods of birth control (One highlyeffective method and one additional effective method) used at the same time,beginning at least 4 weeks before initiation of lenalidomide treatment andcontinuing for at least 6 months after the last dose of Lenalidomide orElranatamab depending on the last treatment taken. Highly effectivecontraceptive methods are defined as any of the following methods: combinedhormonal contraception (containing estrogen and progestin) combined withovulation inhibition (oral, intravaginal, transdermal), progestin-only hormonalcontraception combined with ovulation inhibition (oral, injectable,implantable), intrauterine device (IUD), hormone-releasing intrauterine system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence.Womenmust also agree to notify pregnancy during the study.

10.

• Men must agree to not father a child and agree to use a latex condom duringtherapy and for 6 months after the last dose of study drug, even if they havehad a successful vasectomy, if their partner is of childbearing potential.

Exclusion Criteria:

1.

• Subjects have received any prior anti BCMA therapy.

2.

• Subject have received post transplantation maintenance therapy.

3.

• Subject intolerant to lenalidomide or have discontinued treatment due to any AErelated to lenalidomide.

4.

• Subject is exhibiting clinical signs of meningeal involvement of multiplemyeloma.

5.

• Myocardial infarction within 6 months prior to enrollment according to NYHAClass III or IV heart failure, uncontrolled angina, severe uncontrolledventricular arrhythmias, or electrocardiographic evidence of acute ischemia oractive conduction system abnormalities.

6.

• Uncontrolled hypertension.

7.

• Subjects with known chronic obstructive pulmonary disease (COPD) with a ForcedExpiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1testing is required for patients suspected of having COPD and subjects must beexcluded if FEV1 < 50% of predicted normal.

8.

• Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time ofscreening (Note that subjects who currently have controlled intermittent asthmaor controlled mild persistent asthma are allowed in the study).

9.

• Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells inthe peripheral blood with an absolute plasma cell count of more than 2 × 109/L)or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonalprotein, and skin changes).

10.

• Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin),strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole,voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), oruse of Ginkgo biloba or St. John's wort within 14 days before the first dose ofstudy treatment.

11.

• Known intolerance to steroid therapy.

12.

• History of allergy to any of the study medications, their analogues, orexcipients in the various formulations.

13.

• Subject has had major surgery within 2 weeks before randomization or will nothave fully recovered from surgery, or has surgery planned during the time thesubject is expected to participate in the study. Kyphoplasty or Vertebroplastyare not considered major surgery.

14.

• Clinically relevant active infection or serious co-morbid medical conditions.

15.

• Prior malignancy except adequately treated basal cell or squamous cell skincancer, in situ cervical, breast or prostate cancer free of disease since 5years.

16.

• Female subject who is pregnant or breast-feeding.

17.

• Serious medical or psychiatric illness likely to interfere with participationin study.

18.

• Uncontrolled diabetes mellitus.

19.

• Active HBV, HCV, SARS-CoV-2, HIV, or any active, uncontrolled bacterial,fungal, or viral infection. Active infections must be resolved at least 21 daysprior to enrollment. Treatment with systemic anti-infective agents must havecompleted at least 28 days prior to enrollment. Prophylactic use of systemicagents is permitted.

• COVID-19/SARS-CoV-2: SARS-CoV-2 PCR testing is mandated within 5 days prior toenrollment. Participants with positive PCR test result for SARS-CoV-2 within 5days prior to enrollment, or suspected of having SARS-CoV-2, are excluded.

• HIV: In equivocal cases, participants whose viral load is negative may beeligible. HIV seropositive participants who are otherwise healthy and at lowrisk for AIDS-related outcomes could be considered eligible. Potentialeligibility for a specific HIV positive protocol candidate should be evaluatedand discussed with the sponsor prior to screening, considering current and pastCD4+ and T-cell counts, history (if any) of AIDS defining conditions (eg,opportunistic infections), status of HIV treatment and the potential fordrug-drug interactions.

• HBV:

• Participants with a positive HBsAg test (ie, either acute or chronicactive hepatitis) are excluded.

• Participants with HBV antibody positivity indicating immunity, either dueto vaccination or prior natural infection, are eligible.

• Participants with positive anti-HBcAb but negative HBsAg and negativeanti-HBsAb profile are eligible if HBV DNA is not detected. For additional details, refer to CDC website (https://www.cdc.gov/hepatitis/HBV/PDFs/SerologicChartv8.pdf).

• HCV: Positive HCV antibody is indicative of infection but may not necessarilyrender a potential candidate ineligible, depending on clinical circumstances. Ifexposure to HCV is recent, HCV antibody may not have yet turned positive. In thesecircumstances it is recommended to test for HCV RNA. If HCV RNA is detected, thepatient is not eligible. Refer to CDC website for furtherdetails(https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf).

20.

• Incidence of gastrointestinal disease that may significantly alter theabsorption of oral drugs.

21.

• Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.

22.

• Person under guardianship, trusteeship or deprived of freedom by a judicial oradministrative decision.