Use of Elranatamab in Patients With High-risk Smoldering Multiple Myeloma

Inclusion Criteria:

1. >18 years of age

2. Diagnosis of SMM for ≤5 years with measurable disease, defined as serum M protein:

≥1g/dL or urine M protein ≥200 mg/24 hours or involved serum FLC ≥100 mg/Landabnormal serum FLC ratio.

3. BMPCs ≥10% and <60%

4. Presence of at least 2 high risk factors, including

5. Serum M protein ≥2 g/dL,

6. BMPC >20%

7. Serum involved/uninvolved FLC ratio > 20

8. ECOG performance status score of 0 or 1

9. Subjects must meet the following laboratory parameters, per laboratory referencerange (performed at most 15 days before cycle 1 day 1)

10. Absolute neutrophil count ≥1.0 x 109/L (ie, ≥1000/μL)

11. Platelet count ≥75 x 109/L

12. Aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN)

13. Alanine aminotransferase (ALT) ≤2.5 x ULN

14. Total bilirubin ≤1.5 x ULN, except in subjects with congenitalbilirubinemia,such as Gilbert syndrome (in which case direct bilirubin ≤2.0 xULN is required)

15. Subject must sign an informed consent form (ICF) or their legally acceptablerepresentative must sign indicating that he or she understands the purpose of, andprocedures required for the study and is willing to participate in the study.

16. Women of childbearing potential must have a negative serum or urine pregnancy testat screening and before starting study drug. They must commit to continuedabstinence from heterosexual intercourse or begin 2 acceptable methods of birthcontrol (One highly effective method and one additional effective method) used atthe same time, and continuing for at least 5 months after the last dose ofElranatamab. Women must also agree to notify pregnancy during the study.

Exclusion Criteria:

1. Previous therapy with any systemic therapy for multiple myeloma.

2. Evidence of any of the following calcium, renal failure, anemia, bone lesions (CRAB)criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to theparticipants SMM involvement):

3. Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11mg/dL

4. Renal insufficiency: Determined by glomerular filtration rate (GFR) <40mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serumcreatinine >2 mg/dL

5. Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both)transfusion support or concurrent treatment with erythropoietin stimulatingagents is not permitted

6. ≥ 1 bone lytic lesion

7. BMPCs ≥60%

8. Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L

9. Whole body magnetic resonance imaging (WB-MRI) or positron emissiontomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5mm in diameter)

10. Diagnosis of primary amyloidosis, POEMS syndrome, monoclonal gammopathy ofundetermined significance, symptomatic multiple myeloma, or solitary plasmacytoma.

11. Subject has a diagnosis of Waldenström's macroglobulinemia, or other conditions inwhich IgM M-protein is present in the absence of a clonal plasma cell infiltrationwith lytic bone lesions.

12. Subject has had plasmapheresis within 14 days of elegibility confirmation.

13. Myocardial infarction within 6 months prior to enrolment according to NYHA Class IIIor IV heart failure, uncontrolled angina, severe uncontrolled ventriculararrhythmias, or electrocardiographic evidence of acute ischemia or active conductionsystem abnormalities

14. Ongoing Grade 2 or higher peripheral sensory/motor peripheral neuropathy (PN),history of GBS or GBS variants, or history of grade 3 or higher peripheral motorpolyneuropathy

15. Subject has had major surgery within 2 weeks before elegibility confirmation or willnot have fully recovered from surgery, or has surgery planned during the time thesubject is expected to participate in the study.

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

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

18. Female subject who is pregnant or breast-feeding

19. Serious medical or psychiatric illness likely to interfere with participation instudy

20. Uncontrolled diabetes mellitus

21. Known HIV infection; Known active hepatitis B or C viral infection; known activeCOVID-19/SARS-CoV-2 infection

22. Live attenuated vaccine administered within 4 weeks of the first dose of studyintervention

23. Ongoing treatment with corticosteroids : dose >10mg prednisone etc.

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