Trattamento

Obiettivo primario

This is a multicenter, single arm, open-label, Phase 2 study in high risk smoldering myeloma patients. The primary objective is to determine the efficacy of Elranatamab in patients with previously untreated high-risk SMM. The key-secondary objective is to determine the safety of Elranatamab in patients with previously untreated high-risk SMM.

Criteri di inclusione

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/L and abnormal serum FLC ratio
3. BMPCs ≥10% and <60%
4. Presence of at least 2 high risk factors, including:
   1. Serum M protein ≥2 g/dL
   2. BMPC >20%
   3. Serum involved/uninvolved FLC ratio > 20
5. ECOG performance status score of 0 or 1
6. Subjects must meet the following laboratory parameters, per laboratory reference range (performed at most 15 days before cycle 1 day 1):
   1. Absolute neutrophil count ≥1.0 x 10⁹/L (ie, ≥1000/μL)
   2. Platelet count ≥75 x 10⁹/L
   3. Aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN)
   4. Alanine aminotransferase (ALT) ≤2.5 x ULN
   5. Total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2.0 x ULN is required)
7. Subject must sign an informed consent form (ICF) or their legally acceptable representative must sign indicating that he or she understands the purpose of, and procedures required for the study and is willing to participate in the study.
8. Women of childbearing potential must have a negative serum or urine pregnancy test at screening and before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (one highly effective method and one additional effective method) used at the same time, and continuing for at least 5 months after the last dose of Elranatamab. Women must also agree to notify pregnancy during the study.

Criteri di esclusione

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 the participant’s SMM involvement):
   1. Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11 mg/dL
   2. Renal insufficiency: Determined by glomerular filtration rate (GFR) <40 mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serum creatinine >2 mg/dL
   3. Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both). Transfusion support or concurrent treatment with erythropoietin-stimulating agents is not permitted.
   4. ≥ 1 bone lytic lesion
   5. BMPCs ≥60%
   6. Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100 mg/L
   7. Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5 mm in diameter)
3. Diagnosis of primary amyloidosis, POEMS syndrome, monoclonal gammopathy of undetermined significance, symptomatic multiple myeloma, or solitary plasmacytoma.
4. Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
5. Subject has had plasmapheresis within 14 days of eligibility confirmation.
6. Myocardial infarction within 6 months prior to enrollment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
7. 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 motor polyneuropathy.
8. Subject has had major surgery within 2 weeks before eligibility confirmation or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study.
9. Clinically relevant active infection or serious co-morbid medical conditions.
10. 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.
11. Female subject who is pregnant or breast-feeding.
12. Serious medical or psychiatric illness likely to interfere with participation in the study.
13. Uncontrolled diabetes mellitus.
14. Known HIV infection; Known active hepatitis B or C viral infection; known active COVID-19/SARS-CoV-2 infection.
15. Live attenuated vaccine administered within 4 weeks of the first dose of study intervention.
16. Ongoing treatment with corticosteroids: dose >10 mg prednisone, etc.
17. Person under guardianship, trusteeship, or deprived of freedom by a judicial or administrative decision.