Isatuximab, Iberdomide, Bortezomib, and Dexamethasone Induction in New Myeloma, Followed by Adaptive Consolidation and Maintenance for Transplant-Eligible Patients

Inclusion Criteria:

* N- NDMM based on IMWG criteria with clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024) (See Appendix E)
* \- Age 18 - 75 years. (Patients aged 71-75 years who are deemed transplant-eligible by investigator may be enrolled after discussion with and approval from the Sponsor - Investigator)
* \- Eligible for HDM-ASCT, at time of registration per investigator's assessment, and willing to defer HDM-ASCT if in Cohort 1 or be randomized to HDM-ASCT vs. linvoseltamab if in Cohort 2 (Cohort assignment may not be known until after induction therapy)
* \- Bone marrow analysis with cytogenetic risk status established by fluorescence in situ hybridization (FISH) and NGS with TP53 by PlasmaSEQ at screening and positive identification of B-cell Clonality (ID) conducted by Adaptive Biotechnologies clonoSEQ® assay

  * Qualified archival BMA may be submitted to Adaptive Biotechnologies clonoSEQ® assay.
  * Results from a previously performed clonoSEQ® assay as standard of care may be acceptable if they meet the requirement of B-cell clonality ID.
  * Previously performed BMA for FISH is acceptable if it can establish cytogenetic risk per Section 5.4.2 along with NGS for TP53 by PlasmaSEQ.
  * Results must be within 1 year of screening and be representative of current NDMM. Results older than one year must be approved by the Sponsor-Investigator.
* Measurable disease defined by at least one of the following:

  * Serum protein electrophoresis (SPEP): Serum M protein ≥0.5 mg/dL
  * Urine protein electrophoresis (UPEP): Urine M protein ≥200 mg/24 hours
  * Serum free light chain (FLC) assay: involved FLC ≥10 mg/dL (≥100 mg/L) and abnormal serum FLC ratio (\<0.26 or \>1.65)
* Screening laboratory evaluations meeting the following parameters:

  * Absolute neutrophil count (ANC) ≥1,000 cells/dL (1.0 × 10\^9/L). Growth factor support is not permitted within 10 days \[14 days for pegfilgrastim\], prior to registration
  * Platelet count ≥ 75,000 cells/dL (75 x 109/L) without transfusions required during the 14 days prior to registration
  * Total Bilirubin ≤ 2 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
  * Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3.0 x ULN
  * Calculated creatinine clearance ≥30 mL/min (See Appendix B)
  * Hemoglobin ≥ 8.0 g/dl (red blood cell \[RBC\] transfusions are permitted)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A)
* Ability and willingness to complete HRQoL and PRO-CTCAE® assessments
* Must be able to take antithrombotic prophylaxis
* Sexually active IOCBP agree to use protocol-specified contraceptive methods, at least 28 days prior to starting study drug, while taking study drug, including interruptions in study drugs, and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib, or males (including those who have had a vasectomy), sexually active with IOCBP, agree to use protocol specified contraceptive methods while taking study drug, including interruptions in study drug and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib according the PPP (See Appendix G)
* All patients (male and female with or without childbearing potential) agree to counseling according to the PPP and to abstain from donating blood products for at least 28 days after the last dose of iberdomide and semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP (See Appendix G) and for 3 months after the last dose of isatuximab, 6 months after the last dose of linvoseltamab and bortezomib
* Both men and women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

* Prior therapy for MM. Patients may have received:

  * Corticosteroids for management of MM not exceeding the equivalent of 160 mg of dexamethasone in a 2-week period and without change in dosing requirements within 7 days prior to registration
  * Focal palliative radiation for the management of bone pain ≥ 7 days prior to registration
  * Treatment for smoldering multiple myeloma (SMM) if the prior treatment was not an anti-CD38 or anti-BCMA-based therapy:
  * Patients with a prior history of serious allergic reactions associated with thalidomide, lenalidomide, or pomalidomide should not receive iberdomide as they could be at higher risk of hypersensitivity
  * Resolution of symptoms of prior treatment to ≤ grade 1or baseline
* Known intolerance to steroid therapy
* Central nervous system (CNS) involvement of MM
* History of progressive multifocal leukoencephalopathy (PML), known or suspected PML, or history of a neurocognitive condition, CNS movement disorder, history of seizure within 12 months prior to enrollment
* Peripheral neuropathy grade ≥3, or grade 2 with pain on clinical exam during screening period
* Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years, except for the following non-invasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the TNM clinical staging system), or prostate cancer that is curative
* Any medical or psychiatric illness that in the investigator's opinion would impose excessive risk or would adversely affect patient participation
* Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension \[HTN\], uncontrolled arrhythmias, congestive heart failure \[CHF\], unstable angina, grade 3 thromboembolic event or myocardial infarction in the past 6 months)
* Concurrent symptomatic amyloidosis or plasma cell leukemia
* POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
* Pregnant or breast feeding female or female who intends to become pregnant during the study
* Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B (defined as positive hepatitis B surface antigen \[HepBSAg\] or Hepatitis B core antibody \[HepBcore Ab\]) or hepatitis C (Hep C Ab), or acute hepatitis A; if any history of exposure to hepatitis B or C, then PCR should be negative
* History of tuberculosis or systemic fungal disease
* Concurrent active infection requiring therapeutic treatment
* Lack of clonal identification by Adaptive Biotechnologies clonoSEQ® test