Isatuximab, Iberdomide, Bortezomib, and Dexamethasone for the Treatment of Newly Diagnosed Multiple Myeloma Who Are Transplant Ineligible or Not Intended for Upfront Transplant
This phase I/II trial tests the safety, side effects, best dose and how well giving isatuximab, iberdomide, bortezomib and dexamethasone for the treatment of newly diagnosed multiple myeloma who are transplant ineligible or not intended for upfront transplant. Isatuximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving isatuximab, iberdomide, bortezomib and dexamethasone may be safe, tolerable and/or effective in treating patients with newly diagnosed multiple myeloma who are transplant ineligible or not intended for upfront transplant.
Inclusion Criteria
- Male or female, 18 years of age or older
- Ability to understand and the willingness to sign a written informed consent document
- NDMM based on International Myeloma Working Group (IMWG) criteria with clonal bone marrow plasma cells > 10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more hypercalcemia, renal insufficiency, anemia, and bone disease (CRAB)-features or myeloma defining events (Rajkumar, 2024)
- Ineligible for autologous stem cell transplant (ASCT) as assessed by the treating physician or eligible but prefers and agrees to defer ASCT until after induction and maintenance therapy, upon progression or at a later time
- Measurable disease defined as at least one of the following: * Serum M-protein ≥ 0.5 g/dL * Urine M-protein ≥ 200 mg/24 hours * Serum free light chain (FLC) assay: involved FLC ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal kappa to lambda FLC ratio (< 0.26 or > 1.65)
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 10^9/L) * Note: Growth factor support is not permitted within 10 days, (14 days for pegfilgrastim), prior to the screening hematologic test
- Platelet count ≥ 75,000 cells/dL (75 x 10^9/L) (without transfusions required during the 3 days prior to the screening hematologic test)
- 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)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 x ULN
- Calculated creatinine clearance (CrCl) ≥ 30ml/min
- Hemoglobin ≥ 8.0 g/dl (red blood cell [RBC] transfusions are permitted)
- Individuals of childbearing potential (IOCBP) must have 2 negative pregnancy tests before initiation of therapy, and agree to ongoing testing, based on the frequency outlined in the Pregnancy Prevention Plan (PPP)
- 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 study drug or males sexually active with IOCBP, (including those who have had a vasectomy), 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 and 6 months after bortezomib, according to the PPP
- 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 abstain from donating semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP and for 5 months after the last dose of isatuximab and 6 months after the last dose of bortezomib
- Must be able to take antithrombotic prophylaxis
Exclusion Criteria
- Prior therapy for multiple myeloma (MM). Patients may have received: * Corticosteroids for management of MM not to exceed equivalent of 160 mg of dexamethasone in a 2-week period and should be stable 7 days prior to the registration. * Focal palliative radiation for the management of bone pain completed ≥ 7 days prior to registration * Treatment for smoldering myeloma as long as the prior treatment did not include anti-CD38 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 1 or baseline
- Known intolerance to steroid therapy
- Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years with the exception of 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 Tumor, Node, Metastasis (TNM) clinical staging system), or prostate cancer that is curative
- Central nervous system involvement with MM
- Peripheral neuropathy grade ≥ 3, or grade 2 with pain on clinical exam during screening period
- Any medical or psychiatric illness that in the investigator’s opinion would impose excessive risk to the patient or would adversely affect participation
- Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension, uncontrolled arrhythmias, congestive heart failure, unstable angina, grade 3 thromboembolic event or myocardial infarction) in the past 6 months
- Concurrent symptomatic amyloidosis or plasma cell leukemia
- Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome
- 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 C (Hep C Ab), or acute hepatitis A. If any history of exposure to hepatitis B or C, then polymerase chain reaction (PCR) should be negative
- Pregnant or breast feeding female or IOCBP who intend to become pregnant during the study
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to other agents used in study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07601100.
Locations matching your search criteria
United States
Massachusetts
Boston
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of iberdomide in combination with isatuximab, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible or deferred, dependent on age and frailty status (Group A and Group B). (Phase 1b)
II. To establish the reccomended phase 2 dose (RP2D) of iberdomide in combination with isatuximab, bortezomib and dexamethasone in patients with NDMM who are transplant ineligible or deferred, dependent on age and frailty status (Group A and Group B). (Phase 1b)
III. To determine the complete response and better (≥ complete response [CR]) rate of iberdomide at the RP2D in combination with isatuximab, bortezomib and dexamethasone as best response after 8 cycles of induction in patients with NDMM who are transplant ineligible or deferred, dependent on age and frailty status (Group A and Group B). (Phase 2)
SECONDARY OBJECTIVES:
I. To assess preliminary efficacy. (Phase 1b)
II. To evaluate safety and tolerability over induction and maintenance therapy. (Phase 2)
III. To evaluate the feasibility of induction therapy. (Phase 2)
IV. To evaluate the best response after induction and after 12, 24, and 36 cycles of maintenance therapy. (Phase 2)
V. To evaluate minimal residual disease (MRD) status at end of induction. (Phase 2)
EXPLORATORY CLINICAL OBJECTIVES:
I. To evaluate treatment exposure and adherence.
II. To quantify cumulative toxicity over induction.
III. To estimate time-to-event outcomes including progression-free, event-free, duration of response (DOR) and overall survival (OS) from registration.
IV. To evaluate stem cell mobilization initiation and collection yield.
V. To evaluate MRD status after 12, 24 and 36 cycles of maintenance.
VI. To evaluate association between MRD status and time to event outcomes.
VII. To evaluate types of subsequent therapy.
EXPLORATORY PATIENT REPORTED OUTCOMES OBJECTIVES:
I. To describe quality of life (QoL) levels and changes during induction and maintenance.
II. To estimate best QoL response over induction and maintenance.
III. To tabulate patient reported outcomes (PRO) completion and compliance rates.
EXPLORATORY CORRELATIVE OBJECTIVES:
I. To characterize the genomic alterations and ribonucleic acid (RNA)/protein expression profiles of tumor cells at time of diagnosis of all enrolled patients and evaluate for genomic evolution and expression profile changes at the end of induction in patients who achieve less than a CR response.
II. To define the tumor and immune microenvironment at time of diagnosis, and evaluate microenvironment changes after induction therapy and annually while on maintenance treatment.
III. To evaluate the tumor and tumor microenvironment at the time of disease progression.
IV. To assess correlation of monitoring of paraproteins with mass spectrometry compared to MRD testing by Adaptive next generation sequencing (NGS) (or next generation flow [NGF] if no clonal identification [ID] at baseline) of the bone marrow.
OUTLINE: Patients are assigned to 1 of 2 groups for induction therapy based on their age and frailty score. After induction, patients with at least a partial response or better are assigned to 1 of 2 maintenance treatment groups based on their bassline cytogenetic risk status.
GROUP A INDUCTION: Patients receive isatuximab intravenously (IV), over 30-60 minutes, on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of subsequent cycles, iberdomide orally (PO) daily (QD) on days 1-21, bortezomib subcutaneously (SC) on days 1, 8, 15 and 22 and dexamethasone IV or PO on days 1, 2, 8, 9, 15, 16, 22 and 23 of each cycle. Cycles repeat every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo stem cell mobilization and collection during cycles 4-6.
GROUP B INDUCTION: Patients receive isatuximab IV, over 30-60 minutes, on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of subsequent cycles, iberdomide PO QD on days 1-21, bortezomib SC on days 1, 8, and 15 and dexamethasone IV or PO on days 1, 2, 8, 9, 15, 16, 22 and 23 of each cycle. In cycle 1, doses of dexamethasone may be combined such that a single dose of 20 mg is administered on day 1, 8, 15 and 22 only prior to each dose of isatuximab, at the investigator discretion. Cycles repeat every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
HIGH RISK MAINTENANCE: Patients receive isatuximab IV, over 30-60 minutes, on days 1 and 15, iberdomide PO QD on days 1-21 and bortezomib SC on days 1 and 15. Cycles repeat every 28 days for 36 cycles in the absence of disease progression or unacceptable toxicity.
STANDARD RISK MAINTENANCE: Patients receive isatuximab IV, over 30-60 minutes, on days 1 and 15 and iberdomide PO QD on days 1-21. Cycles repeat every 28 days for 36 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow aspiration/biopsy, positron emission tomography (PET) scan, computed tomography (CT) scan and blood and urine sample collection throughout the study and may undergo bone scan throughout the study.
After completion of study treatment, patients who discontinue therapy for reasons other than disease progression are followed up every 3 months until disease progression or for up to 5 years, following disease progression, patients are followed up every 6 months for up to 5 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorYuxin Liu
- Primary ID25-854
- Secondary IDsNCI-2026-05221
- ClinicalTrials.gov IDNCT07601100