Phase 1b/2: Isatuximab, Iberdomide, Bortezomib, Dexamethasone in Transplant Ineligible/Deferred Newly Diagnosed Myeloma

Official title

A Phase 1b/2 Study of the Combination Isatuximab, Iberdomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma Who Are Transplant Ineligible or Not Intended for Upfront Transplant

Overview

This study is to evaluate the combination of isatuximab, iberdomide, bortezomib, and dexamethasone in newly diagnosed multiple myeloma participants who are transplant ineligible or not intended for upfront transplant. The names of the study drugs used in this research study are: isatuximab, iberdomide, bortezomib dexamethasone

Detailed description

This is an open-label, Phase 1b/2, multicenter study which will enroll patients with newly diagnosed multiple myeloma (NDMM), who are transplant ineligible or deferred, to induction followed by maintenance therapy. Participants will be registered in HCC CTMS OnCore before receiving any study-specific treatment, and study treatment is expected to begin within 5 days after registration.

The study drugs used in this research include bortezomib, dexamethasone, isatuximab, and iberdomide (CC-220). The U.S. Food and Drug Administration (FDA) has approved bortezomib and dexamethasone for the initial treatment of multiple myeloma. The FDA has approved isatuximab for initial treatment of multiple myeloma in transplant ineligible patients and for myeloma that has returned after prior treatment. The FDA has not approved iberdomide (CC-220) for the treatment of multiple myeloma. The combination of these drugs, used as induction and maintenance therapy in this study, is considered investigational.

The research study procedures include: screening for eligibility, in-clinic visits, urine tests, questionnaires, PET scans, blood tests, electrocardiograms (ECGs), bone marrow aspiration and biopsy, biobanking, and pregnancy tests for participants who are able to become pregnant.

It is expected that about 88 people will take part in this study. Participants are classified and assigned treatment for induction based on baseline age 70 years status and myeloma frailty score and further assigned for maintenance based on baseline International Myeloma Working Group (IMWG)/International Myeloma Society (IMS) genomic risk classification.

Interventions

• Drug Isatuximab
  Administration, pre-medications and supportive care per protocol
• Drug Iberdomide
  Administration, pre-medications and supportive care per protocol
• Drug Bortezomib
  Administration, pre-medications and supportive care per protocol
• Drug Dexamethesone
  Administration, pre-medications and supportive care per protocol

Primary outcome measures

• Dose-limiting Toxicities (DLT) by Age-Frailty Group [Phase Ib] [Time frame: Assessed continuously during induction cycle 1, up to day 28 + 30 days]
• Recommended Phase II Dose (RP2D) of Iberdomide by Age-Frailty Group [Phase Ib] [Time frame: Assessed continuously during induction cycle 1, up to day 28 + 30 days]
• Complete Response (CR) or Better Rate by Age-Frailty Group [Phase II] [Time frame: Assessed on day 1 of each cycle over 8 induction cycles (cycle duration=4 weeks), up to 32 weeks.]

Secondary outcome measures (9)

• Induction Grade 3 or 4 Treatment-Related Adverse Event (TRAE) Rate by Age-Frailty Group [Phase Ib] [Time frame: Assessed continuously during induction cycles 1-8 (cycle duration=4 weeks), up to 32 weeks + 30 days.]
• Induction Best Response by Age-Frailty Group [Phase II] [Time frame: Assessed day 1 of each cycle during induction cycles 1-8 (cycle duration=4 weeks), up to 32 weeks.]
• Maintenance Best Response by Age-Frailty Risk Group [Phase II] [Time frame: Assessed day 1 of each cycle during maintenance cycles 1-36 (cycle duration=4 weeks), up to 144 weeks.]
• Induction Minimal Residual Disease (MRD) Negativity Rate by Age-Frailty Group [Phase II] [Time frame: Assessed after induction cycle 8 (cycle duration=4 weeks), at 32 weeks.]
• Induction Feasibility Rate by Age-Frailty Group [Phase II] [Time frame: Assessed after induction cycle 8 (cycle duration=4 weeks), at 32 weeks plus 30 days.]
• Induction Grade 3 or 4 TRAE Rate by Age-Frailty Group [Phase II] [Time frame: Assessed continuously during induction cycles 1-8 (cycle duration=4 weeks), up to 32 weeks + 30 days.]
• Maintenance Grade 3 or 4 TRAE Rate by Age-Frailty Risk Group [Phase II] [Time frame: Assessed continuously during maintenance cycles 1-36 (cycle duration=4 weeks), up to 144 weeks + 30 days.]
• Induction Serious Adverse Event (SAE) Rate by Age-Frailty Group [Phase II] [Time frame: Assessed continuously during induction cycles 1-8 (cycle duration=4 weeks), up to 32 weeks + 30 days.]
• Maintenance SAE Rate by Age-Frailty Risk Group [Phase II] [Time frame: Assessed continuously during maintenance cycles 1-36 (cycle duration=4 weeks), up to 144 weeks + 30 days.]

Eligibility criteria

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 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 G)
• Ineligible for 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 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 (See Appendix A)
• Screening Laboratory evaluations with the following parameters:

• Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/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 109/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)
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
• Calculated creatinine clearance (CrCl) 30ml/min (Appendix B)
• 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) (See Appendix H)
• 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 (See Appendix H)
• 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 (See Appendix H) 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 (See Section 5.9.1)

Exclusion criteria

• Prior therapy for 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
• POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
• 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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Beth Israel Deaconess Medical Center (BIDMC) — Boston
• Dana-Farber Cancer Institute — Boston

Publications

• Avet-Loiseau H, Davies FE, Samur MK, Corre J, D'Agostino M, Kaiser MF, Raab MS, Weinhold N, Gutierrez NC, Paiva B, Neri P, Weisel K, Maura F, Walker BA, Bustoros M, Stewart AK, Usmani SZ, Hillengass J, Chng WJ, Keats JJ, Martinez-Lopez J, Sperling AS, Touzeau C, Zhan F, Raje NS, Cavo M, Bolli N, Ghobrial IM, Dhodapkar MV, Jagannath S, Spencer A, Parekh S, Bahlis NJ, Lonial S, Sonneveld P, Bergsage PMID 40489728
• Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BG, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an Inter PMID 25628469
• Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, PMID 27511158

Identifiers

NCT: NCT07601100 · 25-854

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗