Determination 2 - Isatuximab, Iberdomide, Bortezomib and Dexamethasone Induction, Followed by Risk- and Response-Adapted Consolidation and Maintenance Therapy, in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma

Обзор

The purpose of the study is to determine the best treatment approach based on the risk profile of the cancer cells and on how the disease responds to treatment. This is a randomized research study evaluating treatment for transplant-eligible participants with newly diagnosed multiple myeloma. Induction therapy in this study includes the drugs isatuximab, iberdomide, bortezomib, and dexamethasone. After induction therapy, participants will receive consolidation and maintenance therapy that is adapted based on their risk profile and response to treatment. The research study procedures include: screening for eligibility, study visits, blood and bone marrow tests, disease assessments, treatment with study drugs, and follow-up visits. It is expected that about 720 participants will take part in this study.

Подробное описание

This is a Phase III, open-label, multicenter randomized research study designed to evaluate different treatment strategies for people with multiple myeloma. The study will look at how often participants achieve MRD-negative status after maintenance therapy, compare different consolidation approaches, and assess long-term outcomes. Participants who are eligible will be assigned to study groups based on their cytogenetic risk and how their disease responds to induction therapy.

All participants will first receive induction treatment with isatuximab, iberdomide, bortezomib, and dexamethasone for 8 cycles. After induction, participants with standard-risk disease who are MRD-negative will continue to maintenance treatment with isatuximab and iberdomide for up to 36 cycles. After that, depending on their MRD status, they may continue on iberdomide alone or remain on the combination treatment. Participants with high-risk disease, or those who are MRD-positive or have indeterminate MRD results, will be randomized to receive either consolidation with high-dose melphalan followed by autologous stem cell transplant, or linvoseltamab, followed by maintenance therapy. Participants who are not eligible for consolidation, or who have indeterminate MRD status, may receive maintenance treatment with isatuximab, iberdomide, and bortezomib. The study also includes biomarker testing and participant-reported outcome assessments.

The research study procedures include screening for eligibility, clinic visits, blood tests, urine tests, CT scans, bone marrow sample collection and biobanking, MRD testing, stem cell collection, skeletal survey or PET scans, and electrocardiograms.

The study drugs include melphalan, bortezomib, and dexamethasone are approved by the FDA for the initial treatment of multiple myeloma. Isatuximab and linvoseltamab are approved by the FDA for multiple myeloma that has returned after prior treatment. Iberdomide is currently being studied for the treatment of multiple myeloma and has not been approved by the FDA for any disease.

The study also includes an injector device, referred to as the On Body Delivery System (OBDS), also called Isatuximab subcutaneous Wearable Injection System. OBDS is a sterile, single-use, disposable, elastomeric, user-filled medical device, which includes an on-body delivery device designed for subcutaneous delivery of a defined volume of drug product and an integrated drug product syringe transfer base.

It is expected that about 720 people will take part in this research study.

Sanofi Pharmaceuticals, is supporting this research study by providing isatuximab, Celgene, a subsidiary of Bristol-Myers Squibb, is providing, iberdomide, and Regeneron is providing linvoseltamab. Study drugs are free of charge and all sponsors are providing some funding for the study.

Вмешательства

• Препарат Isatuximab
  Supplied by Sanofi-Aventis (Sanofi); used in induction and maintenance/consolidation strategies in this protocol; administered subcutaneously in the maintenance tables provided; not administered in Arm C.
• Препарат Iberdomide
  Supplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally.
• Препарат Bortezomib (B)
  Commercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle.
• Препарат Dexamethasone
  Commercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G.
• Препарат Melphalan
  Commercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously.
• Препарат Linvoseltamab
  Supplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy.
• Устройство On Body Delivery System (OBDS)
  Device: On Body Delivery System (OBDS) - Sanofi-Aventis device used with isatuximab administration; abdominal/periumbilical single-site application with post-dose needle retraction and lock-out.

Первичные конечные точки

• 3-Year Sustained Minimal Residual Disease (sMRD)-negative Complete Response (CR) Rate [Cohort 1] (Step 2) [Срок оценки: Assessed after Step 2 maintenance cycle 36 (cycle duration=4 weeks), at 144 weeks/36 months.]
• 1-Year MRD-Negative CR Rate [Cohort 2] (Step 2) [Срок оценки: Assessed 1-year after Step 2 consolidation randomization.]

Вторичные конечные точки (12)

• 1-Year MRD-Negative CR Rate [Cohort 1] (Step 3) [Срок оценки: Assessed after Step 3 maintenance cycle 12 (cycle duration=4 weeks), at 48 weeks/12 months.]
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Role Functioning (RF) Subscale Response [Cohort 1] (Step 2) [Срок оценки: Assessed day 1 every 3 cycles during Step 2 maintenance cycles 1-36 (cycle duration=4 weeks), up to 144 weeks/36 months.]
• EORTC QLQ-C30 RF Subscale Response [Cohort 1] (Step 3) [Срок оценки: Assessed day 1 every 2 cycles during Step 3 maintenance cycles 1-12 (cycle duration=4 weeks), up to 48 weeks/12 months.]
• Median Progression-Free Survival (PFS) [Cohort 1] (Step 2) [Срок оценки: Assessed day 1 of each cycle during Step 2 maintenance cycles 1-36 (cycle duration=4 weeks) on treatment, up to 144 weeks/36 months. In long-term follow-up, assessed every 3 months, up to 88 months after Step 2 maintenance registration.]
• Median Progression-Free Survival (PFS) [Cohort 1] (Step 3) [Срок оценки: Assessed day 1 of each cycle during Step 3 maintenance cycle 1 and beyond (cycle duration=4 weeks) on treatment. In long-term follow-up, assessed every 3 months, up to 52 months after Step 3 registration.]
• Best Response [Cohort 1] (Step 2) [Срок оценки: Assessed at day 1 of each cycle over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months.]
• Best Response [Cohort 1] (Step 3) [Срок оценки: Assessed day 1 of every cycle of Step 3 maintenance treatment and in long term follow-up every 3 months, up to approximately 52 months.]
• Serious Adverse Events (SAE) Rate [Cohort 1] (Step 2) [Срок оценки: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.]
• SAE Rate [Cohort 1] (Step 3) [Срок оценки: Assessed continuously over Step 2 maintenance treatment (cycle duration=4 weeks), up to approximately 52 months + 30 days.]
• Grade 3 or Higher Non-Hematologic (NH) Treatment-Related Adverse Event (TRAE) Rate [Cohort 1] (Step 2) [Срок оценки: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.]
• 1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 1] (Step 3) [Срок оценки: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.]
• Grade 3 or Higher TRAE Rate [Cohort 1] (Step 2) [Срок оценки: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Beth Israel Deaconess Medical Center (BIDMC) — Boston
• Brigham and Women's Hospital — Boston
• Dana-Farber Cancer Institute — Boston

Публикации

• 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
• 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
• 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
• Cocks K, Buchanan J. How scoring limits the usability of minimal important differences (MIDs) as responder definition (RD): an exemplary demonstration using EORTC QLQ-C30 subscales. Qual Life Res. 2023 May;32(5):1247-1253. doi: 10.1007/s11136-022-03181-4. Epub 2022 Jul 9. PMID 35809136

Идентификаторы

NCT: NCT07624513 · 25-900

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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