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| Name | Class |
|---|---|
| Sanofi | INDUSTRY |
| Bristol-Myers Squibb | INDUSTRY |
| Celgene Corporation | INDUSTRY |
| Regeneron Pharmaceuticals |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A (Induction and screening) | Other | All enrolled participants begin with Step 1 induction for 8 28-day cycles before end-of-induction cohort assignment. PBSC mobilization/collection is planned between Cycles 4-6 for participants without progression. End-of-induction MRD/response and risk status determine whether participants proceed to Cohort 1 or Cohort 2. |
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| Arm B (Cohort 1 Maintenance Therapy Part 1) | Other | Participants assigned to Cohort 1 enter Arm B and receive isatuximab + iberdomide maintenance for 36 cycles. Maintenance should begin within 28 days of the last induction cycle. |
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| Arm C: Cohort 1 Maintenance Therapy (Part 2), Single-Agent Iberdomide | Other | After completion of Arm B, participants with MRD-negative CR status at Step 3 are assigned to Arm C and continue single-agent iberdomide until progression. Isatuximab is not administered in Arm C. |
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| Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab | Other | After completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or \ |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Isatuximab | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 3-Year Sustained Minimal Residual Disease (sMRD)-negative Complete Response (CR) Rate [Cohort 1] (Step 2) | sMRD-negative CR rate is defined as the proportion of participants who sustain MRD negativity at a minimum 10^-5 sensitivity assessed by next-generation sequencing (NGS) during the time of confirmed CR or better response per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). | 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) | MRD-negative CR rate is defined as the proportion of participants who achieve MRD negativity at a minimum 10^-5 sensitivity assessed by NGS during the time of confirmed CR or better response per IMWG-URC. | Assessed 1-year after Step 2 consolidation randomization. |
| Measure | Description | Time Frame |
|---|---|---|
| 1-Year MRD-Negative CR Rate [Cohort 1] (Step 3) | MRD-negative CR rate is defined as the proportion of participants who sustain MRD negativity or convert to MRD negativity at a minimum 10^-5 sensitivity assessed by NGS during the time of confirmed CR or better response per IMWG-URC. | Assessed after Step 3 maintenance cycle 12 (cycle duration=4 weeks), at 48 weeks/12 months. |
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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
Measurable disease defined by at least one of the following:
Screening laboratory evaluations meeting the following parameters:
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:
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
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Clifton C. Mo, MD | Contact | 617-582-7969 | Clifton_Mo@dfci.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Clifton C. Mo, MD | Dana-Farber Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beth Israel Deaconess Medical Center (BIDMC) | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25628469 | Background | 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 International Myeloma Working Group report. Blood. 2015 Mar 26;125(13):2068-74. doi: 10.1182/blood-2014-12-615187. Epub 2015 Jan 27. | |
| 40489728 |
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The Harvard Cancer Consortium encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Data can be shared no earlier than 1 year following the date of publication
Contact the Belfer office for Dana -Farber Innovations (BODFI) at innovations@dfci.harvard.edu
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| INDUSTRY |
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| Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT Strategy) | Active Comparator | Eligible Cohort 2 participants are randomized to Arm E: HDM-ASCT consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion. |
|
| Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy) | Experimental | Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose. |
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| Arm G: Cohort 2 Non-randomized 3-Drug Maintenance | Other | Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. SR MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G. |
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| Iberdomide | Drug | Supplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally. |
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| Bortezomib (B) | Drug | Commercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle. |
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| Dexamethasone | Drug | Commercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G. |
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| Melphalan | Drug | Commercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously. |
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| Linvoseltamab | Drug | Supplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy. |
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| On Body Delivery System (OBDS) | Device | 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. |
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| 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) | EORTC QLQ-C30 RF subscale response is defined as an increase of ≥15 points in the RF score from Step 2 baseline, based on established guidelines. The RF subscale consists of 2 items scored on a 4-point Likert scale ("Not at all" to "Very much"). Raw scores are reverse scored and linearly transformed to a 0-100 scale then averaged, with higher scores indicating better functioning. Number of responses over Step 2 maintenance treatment is summed by participant. | 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) | EORTC QLQ-C30 RF subscale response is defined as an increase of ≥15 points in the RF score from Step 3 baseline, based on established guidelines. The RF subscale consists of 2 items scored on a 4-point Likert scale ("Not at all" to "Very much"). Raw scores are reverse scored and linearly transformed to a 0-100 scale then averaged, with higher scores indicating better functioning. Number of responses over Step 3 maintenance treatment is summed by participant. | 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) | PFS based on Kaplan-Meier method is defined as the time from maintenance Step 2 registration until the earlier of disease progression (PD) per IMWG-URC or death due to any cause (events). Deaths occurring beyond 6 months from the date last known progression-free are not counted as events and instead censored at the date of last disease evaluation. Patients who start Non-Protocol Therapy (NPT) prior to PD are censored at the date of NPT. Patients alive who did not experience PD or start NPT are censored at the date of last disease evaluation. | 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) | PFS based on Kaplan-Meier method is defined as the time from maintenance Step 3 registration until the earlier of PD per IMWG-URC or death due to any cause (events). Deaths occurring beyond 6 months from the date last known progression-free are not counted as events and instead censored at the date of last disease evaluation. Patients who start NPT prior to PD are censored at the date of NPT. Patients alive who did not experience PD or start NPT are censored at the date of last disease evaluation. | 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) | Frequency of best response over Step 2 maintenance including stringent complete response(sCR), CR, very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) per IMWG-URC. | 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) | Frequency of best response over Step 3 maintenance including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC. | 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) | SAE rate is defined as the proportion of participants who experience any untoward medical occurrence at any dose that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event, not hypothetically), requires inpatient hospitalization or prolongation of existing hospitalization (excluding planned hospitalizations), results in persistent or significant disability or incapacity (defined as substantial disruption of normal life functions), is a congenital anomaly or birth defect, or is considered a medically important event. | 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) | SAE rate is defined as the proportion of participants who experience any untoward medical occurrence at any dose that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event, not hypothetically), requires inpatient hospitalization or prolongation of existing hospitalization (excluding planned hospitalizations), results in persistent or significant disability or incapacity (defined as substantial disruption of normal life functions), is a congenital anomaly or birth defect, or is considered a medically important event. | 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) | Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy. | 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) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy. | 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) | Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or non-hematologic adverse event based on CTCAEv5 with a treatment attribution of possible, probable or definite over maintenance therapy. | 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 Non-Hematologic (NH) Treatment-Related Adverse Event (TRAE) Rate [Cohort 1] (Step 3) | Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy. | Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days. |
| 1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 1] (Step 3) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy. | Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days. |
| 1-Year Grade 3 or Higher TRAE Rate [Cohort 1] (Step 3) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH or hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy. | Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days. |
| 1-Year EORTC QLQ-C30 RF Subscale Response [Cohort 2] (Step 2) | EORTC QLQ-C30 RF subscale response is defined as an increase of ≥15 points in the RF score from Step 2 baseline, based on established guidelines. The RF subscale consists of 2 items scored on a 4-point Likert scale ("Not at all" to "Very much"). Raw scores are reverse scored and linearly transformed to a 0-100 scale then averaged, with higher scores indicating better functioning. Number of responses over Step 2 consolidation and maintenance treatment, up to 1 year, are summed by participant. | Assessed day 1 every 2 cycles or every 2 months on Step 2 treatment, up to 1 year. |
| Median PFS [Cohort 2] (Step 2) | PFS based on Kaplan-Meier method is defined as the time from Step 2 randomization until the earlier of PD per IMWG-URC or death due to any cause (events). Deaths occurring beyond 6 months from the date last known progression-free are not counted as events and instead censored at the date of last disease evaluation. Patients who start NPT prior to PD are censored at the date of NPT. Patients alive who did not experience PD or start NPT are censored at the date of last disease evaluation. | Assessed day 1 of each cycle or every month during Step 2 treatment. In long-term follow-up, assessed every 3 months, up to 88 months after Step 2 randomization. |
| Maintenance Best Response [Cohort 2] (Step 2) | Frequency of best response over Step 2 maintenance including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC. | Assessed at day 1 of each cycle over Step 2 maintenance treatment (cycle duration=4 weeks), up to 80 months. |
| 1-Year Best Response [Cohort 2] (Step 2) | Frequency of best response over Step 2 consolidation and maintenance treatment up, to 1-year, including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC. | Assessed at day 1 of each cycle or every month over Step 2 treatment, up to 1 year. |
| Consolidation Best Response [Cohort 2] (Step 2) | Frequency of best response over Step 2 consolidation treatment up including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC. | Assessed day 1 over 8 cycles of Step 2 consolidation (cycle duration=4 weeks), up to 32 weeks/8 months; or from start of high-dose melphalan (HDM) day -2, though day 0 peripheral blood stem cell (PBSC) infusion up to maintenance start prior to day 110. |
| Maintenance SAE Rate [Cohort 2] (Step 2) | SAE rate is defined as the proportion of participants who experience any untoward medical occurrence at any dose that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event, not hypothetically), requires inpatient hospitalization or prolongation of existing hospitalization (excluding planned hospitalizations), results in persistent or significant disability or incapacity (defined as substantial disruption of normal life functions), is a congenital anomaly or birth defect, or is considered a medically important event over Step 2 maintenance treatment. | Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days. |
| Consolidation SAE Rate [Cohort 2] (Step 2) | SAE rate is defined as the proportion of participants who experience any untoward medical occurrence at any dose that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event, not hypothetically), requires inpatient hospitalization or prolongation of existing hospitalization (excluding planned hospitalizations), results in persistent or significant disability or incapacity (defined as substantial disruption of normal life functions), is a congenital anomaly or birth defect, or is considered a medically important event over Step 2 consolidation. | Assessed continuously over 8 Step 2 consolidation cycles (4 weeks each), up to 32 weeks/8 months +30 days; or from high-dose melphalan (HDM) day -2 through day 0 PBSC infusion to maintenance start before day 110 +30 days. |
| Maintenance Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy. | Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days. |
| 1-Year Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation and maintenance therapy, up to 1-year. | Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days. |
| Maintenance Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy. | Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days. |
| 1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation and maintenance therapy, up to 1- year + 30 days. | Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days. |
| Maintenance Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy. | Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days. |
| 1-Year Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation and maintenance therapy, up to 1-year + 30 days. | Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days. |
| Consolidation Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation. | Assessed continuously over 8 Step 2 consolidation cycles (4 weeks each), up to 32 weeks/8 months +30 days; or from high-dose melphalan (HDM) day -2 through day 0 PBSC infusion to maintenance start before day 110 +30 days. |
| Consolidation Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation. | Assessed continuously over 8 Step 2 consolidation cycles (4 weeks each), up to 32 weeks/8 months +30 days; or from high-dose melphalan (HDM) day -2 through day 0 PBSC infusion to maintenance start before day 110 +30 days. |
| Consolidation Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2) | Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 consolidation. | Assessed continuously over 8 Step 2 consolidation cycles (4 weeks each), up to 32 weeks/8 months +30 days; or from high-dose melphalan (HDM) day -2 through day 0 PBSC infusion to maintenance start before day 110 +30 days. |
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
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| Dana-Farber Cancer Institute | Boston | Massachusetts | 02115 | United States |
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| Background |
| 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, Bergsagel L, Orlowski RZ, Morgan G, Mateos MV, Rajkumar SV, San Miguel JF, Anderson KC, Moreau P, Kumar S, Prosper F, Munshi NC. International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. J Clin Oncol. 2025 Aug 20;43(24):2739-2751. doi: 10.1200/JCO-24-01893. Epub 2025 Jun 9. |
| 27511158 | Background | 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, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-e346. doi: 10.1016/S1470-2045(16)30206-6. |
| 35809136 | Background | 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. |
| ID | Term |
|---|---|
| D009101 | Multiple Myeloma |
| ID | Term |
|---|---|
| D054219 | Neoplasms, Plasma Cell |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010265 | Paraproteinemias |
| D001796 | Blood Protein Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006474 | Hemorrhagic Disorders |
| D008232 | Lymphoproliferative Disorders |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000599209 | isatuximab |
| C000624220 | iberdomide |
| D000069286 | Bortezomib |
| D003907 | Dexamethasone |
| D008558 | Melphalan |
| ID | Term |
|---|---|
| D001897 | Boronic Acids |
| D000148 | Acids, Noncarboxylic |
| D000143 | Acids |
| D007287 | Inorganic Chemicals |
| D001896 | Boron Compounds |
| D009930 | Organic Chemicals |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D010649 | Phenylalanine |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
Not provided
Not provided