This is a phase Ib study to assess the safety, tolerability, preliminary efficacy, and renal response of isatuximab, bortezomib, and dexamethasone in newly diagnosed multiple myeloma patients with severe renal impairment or dialysis-dependent end-stage renal disease. Such patients have limited therapeutic options due to renal clearance or nephrotoxicity of many myeloma therapies and are often excluded from clinical trials. Isatuximab in other regimens has shown efficacy and tolerability in patients with moderate renal impairment, although data are lacking for regimens containing CD38-targeting immunotherapies in severe renal impairment/ESRD.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Isatuximab is supplied by Sanofi.
Bortezomib is commercially available.
Dexamethasone is commercially available.
Washington University School of Medicine
St Louis, Missouri, United States
Safety and tolerability of the regimen as measured by the proportion of patients that discontinue therapy before Cycle 3 for toxicity or intolerance
-Patients who discontinue therapy due to COVID-19 will not be included in the calculation of this proportion and will be replaced. Patients who discontinue therapy due to progressive disease before initiation of Cycle 3 will be replaced in the trial.
Time frame: Through completion of cycle 3 for all enrolled patients (estimated to be 39 months)
Renal response per IMWG criteria
* Dialysis dependent at enrollment: * Conversion to dialysis independence: Return of renal function to where dialysis is not required for at least one consecutive month * Sustained dialysis independence: Return of renal function to where dialysis is not required for at least six consecutive months * Dialysis -independence at baseline or achieved while on therapy: * Complete response: Improved CrCl ≥ 60 mL/min * Partial response: In patients with baseline eGFR \< 15mL/min/1.73 m2, CrCl improved to 30 to 59 mL/min * Minor response: if baseline eGFR \< 15mL/min/1.73 m2, CrCl improved to 15 to 29 mL/min or if baseline eGFR 15 - 29 mL/min/1.73 m2, CrCl improved to 30 to 59 mL/min * Progressive renal disease: requirement of sustained
Time frame: Through completion of treatment (estimated to be 6 months)
Overall response rate (ORR) per IMWG criteria
-Partial response or better includes minimal residual disease (MRD) - negative, stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response per IMWG criteria
Time frame: Through completion of treatment (estimated to be 6 months)
Progression-free survival (PFS)
* PFS is defined as time from cycle 1 day 1 until progressive disease or death from any cause * Progressive disease is defined by IMWG Criteria
Time frame: From cycle 1 day 1 through 5 years after completion of treatment (estimated to be 5 years and 6 months)
Overall survival (OS)
-OS is defined as the time from cycle 1 day 1 until death from any cause
Time frame: From cycle 1 day 1 through 5 years after completion of treatment (estimated to be 5 years and 6 months)
Duration of response (DOR)
-DOR: for patients who achieve partial response or better, time from response was first noted until time of progressive disease; deaths due to causes other than progression are censored.
Time frame: Through completion of treatment (estimated to be 6 months)
Safety and tolerability of regimen as measured by discontinuation rate of each individual drug and duration/dose level exposure for each drug
Time frame: Through completion of treatment (estimated to be 6 months)
Total number of adverse events
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
Time frame: From start of treatment through 30 days after last day of treatment (estimated to be 7 months)
Total number of treatment-emergent adverse events
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
Time frame: From start of treatment through 30 days after last day of treatment (estimated to be 7 months)
Total number of grade 3 or higher adverse events
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
Time frame: From start of treatment through 30 days after last day of treatment (estimated to be 7 months)
Change in quality of life as measured by the EORTC-QLQ 30 questionnaire
The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better quality of life; increase from baseline indicates improvement in quality of life compared to baseline.
Time frame: Baseline, end of cycle 1 (each cycle is 28 days), and end of cycle 3 (each cycle is 28 days)
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