Optimizing lenalidomide therapy in renal impairment: Analysis of renal response in the prospective remnant study in transplant-eligible newly diagnosed multiple myeloma

Abstract

Abstract Background: Renal impairment (RI) is a serious complication in multiple myeloma (MM), associated with poor overall survival and increased early mortality. Rapid renal recovery improves outcomes. In transplant-eligible (TE), newly diagnosed (ND) MM, lenalidomide-based regimes are standard. However, the current label for lenalidomide in the setting of RI is based on studies that excluded NDMM patients. Data are needed to guide safe and effective lenalidomide dosing in this high-risk subgroup. Methods REMNANT is an ongoing academic, multicenter, open-label phase 2/3 study in TE NDMM patients, aged 18-75 years. Eligibility criteria allowed inclusion of patients with renal failure; the key exclusion was > 1 prior induction cycle. All patients received induction therapy with four 21-day cycles of bortezomib, lenalidomide and dexamethasone. Bortezomib subcutaneously at 1.3 mg/m² on days 1, 4, 8, and 11 (adjusted to days 1 and 8 after 50% enrollment). Oral lenalidomide at 25 mg/day on days 1-14, or at 15 mg/day if eGFR<30 mL/min/1.73m2. Dexamethasone orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. This sub-analysis of the REMNANT study evaluated the safety and tolerability of full-dose lenalidomide (25 mg on days 1-14) in NDMM patients with normal or moderately impaired renal function (eGFR ≥30) and reduced-dose lenalidomide (15 mg on days 1–14) in patients with severe renal impairment (eGFR <30), including patients on dialysis, during the four-cycle induction phase. If eGFR improved to ≥30 during treatment, lenalidomide was increased to 25 mg/day. Renal response was assessed (IMWG criteria for renal response) from cycle 1 day 1 to the first post-cycle visit after four induction cycles in all patients with baseline eGFR <50. Results Of 382 patients enrolled between August 2020 and September 2024, 331 were included in this analysis. Exclusions were due to early treatment discontinuation before completing four induction cycles (n=33), missing baseline or post-induction eGFR (n=5) or incomplete induction therapy (n=13). Discontinuation reasons included progressive disease or death (n=15), safety concerns (n=9), patient choice (n=8), and protocol non-compliance (n=1). No patients discontinued due to worsening renal function. Among 331 patients included in the analysis, 268 (81%) had baseline eGFR ≥ 50 (Group A), 30 (9%) had eGFR 30-49 (Group B), and 33 (10%) had eGFR < 30 (Group C), including two patients undergoing dialysis. Median baseline eGFRs were 89, 42 and 18 for Groups A-C, respectively. Median ages were 63, 67 and 61 years, with male predominance across subgroups (59%, 73%, 60%). Markers of disease burden increased with worsening renal function. Free light-chain (FLC) ratio >100 was seen in 30% (Group A), 60% (B) and 76% (C); s-FLC>500 mg/l in 36%, 80% and 94%; anemia in 43%, 77% and 85%; and ≥60% bone marrow plasma cells in 41%, 70% and 60%, respectively. ISS stage III disease was present in 11% (A), 60% (B), and 27% (C) and high-risk cytogenetics in 20%, 20% and 12%, respectively. Comorbidities were more common in lower eGFR groups, including hypertension (21%, 27%, 30%), diabetes mellitus (7%, 13%, 9%), and non-myeloma kidney disease (1%, 10%, 6%). Among 63 patients with baseline eGFR <50 (Groups B and C), 83% achieved renal response, and 65% achieved complete renal response after four induction cycles. The median time to renal response was 21 days. While eGFR remained stable in Group A, Groups B and C showed marked improvement from median 42 to 68 and 18 to 55, respectively. No patients required dialysis following the four inductions cycles. Grade ≥2 adverse events (AE) were more common in patients with eGFR ≥50 compared to patients with eGFR <50, except for anemia (2% vs. 14%). Other AEs included infections (48% vs. 30%), rash (10% vs. 3%), and neutropenia (4% vs. 3%). One Group B patient developed grade 3 renal failure during induction, assessed as possibly related to lenalidomide. Lenalidomide treatment was paused and resumed at 15 mg/day after renal recovery. No decline in eGFR was observed from baseline to the end of study in Groups B and C. Conclusion Renal responses were seen in 83% of patients with eGFR <50 mL/min/1.73m², with no cases of worsening renal function from baseline to end of study.Our results support that lenalidomide at 15 mg/day for patients with eGFR <30 mL/min/1.73m² and 25 mg/day for those with eGFR ≥30 mL/min/1.73m² is safe and effective during induction therapy for TE NDMM patients.