Background:

Daratumumab (Dara) combined with either VRd or Rd is a standard treatment for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). However, lenalidomide often requires dose reductions in elderly patients, especially in those with renal impairment. Dara-VCd, while approved for AL amyloidosis, has also been explored in myeloma.

Methods

The multicenter GMMG DADA study (NCT04656951) evaluated Dara-VCd as first-line therapy for transplant-ineligible NDMM patients across 24 hospitals and community practices in Germany. Patients received 8 cycles of 4 weeks (total duration 32 weeks) induction with Dara-VCd, followed by Dara-Vd maintenance until progression or intolerance. Daratumumab was given subcutaneously (1800 mg) at weekly intervals for cycles 1-2, biweekly for cycles 3-6 and then monthly. Subcutaneous bortezomib (1.3 mg/m2) was given weekly for induction, and biweekly for maintenance. Cyclophosphamide 500mg/m2 was given intravenously once per cycle for 8 cycles and then stopped. Dexamethasone was given orally at 20 mg weekly during induction and biweekly during maintenance. At first relapse, patients transitioned to Dara-Rd per protocol to explore re-treatment with Dara using a different backbone. Primary endpoint was the rate of VGPR or better after 8 cycles of Dara-VCd, assessed by central laboratory. Here we report first results of the Dara-VCd regimen as part of the trial.

Results

Between study start and the end of recruitment in June 2024, 74 patients were screened. After excluding 7 screening failures 67 patients were eligible for the study. With 3 withdrawals before starting treatment, 64 patients received at least one dose of Dara-VCd and constituted the safety population per protocol. Age at enrollment ranged from 56 to 84 years, median age was 75 years in male patients and 71 years in female patients. 2 patients did not complete the first cycle of Dara-VCd (1 early death, 1 withdrawal of consent). 62 patients completed at least 1 cycle of Dara-VCd and were analyzed per protocol as efficacy population. Four patients did not complete 8 cycles of Dara-VCd (1 lost to follow-up, 3 patient withdrawals in VGPR or CR). In addition, there was missing response data in 2 patients. Among 58 evaluable patients at the end of cycle 8, 14 achieved CR, 30 VGPR, 8 PR, 2 SD, and 4 PD. The VGPR-or-better rate in the efficacy population was 71.0% (44/62), the overall response rate was 83.9% (52/62). In addition, central MRD assessment by bone marrow flow cytometry (10-5 sensitivity) after 8 cycles of Dara-VCd was available for 50 patients, with 27 (54%) achieving MRD-negativity.

Safety

A total of 72 serious adverse events occurred in the safety population, including infections (n=25; 4 COVID-19), hematologic (n=5), skeletal (n=5), renal (n=5), cardiac (n=4), neurological (n=3) and gastrointestinal (n=3) events. The most common grade 3/4 adverse events were infections (n= 25, 39.1%, including 4 COVID-19), anemia (n=18, 28.1%), neutropenia (n=9, 14.1%) and renal failure (n=6, 9.4%). Peripheral neuropathy (PNP) of any grade was noted in 26 patients (40.6%). It was predominantly grade 1 or 2, while only 2 patients were found to have grade 3 PNP. Overall, no new safety signals for Dara-VCd were observed.

Conclusion

This prospective, multicenter trial demonstrates the feasibility of Dara-VCd as first-line therapy in transplant-ineligible NDMM patients, including those with renal impairment, dialysis dependence, and without upper age limit. The safety results showed a manageable toxicity with a remarkably low rate of severe PNP, underlining the advantage of a weekly bortezomib regimen. After 8 cycles, 71% of patients achieved a VGPR or better, and 54% were MRD-negative, suggesting efficacy comparable to other quadruplet regimens despite the absence of an IMiD. These findings support Dara-VCd as a potential alternative for elderly patients, particularly those with renal dysfunction.

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2025
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