A multicenter observational retrospective study of second-line treatment with daratumumab–bortezomib–dexamethasone (DaraVd) in multiple myeloma patients refractory to lenalidomide

Upfront lenalidomide in newly diagnosed multiple myeloma has become the gold standard. Nonetheless, proper management of lenalidomide-refractory patients is challenging. Daratumumab-bortezomib-dexamethasone (DaraVd) has been approved after ≥ 1 prior therapy, but data on upfront lenalidomide refractoriness are scarce. We run a retrospective study to assess the outcomes of 85 lenalidomide-refractory patients treated at first relapse with DaraVd in 10 Italian centers. Baseline characteristics were representative of a general population, despite inferior median age (57 years). Sixteen (27%) at diagnosis and 7 (29%) at relapse had high-risk cytogenetics (t(4;14) and/or t(14;16) and/or del17). Furthermore, one had del1p, one gain1q (3 copies) and one amp1q (≥ 4 copies) at diagnosis; one gain1q and one amp1q at relapse. Overall response rate was 86% (61% ≥ VGPR). Median PFS and OS were 15 and 47 months, respectively (25-months median follow-up). Previous dose/duration of lenalidomide did not influence PFS, favorably affected by the absence of amp1q (p = 0.04), bone marrow plasma cells < 60% (p = 0.003), absence of extramedullary-disease (p = 0.009), and ≥ VGPR (p < 0.001) or ≥ CR (p = 0.012). In a multivariate model, response ≥ VGPR was confirmed to be independently associated to PFS (median: 26 vs. 7 months). At least one grade ≥ 2 adverse event (AE) occurred in 67 (85%) patients. Most common AEs were hematological (72%), infections (30%, 8% grade-3, 1% grade-5), pneumonia (14%), and asthenia (38%). Peripheral neuropathy rate was 58% (8% grade-3). Toxicity-related bortezomib dose reduction occurred in 39 (49.4%) patients; 27 (44%) delayed Dara (1 median dose), mostly for infections. Three patients discontinued for toxicity. Collectively, second-line DaraVd remains an alternative in lenalidomide-refractory patients, especially for those ineligible for pomalidomide/carfilzomib-based regimens, T-cell-redirecting therapies or other experimental drugs.