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<p>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&#xa0;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&#xa0;months, respectively (25-months median follow-up). Previous dose/duration of lenalidomide did not influence PFS, favorably affected by the absence of amp1q (<i>p</i> = 0.04), bone marrow plasma cells &lt; 60% (<i>p</i> = 0.003), absence of extramedullary-disease (<i>p</i> = 0.009), and ≥ VGPR (<i>p</i> &lt; 0.001) or ≥ CR (<i>p</i> = 0.012). In a multivariate model, response ≥ VGPR was confirmed to be independently associated to PFS (median: 26 vs. 7&#xa0;months). At least one grade ≥ 2 adverse event (AE) occurred in 67 (85%) patients. Most common AEs were hematological (72%), infections&#xa0;(30%, 8% grade-3,&#xa0;1% grade-5), pneumonia&#xa0;(14%), and asthenia&#xa0;(38%). Peripheral neuropathy rate was 58%&#xa0;(8% grade-3). Toxicity-related bortezomib dose reduction occurred in 39&#xa0;(49.4%) patients; 27 (44%) delayed Dara (1 median dose), mostly for infections. Three patients discontinued for toxicity.&#xa0;Collectively, second-line DaraVd remains an alternative in lenalidomide-refractory patients, especially for those ineligible&#xa0;for pomalidomide/carfilzomib-based regimens, T-cell-redirecting therapies or other experimental drugs.</p>

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

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  • 发表日期：

    2025年11月25日

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  • I. Rizzello,
  • I. Sacchetti,
  • S. Barbato,
  • V. Solli,
  • P. Stefanoni,
  • L. Cani,
  • M. Quaresima,
  • A. Belotti,
  • N. Sgherza,
  • M. Gentile,
  • R. Zambello,
  • G. Barilà,
  • M. Celli,
  • G. Mele,
  • K. Mancuso,
  • L. Pantani,
  • P. Tacchetti,
  • M. Talarico,
  • M. Puppi,
  • E. Manzato,
  • R. Restuccia,
  • S. Masci,
  • S. Ghibellini,
  • F. Bigi,
  • M. Cavo,
  • E. Zamagni

摘要

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.