We performed real world evidence (RWE) analysis of daratumumab, lenalidomide and dexamethasone (Dara-Rd) versus lenalidomide and dexamethasone (Rd) treatment in relapsed/refractory multiple myeloma patients (RRMM). In total, 240 RRMM patients were treated with Dara-Rd from 2016 to 2022 outside of clinical trials in all major Czech hematology centers. As a reference, 531 RRMM patients treated with Rd were evaluated. Patients' data were recorded in the Czech Registry of Monoclonal Gammopathies (RMG). Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd than in Rd group (91.2% vs. 69.9%; p < 0.001). The median progression free survival (PFS) was 26.9 months in the Dara-Rd and 12.8 months in the Rd group (p < 0.001). Median overall survival (OS) was not reached in the Dara-Rd compared to 27.2 months in the Rd group (p = 0.023). In patients with 1-3 previous treatment lines, there was significant PFS benefit of Dara-Rd compared to Rd (median PFS not reached vs. 13.2 months; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months vs. 9.9 months; p = 0.874), similarly in patients refractory to PI + IMIDs (11.5 months vs. 9.2 months; p = 0.376). In RWE conditions, the median PFS in RRMM patients treated with Dara-Rd is shorter when compared to clinical trials. In heavily pretreated RRMM patients, efficacy of Dara-Rd treatment is limited; best possible outcomes of Dara-Rd are achieved in minimally pretreated patients.

1st Medical Department Clinical Department of Hematology of the 1st Faculty of Medicine General Teaching Hospital Charles University Prague Czech Republic

4th Department of Medicine Hematology Faculty of Medicine Charles University Hospital Hradec Kralove Czech Republic

Babak Myeloma Group Department of Pathophysiology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Hemato Oncology Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University Olomouc Olomouc Czech Republic

Department of Hematooncology Faculty of Medicine University Hospital Ostrava University of Ostrava Ostrava Czech Republic

Department of Internal Medicine and Hematology University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Internal Medicine Hematology and Oncology Faculty of Medicine University Hospital Brno Masaryk University Brno Czech Republic

Hematology and Oncology Department Charles University Hospital Pilsen Czech Republic

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

See more in PubMed

Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97:1086–1107. doi: 10.1002/ajh.26590. PubMed DOI PMC

Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34:1875–1884. doi: 10.1038/s41375-020-0711-6. PubMed DOI PMC

Avet-Loiseau H, San-Miguel J, Casneuf T, et al. Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR. J Clin Oncol. 2021;39:1139–1149. doi: 10.1200/JCO.20.01814. PubMed DOI PMC

Voorhees PM, Rodriguez C, Reeves B, et al. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021;5:1092–1096. doi: 10.1182/bloodadvances.2020003642. PubMed DOI PMC

Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380:2104–2115. doi: 10.1056/NEJMoa1817249. PubMed DOI PMC

Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096–2107. doi: 10.1016/S0140-6736(19)32556-5. PubMed DOI

Usmani SZ, Nahi H, Plesner T, et al. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020;7:e447–e455. doi: 10.1016/S2352-3026(20)30081-8. PubMed DOI

Wang W, Erbe AK, Hank JA, et al. NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Front Immunol. 2015;6:368. doi: 10.3389/fimmu.2015.00368. PubMed DOI PMC

van de Donk NWCJ, Usmani SZ. CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance. Front Immunol. 2018;9:2134. doi: 10.3389/fimmu.2018.02134. PubMed DOI PMC

Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–394. doi: 10.1182/blood-2015-12-687749. PubMed DOI PMC

van de Donk NWCJ. Reprint of “Immunomodulatory effects of CD38-targeting antibodies”. Immunol Lett. 2019;205:71–77. doi: 10.1016/j.imlet.2019.02.002. PubMed DOI

Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373:1207–1219. doi: 10.1056/NEJMoa1506348. PubMed DOI

van der Veer MS, de Weers M, van Kessel B, et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011;96:284–290. doi: 10.3324/haematol.2010.030759. PubMed DOI PMC

Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375:1319–1331. doi: 10.1056/NEJMoa1607751. PubMed DOI

Mateos M-V, Ludwig H, Bazarbachi A et al. (2018) Insights on Multiple Myeloma Treatment Strategies. Hemasphere 3:e163 10.1097/HS9.0000000000000163 PubMed PMC

Terpos E, Engelhardt M, Cook G, et al. Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN) Leukemia. 2020;34:2000–2011. doi: 10.1038/s41375-020-0876-z. PubMed DOI PMC

Chari A, Romanus D, Palumbo A, et al. Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2020;20:8–17.e16. doi: 10.1016/j.clml.2019.09.625. PubMed DOI

Richardson PG, San Miguel JF, Moreau P, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8:109. doi: 10.1038/s41408-018-0141-0. PubMed DOI PMC

Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7:e370–e380. doi: 10.1016/S2352-3026(20)30070-3. PubMed DOI

Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374:1621–1634. doi: 10.1056/NEJMoa1516282. PubMed DOI

Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019;133:660–675. doi: 10.1182/blood-2018-09-825331. PubMed DOI PMC

Szabo AG, Klausen TW, Levring MB et al. (2021) The real-world outcomes of multiple myeloma patients treated with daratumumab. PLoS One 16:e0258487. 10.1371/journal.pone.0258487 PubMed PMC

Fazio F, Franceschini L, Tomarchio V, et al. Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. EJHaem. 2022;3:121–128. doi: 10.1002/jha2.359. PubMed DOI PMC

Antonioli E, Staderini M, Pilerci S, et al. Daratumumab, lenalidomide, and dexamethasone combination in relapsed/refractory myeloma patients: a real-life single-center experience. Leuk Lymphoma. 2020;61:3255–3258. doi: 10.1080/10428194.2020.1802452. PubMed DOI

Fucci L, Gensini L, Coppetelli U et al. (2022) Daratumumab triplet therapies in patients with relapsed or refractory multiple myeloma: A “real world” experience. Leuk Res Rep 17:100330 10.1016/j.lrr.2022.100330 PubMed PMC

Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:781–794. doi: 10.1016/S1470-2045(19)30152-4. PubMed DOI

Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–152. doi: 10.1056/NEJMoa1411321. PubMed DOI

Rocchi S, Tacchetti P, Pantani L, et al. A real-world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma. Hematol Oncol. 2021;39:41–50. doi: 10.1002/hon.2820. PubMed DOI

van de Donk NWCJ, Usmani SZ, Yong K. CAR T-cell therapy for multiple myeloma: state of the art and prospects. Lancet Haematol. 2021;8:e446–e461. doi: 10.1016/S2352-3026(21)00057-0. PubMed DOI

Rodriguez-Otero P, Paiva B, San-Miguel JF (2021) Roadmap to cure multiple myeloma. Cancer Treat Rev 100:102284. 10.1016/j.ctrv.2021.102284 PubMed

Lancman G, Sastow DL, Cho HJ, et al. Bispecific Antibodies in Multiple Myeloma: Present and Future. Blood Cancer Discov. 2021;2:423–433. doi: 10.1158/2643-3230.BCD-21-0028. PubMed DOI PMC

Fonseca R, Bergsagel P, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23:2210–2221. doi: 10.1038/leu.2009.174. PubMed DOI PMC

Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955–2962. doi: 10.1182/blood-2016-01-631200. PubMed DOI PMC

Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol. 2020;13:115. doi: 10.1186/s13045-020-00948-5. PubMed DOI PMC

Landgren O, Weisel K, Rosinol L, et al. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol. 2022;198:988–993. doi: 10.1111/bjh.18233. PubMed DOI

Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378:518–528. doi: 10.1056/NEJMoa1714678. PubMed DOI

Bahlis N, Facon T, Usmani SZ, et al. Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of Maia. Blood. 2019;134:1875. doi: 10.1182/blood-2019-123426. DOI

Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38. doi: 10.1016/S0140-6736(19)31240-1. PubMed DOI

Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33:2863–2869. doi: 10.1200/JCO.2015.61.2267. PubMed DOI PMC

Pour L, Sevcikova S, Greslikova H, et al. Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. 2014;99:360–364. doi: 10.3324/haematol.2013.094409. PubMed DOI PMC

Jelinek T, Bezdekova R, Zihala D et al. (2022) More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma. J Clin Oncol JCO2201226 10.1200/JCO.22.01226 PubMed PMC

Jelinek T, Sevcikova T, Zihala D, et al. Limited efficacy of daratumumab in multiple myeloma with extramedullary disease. Leukemia. 2022;36:288–291. doi: 10.1038/s41375-021-01343-w. PubMed DOI

Byun JM, Min C-K, Kim K, et al. Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease. J Hematol Oncol. 2022;15:150. doi: 10.1186/s13045-022-01374-5. PubMed DOI PMC

Beksac M, Spicka I, Hajek R et al. (2022) Evaluation of isatuximab in patients with soft-tissue plasmacytomas: An analysis from ICARIA-MM and IKEMA. Leuk Res 122:106948. 10.1016/j.leukres.2022.106948 PubMed

Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Shang-Yi Huang J, Minarik J, Cavo M, Prince HM, Malinge L, Dubin F, van de Velde H, Anderson KC (2022) Isatuximab plus pomalidomide and lowdose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refraktory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol 23(3):416–427. 10.1016/S1470-2045(22)00019-5 PubMed

Stork M, Sevcikova S, Jelinek T, et al. Unexpected Heterogeneity of Newly Diagnosed Multiple Myeloma Patients with Plasmacytomas. Biomedicines. 2022;10:2535. doi: 10.3390/biomedicines10102535. PubMed DOI PMC

Gagelmann N, Eikema D-J, Iacobelli S, et al. Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. Haematologica. 2018;103:890–897. doi: 10.3324/haematol.2017.178434. PubMed DOI PMC

Cavo M, San-Miguel J, Usmani SZ, et al. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022;139:835–844. doi: 10.1182/blood.2021011101. PubMed DOI PMC

Lenalidomide based triplets in relapsed/refractory multiple myeloma: analysis of the Czech Myeloma Group