The phase 3 POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival versus lenalido-mide/dexamethasone (median: 28.9 versus 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; P=0.0042) and increased overall response rate (93.1% versus 76.5%; P=0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 versus 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; P=0.0022) and increased overall response rate (95.0% versus 78.8%; P=0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of daratumumab was largely consistent with the overall populations.

Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Internal Medicine Seoul National University College of Medicine Seoul South Korea

Institute of Hematology Department of Experimental Diagnostic and Specialty Medicine University of Bologna Bologna Italy

Janssen Global Medical Affairs Horsham PA USA

Janssen Research and Development LLC Raritan NJ USA

Janssen Research and Development LLC Spring House PA USA

Levine Cancer Institute Atrium Health Charlotte NC USA

Malignant Haematology and Stem Cell Transplantation Service Alfred Health Monash University Melbourne Australia

Nagoya City University Graduate School of Medical Sciences Nagoya Japan

National and Kapodistrian University of Athens Athens Greece

Service d'Hématologie et Thérapie Cellulaire Hôpital Bretonneau Centre Hospitalier Régional Universitaire Tours France

St James's Institute of Oncology Leeds Teaching Hospitals NHS Trust and University of Leeds Leeds United Kingdom

Tom Baker Cancer Center University of Calgary Calgary Alberta Canada

University Hospital Brno Brno Czech Republic

University Hospital of Salamanca IBSAL Salamanca Spain

University Medical Center of Hamburg Eppendorf Hamburg Germany

Winship Cancer Institute Emory University Atlanta GA USA

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Madan S, Kumar S. Current treatment options for elderly patients with multiple myeloma: clinical impact of novel agents. Therapy. 2011;8(4):415–429.

Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014, National Cancer Institute; 2017.

Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–2520. PubMed PMC

Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;118(17):4519–4529. PubMed

Ludwig H, Bolejack V, Crowley J, et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol. 2010;28(9):1599–1605. PubMed

Willan J, Eyre TA, Sharpley F, Watson C, King AJ, Ramasamy K. Multiple myeloma in the very elderly patient: challenges and solutions. Clin Interv Aging. 2016;11:423–435. PubMed PMC

de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–1848. PubMed

Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014; 124(21):3474.

Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311–321. PubMed PMC

Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcgamma receptor-mediated cross-linking. J Immunol. 2016;197(3):807–813. PubMed

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(3):384–394. PubMed PMC

Chiu C, Casneuf T, Axel A, et al. Daratumumab in combination with lenalidomide plus dexamethasone induces clonality increase and T-cell expansion: results from a phase 3 randomized study (POLLUX). Blood. 2016;128(22):4531.

Adams HC, III, Stevenaert F, Krejcik J, et al. High-parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action. Cytometry A. 2019;95(3):279–289. PubMed PMC

Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexam-ethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319–1331. PubMed

Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexam-ethasone for multiple myeloma. N Engl J Med. 2016;375(8):754–766. PubMed

Blair HA. Daratumumab: a review in relapsed and/or refractory multiple myeloma. Drugs. 2017;77(18):2013–2024. PubMed

Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–1473. PubMed

Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18): 4691–4695. PubMed PMC

Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–2074. PubMed PMC

Dimopoulos M, San Miguel J, Belch A, et al. Daratumumab plus lenalidomide and dex-amethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POL-LUX. Haematologica. 2018; 103(12):2088–2096. PubMed PMC

Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CAS-TOR. Haematologica. 2018;103(12):2079–2087. PubMed PMC

Zweegman S, Palumbo A, Bringhen S, Sonneveld P. Age and aging in blood disorders: multiple myeloma. Haematologica. 2014;99(7):1133–1137. PubMed PMC

Castelli R, Pantaleo G, Gallipoli P, et al. Salvage therapy with bortezomib and dex-amethasone in elderly patients with relapsed/refractory multiple myeloma. Anticancer Drugs. 2015;26(10):1078–1082. PubMed

Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib, lenalidomide, and dexam-ethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol. 2017;177(3):404–413. PubMed PMC

Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment. Blood Cancer J. 2017;7(4):e554. PubMed PMC

Niesvizky R, Ludwig H, Spencer A, et al. Overall survival of relapsed/refractory multiple myeloma patients treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone: results from the phase 3 endeavor study according to age subgroup. Presented at the 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA.: 1885.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–917. PubMed

Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518–528. PubMed

Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–2115. PubMed PMC

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(11):109. PubMed PMC

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis

Carfilzomib, Pomalidomide, and Dexamethasone As Second-line Therapy for Lenalidomide-refractory Multiple Myeloma

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Intercellular Mitochondrial Transfer in the Tumor Microenvironment

Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis

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ClinicalTrials.gov
NCT02076009, NCT02136134