Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

ABSTRACT

Introduction: Extramedullary disease (EMD) in patients (pts) with multiple myeloma (MM) is a poor prognostic feature which is not curable with currently approved treatments. Consequently, there is a significant unmet need for effective therapies with good safety profiles. Daratumumab with cyclophosphamide, bortezomib and dexamethasone (daraVCD) is a novel treatment combination with a good efficacy profile in pts with EMD based on preclinical synergistic data. Methods: EMN19 is a phase 2, open-label, multicenter study which aims to enroll 40 MM pts presenting with EMD either at diagnosis or following one line of treatment but not refractory to bortezomib-based regimens, from 8 sites in Turkey, Greece and Italy. Pts with bortezomib or daratumumab hypersensitivity, who received previous autologous stem cell transplant (ASCT) ≤12 weeks before Day 1 of treatment Cycle 1, or with previous allogenic stem cell transplant were excluded. Daratumumab was initially administered intravenously at 16 mg/mL, and since July 2020 has been administered subcutaneously at a fixed dose of 1800 mg, weekly during Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Intravenous bortezomib 1.5 mg/m 2 and oral/intravenous cyclophosphamide 300 mg/m 2 is administered weekly, and oral/intravenous dexamethasone 20 mg is administered on Days 1, 2, 8, 9, 15, 16, 22 and 23. DaraVCD will be administered until progression or unacceptable toxicity unless refractory disease is detected by the end of Cycle 3 (progressive disease [PD] or failure to achieve a confirmed partial response [PR] or better). The present analysis includes pts who initiated study treatment ≥3 months prior to the cut-off date (01 June 2021). Results: In total, 34 patients were screened, 27 patients were enrolled, 2 relapsing patients died during the screening phase due to severe COVID-19 infection, 22 pts were analyzed (59% female;median age 56 years, range 44-77);14 pts (64%) were still on treatment and 8 (36%) discontinued;due to inadequate response after 3 cycles of treatment (n=3, 38%), PD (n=4, 50%), death (n=1, 13%). Fourteen pts (64%) were newly diagnosed and 8 (36%) first relapsed. International Staging System stage at baseline was I, II and III for 8 (36%), 9 (41%) and 5 (23%) pts, respectively. Eastern Cooperative Oncology Group performance status was 0, 1 and 2 for 14 (64%), 7 (32%), and 1 patient (5%), respectively. On average, 3.0 (range 1-20) extramedullary plasmacytomas were observed per patient;most commonly reported sites were thorax (6 pts, 27%), brain, head and lower extremities (4 pts, 18% each). Twenty (91%) pts had ≥1 serious or non-serious treatment-emergent adverse event (TEAE);8 pts (36.4%) experienced ≥1 sTEAEs;COVID-19 infection (n=3, 14%) urinary tract infection (n=2, 9%), infectious myocarditis, hip arthroplasty, pneumonia, cytomegaloviral pneumonia and thrombocytopenia (n=1 each, 4.5%). Thirteen (59%) pts ≥1 Grade 3/4 TEAE;neutropenia observed in 8 pts (36%), followed by thrombocytopenia (n=4, 18%) and COVID-19 infection (n=3, 14%). Overall, 16 (73%) pts missed ≥1 dose of any of the study drugs;2 (9%) pts missed ≥1 dose due to COVID-19 infection (7 doses), 8 (36%) due to COVID-19 vaccination (37 doses), 2 (9%) due to other COVID-19-related issues (65 doses), 10 (46%) due to other safety events (104 doses) and 9 (41%) due to other reasons (25 doses). Overall, 20 cycle delays were observed in 13 (59%) pts, with median (range) delay of 12.0 (4-133) days. Two pts (9%) had a cycle delay due to COVID-19 infection (2 cycles), 1 (5%) due to COVID-19 vaccination (1 cycle), 5 (23%) due to adverse events (8 cycles), 2 (9%) due to ASCT (2 cycles) and 7 (32%) due to other reasons (7 cycles). Total number of missed doses (missed doses due to COVID-19-related issues) were 17 (3) for daratumumab, 53 (11) for bortezomib, 45 (9) for cyclophosphamide and 123 (86) for dexamethasone;238 doses missed in total. No fatalities occurred due to any infection. Conclusions: DaraVCD was associated with a good safety profile in this high ri k MM with EMD patient population. The COVID-19 impact on missed doses was greater for dexamethasone (>60% of missed doses) than other components (~20%), however overall, the pandemic did not significantly affect the patients' safety and data integrity of the study. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Beksac Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi Consultancy, Speakers Bureau. Tuglular GSK Honoraria, Research Funding;Amgen Honoraria, Research Funding;Karyopharm Honoraria, Research Funding;Abbvie Honoraria, Research Funding;Janssen-Cilag Honoraria, Research Funding;Genesis Pharma Honoraria, Research Funding;Sanofi Honoraria, Research Funding. Cavo Takeda Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis Honoraria;Amgen Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other Travel Accommodations, Speakers Bureau;Janssen Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau;Sanofi Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;GlaxoSmithKline Consultancy, Honoraria;AbbVie Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squib Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Adaptive Biotechnologies Consultancy, Honoraria. Gay GSK Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies Membership on an entity's Board of Directors or advisory committees;Takeda Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides Membership on an entity's Board of Directors or advisory committees;Bluebird bio Membership on an entity's Board of Directors or advisory committees. Katodritou GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi Honoraria, Research Funding. Merante EMN Italy Medical Monitor Research Funding. Manousou Health Data Specialists Current Employment. Sonneveld Karyopharm Consultancy, Honoraria, Research Funding;Janssen Consultancy, Honoraria, Research Funding;Celgene/BMS Consultancy, Honoraria, Research Funding;SkylineDx Honoraria, Research Funding;Takeda Consultancy, Honoraria, Research Funding;Amgen Consultancy, Honoraria, Research Funding. Terpos GSK Honoraria, Research Funding;Celgene Consultancy, Honoraria, Research Funding;Genesis Consultancy, Honoraria, Research Funding;Novartis Honoraria;Janssen-Cilag Consultancy, Honoraria, Research Funding;Amgen Consultancy, Honoraria, Research Funding;BMS Honoraria;Takeda Consultancy, Honoraria, Research Funding;Sanofi Consultancy, Honoraria, Research Funding.