COVID-19 AND MYELOMA

The disease- and treatment-induced immunosuppression in MM accounts for a two-fold higher risk for infection with the SARS-CoV-2 virus, an increased risk for a prolonged, severe symptomatic disease, and an increased mortality. Most pts are aware of these risks and show a higher compliance with vaccination recommendations compared to the general population. Several studies revealed differences in the humoral and cellular immune response between pts with MGUS, SMM, and MM, with normal median antibody titers in MGUS, moderately impaired response in SMM, and significantly reduced antibody response in MM, albeit with a wide variation in titers between individual pts. Pts with active, poorly controlled disease and those exposed to CD38 and BCMA-targeting treatments frequently show no or reduced SARS-CoV-2 antibody responses. The EMN issued a consensus that MM pts should ideally be vaccinated before onset of active disease and/or during periods of well controlled disease. A third dose should be administered after an interval of approximately 6 months, and early data in immunocompromised pts show a vaccination response in several previously poorly responding pts after a forth dose. An open question pertains to the role of the interrelationship between the innate, humoral and cellular immune system. Neutralizing antibodies provide the best proxy for protection, although specific thresholds associated with protection against infection are unlikely to be established given the many factors associated with infection control. Antibody titers decline with time from vaccination and more so in vaccinated pts compared to those who have been infected and vaccinated, mandating booster shots in time intervals that need to be established. Pts may present without measurable antibody titers but with detectable cellular immunity or vice versa, although in most reports, correlations between antibody and cellular response were noted. Data suggest that SARSCoV- 2 specific memory B and T cells persist for prolonged periods. One of the threads to patient protection is the substantial mutational activity of the SARS-CoV-2 virus with reduced neutralizing capacity of vaccine induced antibodies against recent variants of concern, particularly the omicron variant, posing vaccinated pts at risk for breakthrough infections. Recent research efforts resulted in new prophylactic treatments for pts with high risk for severe COVID-19 disease (Table 1) that have been shown to reduce the incidence of severe complications. .

Managing hematological cancer patients during the COVID-19 pandemic: an ESMO-EHA Interdisciplinary Expert Consensus.

BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.

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

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.