Cilta-Cel Efficacy and Safety in Patients with Progressive Multiple Myeloma after Exposure to Non-Cellular Anti-BCMA Immunotherapy

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy

Report of consensus panel 5 from the 11th international workshop on Waldenstrom's macroglobulinemia on COVID-19 prophylaxis and management.

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.

Report of Consensus Panel 5 from the 11th International Workshop on Waldenstrom's Macroglobulinemia on COVID-19 Prophylaxis and Management

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11;held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2;thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for pre-exposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Co-administration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza and S. pneumoniae.

Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

Severity of Covid-19 Clinical Outcomes and Mortality in Multiple Myeloma Patients over Year 1 of the Pandemic

Introduction In the first weeks of the Covid-19 pandemic when healthcare systems in many areas were overstretched, we documented that hospital mortality in multiple myeloma (MM) patients infected by Sars-Cov-2 was 50% higher than in age matched Covid-19 patients without cancer. In the following months, the pressure on healthcare systems in Spain continued although it did not reach the extreme levels of the first weeks of the pandemic. In this study, we proposed to determine if the severity of Covid-19 outcomes in MM patients has changed over the first year of the pandemic. Patients and methods The Spanish MM Collaborative Group (Pethema-GEM) conducted a survey at national level on plasma cell disorder patients infected by SARS-Cov-2 between March 2020 and February 2021. Sixty-six (69%) out of 96 contacted healthcare centers, from all 17 regions in Spain, reported 502 patients. Data on Covid-19 acute and post-acute phase outcomes (hospitalization, oxygen requirements, severity of symptoms and mortality) were reported first in May 2020 (Martinez-Lopez et al, BCJ 2021) and updated in February 2021. In this study, we compared outcome occurrence between two study periods: P1, a period of extreme stress for the healthcare system in Spain, from March to mid-June 2020;and a second period, P2, up to mid-February 2021 with a sustained but lower burden on the national health care system. Results Among the 451 patients with plasma cell disorders and a Sars-Cov-2 infection documented with an rRT-PCR positive test, 377 (84%) were MM patients, 15 SMM (3%), 40 MGUS (9%) and 19 amyloidosis (4%). The number of MM weekly reported cases was 57% (95%CI, 48-65) lower in P2 (188 cases in 35 weeks) compared to P1 (189 cases in 15 weeks), p<0.001. The mean (SD) age and the proportion of men did not differ between P1 and P2, respectively 69.8 (10.9) vs 68.6 (11.0) years, p=0.6, and 53.3% vs 59.6%, p=0.2. MM patients with active or progressive disease at time of Covid-19 diagnosis were 24% in P1 and 34% in P2, p=0.05;patients on active treatment were more frequent in P1, 89%, than in P2, 79%, p=0.01. MM treatment was withheld in 78% and 82% of patients, p=0.4. Covid-19 treatment changed over time: MM inpatients received more remdesivir and corticoids in the second period (3% vs 31% p<0.001, and 49% vs 73%, p<0.001, respectively). In P1, 90% of the reported MM patients were hospitalized compared to 71% in P2, p<0.001. Thirty-one and 41% of patients did not require oxygen support during P1 and P2, respectively;non-invasive ventilation in 19% and 14%, and mechanical ventilation in 7% and 8%, p=0.12. Overall, acute clinical Covid-19 severity was reduced from P1 to P2: 75% to 51%, p<0.001: moderate/severe pneumonia was reduced from 68% to 36%, p<0.001 but severe distress syndrome increased from 7% to 15%, p=0.03. However, mortality in all reported patients was 30.7% in P1 vs 26.1% in P2, p=0.3;and no differences in mortality were observed in hospitalized patients, 32.2% in P1 and 35.3% in P2, p=0.6. We performed a multivariable adjustment with the predictors identified in our previous study (BCJ 2021) and confirmed that inpatient mortality was similar in both study periods, odds ratio (OR) 0.99 (95%CI 0.59-1.66). Independently of the study period, an increased mortality was observed in men (OR 1.81, 1.08-3.05), patients over 65 (OR 2.40, 1.33-4.36), and patients with active or progressive disease (OR 2.12, 1.24-3.62). The severity of Covid-19 clinical outcomes -besides mortality, was associated with increased age but not with active or progressive disease. Conclusions Although COVID-19 clinical severity has decreased over the first year of the pandemic in multiple myeloma patients, mortality remains high with no change between the initial weeks of the pandemic and the following months. Prevention and vaccination strategies should be strengthened in this vulnerable population, particularly in patients with active or progressive disease at time of Covid-19 diagnosis. Disclosures: Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfi er: Consultancy;Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: 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;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: 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;Bluebird bio: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria. López-Muñoz: Amgen: Consultancy. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Other: Support for attending meetings and/or travel;Mundipharma: Consultancy;Bluebird: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Consultancy, Honoraria, Speakers Bureau;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Lahuerta: Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy;Celgene: Other: Travel accomodations and expenses. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.

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.