Zhang, Xinke

ABSTRACT Introduction A novel therapy for heavily pretreated triple‐class–exposed multiple myeloma (TCE MM) is B‐cell maturation antigen (BCMA)‐targeted immunotherapy. While the number of TCE+BCMA‐exposed patients is growing, real‐world data for this group are limited. Methods We present real‐world data from patients with TCE+BCMA‐exposed MM who initiated a subsequent line of therapy (LOT) using a US‐based claims database, Komodo's Healthcare Map. Results We identified 656 TCE+BCMA‐exposed patients; mean age was 66.5 years. Time from MM diagnosis to index was 5.4 years; mean number of prior LOTs was 5.9. The most prevalent prior therapy received within each drug class was daratumumab (98.5%), pomalidomide (86.0%), carfilzomib (85.8%) and belantamab mafodotin (74.5%). A total of 137 different subsequent treatment regimens were observed following TCE+BCMA exposure; the most common regimen was teclistamab (10.4%). The top three targeted agents within the subsequent regimen were carfilzomib (20.2%), pomalidomide (20.1%) and bortezomib (16.6%). Among this TCE+BCMA‐exposed population who received subsequent treatment, the median time to next treatment or death was 6.8 (95% CI, 6.1–7.5) months; time to treatment discontinuation or death was 3.5 (95% CI, 3.2–3.7) months. Conclusion This first real‐world analysis of patients with heavily pretreated TCE+BCMA‐exposed MM shows poor clinical outcomes, frequent therapy retreatment and no standard‐of‐care, highlighting the need for novel treatments. Clinical Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

Introduction Relapsed/refractory multiple myeloma (RRMM) is a hematologic cancer associated with no current widely-accepted cure, cycles of relapse and remission, treatment resistance, and high morbidity and mortality, which necessitate new treatments and therapeutic targets. 1-3 Innovative therapies that target BCMA, CD38, GPRC5D, FcRH5, and others in the RRMM development pipeline are recently approved or under investigation, but real-world evidence on clinician perceptions of emerging trends and unmet needs remains limited. A Delphi panel was conducted with US clinicians to evaluate the level of unmet need and treatment decisions among patients with RRMM who are triple-class-exposed (TCE). Methods This double-blinded study consisted of two phases: a web survey (phase 1) and a Delphi panel (phase 2). A targeted literature review was conducted first to understand unmet needs and treatment decisions associated with management of RRMM in the US and inform the development of primary research materials. The web survey was completed by 21 US clinicians. Survey findings were then used to inform the phase 2 Delphi panel, a systematic, validated approach to gain consensus. This consisted of two iterative rounds of a question answered by nine experts selected from participants in the web survey. Consensus on a question was defined as at least 70% agreement. The double-blinded panel was conducted via the Microsoft Teams platform, and poll questions were administered through Vevox. Responses were blinded to preserve respondents' anonymity and participants were also blinded to the study sponsor. Results Overall, consensus was reached that despite recent improvement in treatment landscape, there is still a high level of unmet need for patients with RRMM who are TCE (89% of participants). More specifically, consensus was reached (89%) that the top three areas of unmet need were treatment resistance, guidance on treatment sequencing, and novel mechanisms of action (MoAs) and targets (Figure 1). Unmet need is also particularly pronounced for certain patient subgroups, with 89% and 78% of participants agreeing that patients who are functionally high-risk and penta-refractory, respectively, experience the greatest unmet need. When asked about which novel therapies would be most promising for addressing the unmet needs, participants agreed that the top 4 therapeutic targets are GPCR5D (95%), BCMA (81%), FcRH5 (81%), and BCL-2 (81%). Various factors impact treatment choice and sequencing, with most participants (78%) agreeing that treatment history is the most influential factor impacting sequencing. The panel also agreed that prior toxicity (grade 3-4 AEs, 89%) and convenience of dosing frequency (78%), respectively, most impact dosing decisions. All agreed there is a need for resources to manage some AEs, particularly newer AEs (like skin and nail effects) of emerging treatments. Of the AEs identified in the survey as top drivers of treatment choice, participants reached consensus on two: neurotoxicity (e.g., ICANS) (89%) and infection (100%). Conclusions In this Delphi study, consensus was reached that a high level of unmet need remains for patients with RRMM, who are TCE with unmet need varying dependent on patient subgroup and treatment history. There was consensus that additional treatment choices with novel targets/MoAs are needed. Participants agreed that AEs, toxicity, infection, and treatment history impact treatment choice and sequencing, and considerations and challenges vary by subgroup. Overall, findings from this study support that there is a need for additional treatment options with novel MoAs/therapeutic targets that address priority unmet needs for patients with RRMM, who are TCE. References 1. Gonsalves W et al. The next generation of novel therapies for the management of relapsed multiple myeloma. Future Oncol (London, England). 2017;13(1):63-75. https://doi.org/10.2217/fon-2016-0200 2. Braunstein M et al. A new decade: novel immunotherapies on the horizon for relapsed/refractory multiple myeloma. Expert Rev Hematol. 2022;14(4):377-389. doi:10.1080/17474086.2021.1909469 3. Bruno AS et al. Recent real-world treatment patterns and outcomes in US patients with relapsed/refractory multiple myeloma. Expert Rev Hematol. 2020;13(9):1017-1025. doi:10.1080/17474086.2020.1800451

Introduction: Despite the development of advanced treatment options, multiple myeloma (MM) remains an incurable disease. Most MM patients relapse and require further treatments. B-cell maturation antigen (BCMA) targeted immunotherapy is a novel MM therapy class that is now available to heavily pre-treated relapse/refractory MM (R/R MM) patients, who were triple class exposed (TCE) to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. As BCMA therapies continue to be further utilized and become an integral part of MM treatment, the proportion of TCE patients who are also BCMA exposed (TCE+BCMA exposed) is expected to grow. However, the clinical outcomes of TCE+BCMA exposed RRMM patients have not been previously assessed. The objective of this study was to evaluate the real-world outcomes of TCE+BCMA exposed MM patients who started a subsequent LOT, describing their characteristics, treatment patterns, and clinical outcomes. Subgroups of penta-drug exposed (at least two PIs, at least two IMiDs, and at least one anti-CD38) patients, as well as White and African American patients were also evaluated as penta-drug exposure status and race were known to impact clinical outcomes. Methods: Adult patients with MM who were TCE+BCMA exposed and started a subsequent LOT starting from July 03, 2019 (when additional new treatment options became available) were selected from the Komodo Healthcare Map (a US claims dataset) and were followed until the earliest of death, last claim, or end of study period (December 31, 2022). Index date was defined as the start date of the subsequent LOT following TCE and BCMA exposure. Descriptive statistics were provided for patient characteristics and treatment patterns. Clinical outcomes including time to treatment discontinuation or death (TTD) and time to next treatment or death (TTNT) were estimated using the Kaplan-Meier method. Results: A total of 344 TCE+BCMA exposed patients, who received the next LOT were included in the study, including 152 (44.2%) patients who were penta-drug exposed before index, 57 (16.6%) African American, and 185 (53.8%) White patients. Key baseline demographic characteristics and treatment history for the overall group and the three subgroups are listed in Table 1. The mean (SD) and median number of prior LOTs for the overall group before index date were 5.7 (1.7) and 6.0, respectively. The most prevalent prior treatments before the index date for the overall group were daratumumab (99.1%), belantamab mafadotin (91.9%), pomalidomide (84.3%), carfilzomib (83.1 %), bortezomib (76.2%) and lenalidomide (72.1%). Excluding corticosteroids, the most frequently used index treatments (i.e., treatment used post TCE+BCMA exposure) were carfilzomib- (21.9%), bortezomib- (20.8%), pomalidomide- (18.3%), and belantamab mafadotin- (18.3%) based regimens. The median (95% confidence interval [CI]) TTD was 3.7 (3.3, 4.4) months, and the median (95% CI) TTNT was 6.4 (5.5, 7.6) months. TTD and TTNT estimates for the three subgroups are listed in Table 2. Conclusions: To our knowledge, this is the first real-world study of treatment patterns and outcomes for TCE+BCMA exposed MM patients who started a subsequent LOT. The findings showed that this group of heavily pretreated MM patients were often retreated with the same therapies or therapies in the same classes, as they have limited effective treatment options. TCE+BCMA exposed patients exhibited poor clinical outcomes, as demonstrated by the rapid treatment discontinuation and moving on to the next treatment shortly after initial treatment. Many patients were already penta-drug exposed, and they appear to have worse clinical outcomes than the overall patient group. A shorter TTD was observed, and a trend for shorter TTNT was observed among African American patients than White patients. The findings highlight the continued need for effective treatments for heavily treated MM patients and particularly those with poor outcomes.