Inclusion criteria of currently enrolling T‐cell engaging trials in multiple myeloma: Should we be focusing on lines of prior therapy?

The advent of novel immune-based treatments such as bispecific/trispecific T-cell engagers and chimeric antigen receptor T-cell (CAR-T) therapy has changed the landscape of treatment for patients with relapsed multiple myeloma (MM).1 Currently, there are two FDA approved CAR-T cell products for the treatment of multiple myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) respectively, both significantly prolonging remissions for patients compared to historical outcomes.2 There is now one bispecific therapy currently approved for patients with MM, teclistamab,3 and other products are in various stages of development.1 However, with the broad use of multiple active agents early in the disease course, there are patients who experience progressive disease and hence become refractory to multiple classes of drugs despite having undergone only a limited number of prior ‘lines of treatment’.4, 5 The current FDA labels for teclistamab, cilta-cel and ide-cel require four prior lines of therapy and exposure to three classes to drugs (anti-CD-38, immunomodulatory drugs and proteasome inhibitors). This limits use for patients whose disease become refractory to these classes of drugs within one or two prior lines of therapy. The FDA label for these drugs is in part because patients enrolled in the trials that led to approval of these drugs required a minimum number of lines of therapy. We aimed to investigate what enrollment criteria are for currently enrolling trials of novel immune-based treatments for MM and whether they specify a minimum number of lines of therapy, or whether they allow for patients with class refractoriness or exposure to be enrolled regardless of prior lines of therapy. A search on clinicaltrials.gov (search listed in supplement) was conducted for all clinical trials enrolling patients in the United States with MM that were currently enrolling or awaiting activation. This search was conducted by GRM on 3 December 2022 and verified by RK. Among these clinical trials, those that prospectively evaluated novel immune-based treatments such as T-cell directing therapies (bispecific, trispecifics, CAR-T), that either focused exclusively on MM or had a clearly defined cohort of patients with MM were included. All non-interventional studies were excluded. In situations where information was not available on clinicaltrials.gov, the sponsor was emailed to inquire about these criteria. A total of 378 studies were identified of which 42 met the inclusion criteria (all studies listed in supplement). Table 1 lists the characteristics of these studies. Among these 42 studies, 25 assessed bispecifics/trispecifics and 17 assessed cellular therapies. Excluding registrational trials targeting earlier lines of therapies, 18 of 38 studies (47.4%) required three or more prior lines of therapy with or without additional criteria for class exposure/refractoriness. Among all 42 studies, five (11.9%) mandated a number of prior lines of therapy without regard to class refractoriness/exposure, 25 (59.5%) studies mandated both a number of prior lines of therapy and class refractoriness/exposure and 12 studies (28.6%) mandated refractoriness/exposure without regards to number of prior lines. We demonstrate that among currently enrolling novel immune-based treatment trials in MM in the United States, nearly half have arbitrary cut-offs that require three or more lines of therapy regardless of class refractoriness, and most studies require a pre-specified lines of therapy as part of enrollment criteria. This may prevent access to those trials for patients that become class refractory with less therapies, and furthermore decreases the likelihood that future FDA labels will allow for patients with lesser line of therapies. European regulatory approval and reimbursement also strictly follow these labels, and inclusion of a minimum number of line of therapies in the approval label may prevent access for some patients. Given that class refractoriness has been shown to be a much more important determinant of prognosis than lines of therapy in recent studies,6-8 we urge these currently enrolling clinical trials to amend their protocols and allow for broader enrollment of patients that may benefit most from these treatments. As these inclusion criteria requirements may be due to regulations by the FDA and European authorities, greater regulatory flexibility in these inclusion criteria may allow for more patients to receive these treatments in the future. GRM and LJC conceived the idea. GRM and RK collected the data. GRM analysed the data. GRM wrote first draft of paper. GRM, RK and LCJ revised manuscript and approved final draft. None. GRM and RK declare no conflict of interest. LJC reports consulting with BMS, Janssen, Amgen, Sanofi, Adaptive and research support from Janssen, BMS, Amgen. N/A. N/A. N/A. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.