In the ever-evolving treatment landscape of multiple myeloma (MM), T-cell redirection therapies have changed the treatment paradigm and are rapidly moving from clinical trials to the commercial setting. In the last two years, the US Food and Drug Administration (FDA) has approved two BCMA-targeting chimeric antigen receptor (CAR) T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) and a bispecific BCMA-directed CD3 T-cell engager (teclistamab-cqyv), which are all indicated for the treatment of adult patients with relapsed or refractory MM after four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
Talquetamab, a first-in-class bispecific T-cell engager antibody targeting GPRC5D and CD3, has demonstrated robust efficacy and a manageable safety profile in patients with heavily pretreated relapsed or refractory MM. It received a Breakthrough Therapy Designation from the FDA in June 2022. The Biologics License Application for talquetamab was then submitted to the FDA in December 2022. The application is under review and hopefully will receive accelerated approval. As T-cell redirection therapies become commonplace in the treatment of MM, practical considerations for the use of these therapies are important, particularly patient selection based on disease biology and toxicity profiles. Here, we highlight the most up-to-date efficacy and safety data for talquetamab and consider key practical points for the use of talquetamab in relapsed or refractory MM.
In the phase I/II MonumenTAL-1 study published in the New England Journal of Medicine, the two recommended phase II subcutaneous doses of talquetamab (405-μg/kg weekly and 800-μg/kg every other week) demonstrated similar efficacy and safety. In phase I, of the 30 patients who had received the 405-μg dose level and of the 44 patients who had received the 800-μg dose level, responses (partial response or better) were observed in 70% at a median follow-up of 11.7 months and 64% at a median follow-up of 4.2 months, respectively.1 Notably, responses were also seen at both dose levels among patients with triple-class refractory disease (65% and 70% at the 405-μg and 800-μg dose levels, respectively) and penta-drug refractory disease (83% and 78% at the 405-μg and 800-μg dose levels, respectively). Updated results from a combined analysis of 288 patients treated at the recommended phase II doses in both phase I and II of MonumenTAL-1 were presented at the 64th ASH Annual Meeting and Exposition.2 Patients had a median of five prior lines of therapy, and about one-third of patients had high-risk cytogenetics. Most patients were refractory to their last line of therapy, including about 70% who were triple-class refractory. Remarkably, in this heavily pretreated population, the overall response rate in both dosage groups was about 73%, with comparable responses seen in triple-class refractory and penta-drug refractory patients. Moreover, talquetamab demonstrated rapid and durable responses, with a median time to response of 1.2 months. Among patients who achieved a complete response or better, the median duration of response was not reached.
The most common adverse events (AEs) reported in the combined phase I and II analysis of MonumenTAL-1 included cytokine release syndrome (CRS), skin-related events, nail-related events, and dysgeusia.2 Overall, CRS occurred in 79% and 72% of patients in the 400-μg/kg weekly and 800-μg per kilogram every other week dosing groups, respectively, with the majority of CRS events being grade 1 or 2. Skin- and nail-related events were reported in 56% and 52% of patients in the 400-μg dose level group, respectively, and 68% and 43% of patients in the 800-μg dose level group. All but one skin- and nail-related AEs were grade 1 or 2 and well-managed with topical treatments such as glucocorticoids. Taste alteration is a unique toxicity of talquetamab, with dysgeusia occurring in about 47% of patients at both dose levels. Additional oral toxicities such as dry mouth occurred in 25% and 37% of patients at the 400-μg and 800-μg dose levels, respectively. Moreover, 40% and 32% of patients experienced weight loss at the 400-μg and 800-μg dose levels, respectively, likely attributable in part due to difficulties with oral intake secondary to dysgeusia and dry mouth. Although the pathophysiology of oral toxicities such as dysgeusia due to talquetamab has yet to be determined, management with supportive care and reduction of dose intensity appear to improve severity of symptoms, as only about 5% of patients discontinued the study due to AEs. Hematologic toxicities such as cytopenias were generally grade 1 or 2 and limited to the first few cycles.
The infection profile of this agent compares favorably with T-cell redirection efforts targeting BCMA, as grade 3/4 infections occurred in less than 17% of patients. Despite enrollment in the era of COVID-19, grade 3 and higher COVID-19 complications or deaths were very rare, and only approximately 10% of patients received intravenous immunoglobulin support. In practice, the off-the-shelf availability of bispecific T-cell engager therapies remains an advantage compared with CAR T-cell therapies, which require a prolonged manufacturing time, when considering a clinical scenario in which a patient is exhibiting rapid disease progression and requires prompt initiation of therapy.
In terms of dosing, based on currently available data, bispecific T-cell engager therapies such as talquetamab are continued until progression, in contrast to CAR T-cell therapies, which are a one-time treatment. As more T-cell redirection therapies become available for the treatment of MM, disease characteristics are an important consideration when extrapolating efficacy data. For example, similar to other T-cell redirection therapies, current data from MonumenTAL-1 showed lower response rates in patients with extramedullary disease.1 Of 51 patients with previous exposure to T-cell redirection therapies, 63% achieved a response to talquetamab in MonumenTAL-1, suggesting a potential to induce immune responses with different T-cell engager targets despite previous exposure to T-cell redirection therapies, although progression-free survival data are needed.2 In regard to AE management, given the CRS associated with T-cell engager therapies, hospital admission for AE monitoring is currently the standard of care during initial step-up dosing with agents such as talquetamab.
Talquetamab is an ideal candidate for combination strategies due to its efficacy and unique adverse effect profile that does not overlap with current antimyeloma therapies. Multiple early-phase studies combining talquetamab with standard myeloma therapies (TRIMM-2 [NCT04108195], MonumenTAL-2 [NCT0505009]), with teclistamab (RedirecTT-1 [NCT04586426]), as well as with a PD-1 inhibitor (TRIMM-3 [NCT05338775]) are currently underway. Additionally, the confirmatory study that would lead to full registration is MonumenTAL-3 (NCT05455320), a randomized, phase III study combining talquetamab with daratumumab and pomalidomide in comparison with a control arm for patients who have received at least one prior therapy. The remarkable efficacy and manageable safety profile of talquetamab seen in the phase I/II MonumenTAL-1 clinical trial is very encouraging, and we are hopeful talquetamab will become another option in the growing arena of T-cell redirection therapies in MM.
Larysa Sanchez, MD, is an Assistant Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of Geriatrics in Myeloma at the Center of Excellence for Multiple Myeloma.
Donna Catamero, ANP-BC, OCN, is the Associate Director of Myeloma Research at the Icahn School of Medicine at Mount Sinai.
Ajai Chari, MD, is a Professor of Medicine, the Director of Clinical Research in the Multiple Myeloma Program, and the Associate Director of Clinical Research at the Mount Sinai Cancer Clinical Trials Office.
- Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387:2232-2244. doi:10.1056/NEJMoa2204591
- Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Abstract #157. Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana.