Talquetamab, a GPRC5D-directed bispecific antibody, is demonstrating promising efficacy in patients with relapsed/refractory multiple myeloma (RRMM), including those who have previously failed BCMA-targeted therapies. Data from the phase 1/2 MonumenTAL-1 study (NCT04634552) and real-world clinical experience suggest that talquetamab offers a valuable treatment option, particularly in the context of increasingly aggressive upfront regimens and the need for novel later-line therapies.
Efficacy in BCMA-Exposed Patients
Notably, talquetamab has shown significant activity in patients who have progressed after prior BCMA-directed T-cell redirection therapy. "One thing which strikes me is the response targeting GPRC5D after targeting B-cell maturation antigen one after the other... two-thirds of those patients with prior T-cell redirection therapy did respond to talquetamab," said Peter Georges, MD. This is particularly relevant as BCMA-targeted therapies become more prevalent in earlier lines of treatment.
Eric Bravin, MD, highlighted the response rates observed even in high-risk subgroups: "There was a group of patients with at least 1 extramedullary plasmacytoma only had a response rate of over 40%, but that group with prior generations of drugs may have single digit or 10% to 15% response rates. Even those numbers, relatively speaking, are good."
Managing Tolerability and Toxicity
While talquetamab offers significant clinical benefit, it is associated with unique toxicities that require careful management. Dysgeusia, leading to weight loss, and skin toxicities are among the most commonly reported adverse events. Omar Nadeem, MD, emphasized the importance of dose modifications and supportive care to mitigate these effects. "Dose modifications and dose holds are critical, especially for people who are in response, and then being more preventative about some of these known toxicities of this target is important to try to get people through it."
The effects of talquetamab can linger, requiring extended dose holds. "Because this binds the target and continues to deliver the T cell response to those areas, which then leads to the inflammation and persistent symptoms, it can linger for patients who have had severe toxicity," Dr. Nadeem explained.
The Need for Predictive Biomarkers
A key challenge in the field is the lack of reliable biomarkers to predict response to T-cell redirecting therapies. "We have patients who go on to these therapies that we're giving and hoping that they respond. There's no biomarker to guide us," Dr. Nadeem noted. T-cell exhaustion and BCMA resistance are potential mechanisms of treatment failure, but routine clinical assays are not yet available to assess these factors.
Adverse Events and Response Correlation
Interestingly, early clinical experience suggests a potential correlation between the severity of adverse events and treatment response. "In my experience so far, yes, patients who have had the most profound AEs have been in a complete response, many times with undetectable light chains," Dr. Nadeem stated. This observation warrants further investigation to determine if specific toxicity profiles can serve as a surrogate marker for efficacy.
Optimizing Dosing Strategies
Flexibility in dosing schedules may be necessary to manage toxicity without compromising efficacy. While strict adherence to the recommended dosing schedule is generally advised, Dr. Nadeem indicated that some deviations may be acceptable, particularly in patients who are responding to treatment. Prophylactic tocilizumab and dexamethasone are being studied and may help mitigate cytokine release syndrome (CRS) and other toxicities, potentially allowing for more consistent dosing.
