Optimizing BCMA-Directed Sequencing in Multiple Myeloma Therapy: Ajai Chari, MD

The recent FDA approval of teclistamab (Tecvayli) in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro), both from Janssen Biotech, Inc, marks a significant shift in treating relapsed or refractory multiple myeloma (R/R MM), potentially as early as the second line. However, as Ajai Chari, MD, professor of medicine and director, Multiple Myeloma Program, at University of California, San Francisco, points out in this interview with The American Journal of Managed Care^®, the rapidly evolving treatment landscape raises critical questions about how trial results translate to modern clinical practice.

The MajesTEC-3 trial (NCT05083169), which supports this approval, launched in 2021 when the use of T-cell redirection was less common in early relapse. A key consideration for today’s clinicians is that MajesTEC-3 excluded patients who were refractory to anti-CD38 therapy, Chari explained. In a real-world setting where daratumumab is increasingly used frontline (eg, the MAIA study [NCT02252172]), many patients arrive at their first relapse already daratumumab-refractory. For these patients, the MajesTEC-3 results may not directly apply; instead, monotherapy or other strategies—supported by data from the MajesTEC-9 trial (NCT05572515) in double-refractory populations—may be more appropriate. The true target patient for this new combination includes those who are CD38-exposed but not refractory, such as posttransplant patients who discontinued daratumumab maintenance after 2 years. Chari emphasizes that despite these nuances, clinicians should prioritize using the most effective products early rather than “saving” them, due to the high risk of patient attrition.

Regarding the sequencing of B-cell maturation antigen (BCMA)–directed therapies, clinical evidence suggests that prior BCMA exposure may compromise the durability of subsequent treatments. Although response rates may remain similar, multiple data sets indicate that progression-free survival is often reduced when a patient has previously received a BCMA-targeting agent. However, Chari cautions that current data may be skewed; the patients transitioning between BCMA therapies in these studies often represent the “worst of the worst” cases, with highly aggressive disease or weakened immune systems.

As the field navigates this “steep learning curve,” the focus is shifting toward optimal dosing and duration to preserve T-cell fitness. Ultimately, the availability of several phase 3 studies for BCMA therapies allows clinicians the “luxury” of tailoring combinations to specific patient characteristics, ensuring the right mechanism of action is used at the right time. With data continuing to emerge, the landscape represents an area of active investigation.

In this first clip of our recent discussion with Chari, he addresses key questions about how emerging immunotherapies are being sequenced in MM treatment. Specifically, he discusses how the results of the MajesTEC-3 trial may translate to a real-world second-line population increasingly exposed to frontline daratumumab and earlier use of BCMA-directed CAR T-cell therapies. He also examines the ongoing debate over whether prior exposure to T-cell–engaging therapies, including bispecific antibodies, may affect T-cell fitness and influence the effectiveness of subsequent cellular therapies, and how emerging evidence is shaping treatment sequencing decisions in clinical practice.