New T-cell–directing approaches in multiple myeloma (MM), including chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) are effective, but mechanisms of resistance and lack of durable responses remain a challenge. New research indicates that baseline soluble B-cell maturation antigen (sBCMA) levels, disease burden, and TCE dose intensity are all important factors that determine responses to TCE BCMA therapies. Holly Lee, MD, clinical investigator at the University of Calgary in Canada, and colleagues published these critical insights for optimizing therapeutic strategies to overcome specific high-risk features and primary anti-BCMA TCE refractoriness in Blood.1
Senior investigator Nizar J. Bahlis, MD, associate professor at the University of Calgary, explained that the investigators used a preclinical model to determine how variable factors collectively affect the efficacy of anti-BCMA TCE in MM. The researchers first analyzed 163 patients treated with the anti-BCMA TCE teclistamab and confirmed the association between elevated baseline sBCMA (>400 ng/mL) and refractoriness. They confirmed, as shown by others,2 that gamma secretase complex mediates BCMA shedding, thereby reducing its surface expression on MM cells and generating high serum levels of sBCMA, which act as a sink and block the ability of TCE to target myeloma cells.
“The sink effect of sBCMA did not necessarily surprise us,” Dr. Bahlis said. “However, the collective dynamics of sBCMA with other clinical variables (surface antigen BCMA density, absolute T-cell count, T-cell fitness, TCE dose, and effector-to-target ratio) and how they influenced the efficacy of anti-BCMA TCEs was previously unknown to us. In particular, we were able to show that favorably skewing the other variables may overcome or reduce the negative effect of sBCMA.”
The observation that multiple factors can modulate the sink effect led Dr. Bahlis to recommend consideration of these collectively when evaluating the impact of sBCMA on the efficacy of anti-BCMA TCEs. The anti-BCMA TCE clinical studies emphasize the relevance of adaptive and adequate dosing of anti-BCMA TCE to overcome the sink effect of the high levels of sBCMA, which frequently occur in patients with high disease burdens. “We showed that higher TCE dosing does partially overcome the sBCMA sink effect, particularly in the context of high effector-to-target ratio,” Dr. Bahlis said.
The findings point to several additional strategies to reduce the effect of the sBCMA sink. “In a patient with high disease burden and high sBCMA (>400 ng/mL),” Dr. Bahlis said, “clinicians should consider one of the following options: 1) debulking therapies (when feasible) to help reduce disease burden prior to initiating anti-BCMA TCEs; 2) combination therapies (such as anti-CD38 antibodies) or with non-BCMA-targeting TCE such as talquetamab (as in the REDIRECT clinical trial) to help reduce disease burden; 3) using gamma secretase inhibitors to reduce BCMA shedding and augment surface antigen density (currently an investigational approach being studied in clinical trials); and 4) using combination therapies with immunomodulatory imide drugs and cereblon E3 ligase modulators, molecules that expand T cells and hence favorably skew the effector-to-target ratio.”
Dr. Bahlis explained that the investigators were surprised to discover that anti-BCMA CAR T cells were less directly influenced by high sBCMA levels than were TCE. Target binders in CAR T cells are typically designed to have a low binding affinity and short dissociation constant off rate to enhance the serial killing of target cells and minimize T-cell exhaustion. Dr. Bahlis suspected that this reduced affinity and avidity of the CAR-T BCMA binders relative to TCE account for the difference in vulnerability to high sBCMA levels.
The authors did not discuss limitations to their study.
Any conflicts of interest declared by the authors can be found in the original article.
References
- Lee H, Durante M, Skerget S, et al. Impact of soluble BCMA and non-T cell factors on refractoriness to BCMA targeting T cell engagers in multiple myeloma [published online ahead of print, 2024 September 25]. Blood. doi: 10.1182/blood.2024026212.
- Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585-1597.
