sBCMA and MTV prediction of outcome for CART

In this issue of Blood, Freeman et al¹ identified novel biomarkers that quantify the tumor burden that affects the outcome of chimeric antigen receptor T-cell (CAR-T) therapy, approved for the treatment of patients with relapsed/refractory lymphoid malignancies. In multiple myeloma (MM), 2 CAR-T-cell products, targeting B-cell maturation antigen (BCMA), are commercially available for use in patients with MM who have received 1 or 2 lines of prior therapy. BCMA-directed CAR-T cells and bispecific antibodies have produced unprecedented response rates in patient populations with advanced MM.

However, one-third of patients receiving bispecifics and between 5% and 20% of patients receiving CAR-T cells are refractory to treatment. Ultimately, all patients relapse, and a cure has yet to be achieved.^2,3 The administration of CAR-T-cell products is complex and may be associated with significant toxicity at high costs. Therefore, the development of biomarkers that can predict the efficacy and toxicity of CAR-T-cell engaging therapy, particularly CAR-T-cell therapy, is urgently needed.

The efficacy of all cell-based immunotherapies, including CAR-T cells, but also allogeneic stem cell transplantation, is constrained by the presence of a high tumor burden. In addition, those with rapidly progressing tumors exhibit increased toxicity.^4,5 Classic markers of disease burden, such as the M-protein or bone marrow infiltration, are often inadequate for accurately assessing tumor load in patients with advanced MM, who frequently present with nonsecretory or oligosecretory disease. Furthermore, in such patients, the disease may be located partially or exclusively outside the marrow, which is referred to as extramedullary disease (EMD). In this retrospective study, Freeman et al evaluated 183 patients with relapsed/refractory MM using serum-based biomarkers and an advanced imaging technology to assess baseline tumor load in patients with relapsed/refractory MM and to correlate the findings with the toxicity and safety profiles of consecutive BCMA-directed CAR-T-cell therapy. They assessed serum levels of cleaved soluble BCMA (sBCMA), a circulating form of the BCMA receptor, at different time points before and after CAR-T-cell therapy. Baseline whole body 18-fludeoxyglucose (FDG) positron emission tomography (FDG-PET) was performed with a median time from imaging to infusion of cells of −16 days to assess the metabolic tumor volume (MTV). Pretreatment sBCMA correlated with bone marrow infiltration. Likewise, high sBCMA and high MTV, as determined by FDG-PET imaging, were predictive of inferior outcomes, including shorter progression-free survival (PFS) and overall survival (OS), as well as increased cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome toxicities. However, the correlation between the 2 measures was weak. The discordant results with low sBCMA and high MTV were indicative of low or even absent BCMA expression on the tumor cells and a suboptimal response to treatment. Notably, day 90 postinfusion sBCMA above the median was correlated with EMD before treatment.

In a recent publication, Lee et al⁶ described increased sBCMA as a potential predictor of primary refractoriness to anti-BCMA therapies, suggesting that alterations in the effector-to-target ratio may be a contributing factor. The addition of >400 ng/mL of recombinant sBCMA resulted in a reduction in BCMA-directed T-cell engaging antibodies (TCE) binding on MM cells. Levels of >1000 ng/mL were observed to completely abrogate TCE binding, irrespective of the density level of surface BCMA. In contrast to TCEs, CAR-T cells exhibit higher binding affinities to the target antigen and induce serial killing of cells expressing the target antigen at much lower densities. This may explain why increasing concentrations of sBCMA had little effect on the cytolytic activity of CAR-T cells in this investigation, in contrast to the effects observed with bispecific antibodies. Fandrei et al⁷ reported that in patients with increased sBCMA levels on the day of CAR-T-cell infusion, there was a shorter PFS, but the increased sBCMA levels did not affect CAR-T-cell expansion. The role of the host T-cell repertoire, before the initiation of therapy with T-cell–engaging therapies, has been explored by Cortes-Selva et al.⁸ A lower proportion of immunosuppressive regulatory T-cells, T-cells expressing coinhibitory receptors, and soluble BCMA, as well as a T-cell profile mediating increased cytolytic potential were predominantly found in the responders in the teclistamab-treated cohort. Notably, neither the baseline bone marrow BCMA expression nor the BCMA-receptor density was associated with the clinical response to teclistamab. Therefore, it is evident that increased baseline immune fitness is advantageous, and immune suppression and T-cell dysfunction must be avoided for successful T-cell–engaging therapies.

What measures can be taken to improve the prognosis of patients with MM and a high tumor load? Modifying the dosage of TCE or of CAR-T cells targeting BCMA in patients with high sBCMA to augment the effector-to-target ratio and the treatment efficacy may represent a viable strategy. As an alternative, TCE or CAR-T cells with other targets (eg, G protein-coupled receptor, class C group 5 member D [GPRC5D]) could be used. Notably, elevated sBCMA did not impede the cytotoxic activity of talquetamab, a GPRC5D-directed bispecific antibody. An additional strategy could be the use of γ secretase inhibitors (GSIs) to circumvent receptor shedding and to augment BCMA density on the MM cell surface. Indeed, preliminary findings suggest that GSIs enhance the cytotoxic capacity of BCMA-directed TCE and BCMA-directed CAR-T cells in patients with elevated sBCMA.⁹ The most promising strategy to enhance tumor control and elevate the safety of BCMA-directed CAR-T-cell therapy is to implement efficacious bridging therapy to induce substantial tumor debulking, thereby improving response rate, complete remission rate, PFS, and OS.⁷ Moreover, this approach has the potential to mitigate the toxicity associated with CAR-T-cell therapy. Recently, it has been demonstrated that bridging therapy with bispecific antibodies is both efficacious and safe, achieving overall response rates (ORRs) of 100%. This represents a markedly superior outcome compared with that achieved by combination chemotherapies, including monoclonal antibodies, which result in ORRs of only 40%.⁷ Taken together, Freeman et al highlight the potential utility of sBCMA and MTV in facilitating more personalized treatment strategies for managing patients with relapsed/refractory MM eligible for BCMA-directed CAR-T therapy, with the ultimate goals of increasing the efficacy of CAR-T treatment, reducing toxicity, and enhancing patient outcomes in myeloma care.

Conflict-of-interest disclosure: The authors declare no competing financial interests.