More Info Needed to Establish Utility of MRD, SFLC Levels as Biomarkers in MM

Minimal residual disease (MRD) detection, through next-generation sequencing, and involved serum-free light chain (iSFLC) levels both had strong correlations with ability to predict progression-free survival (PFS) among individuals with multiple myeloma (MM) receiving anti–B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies, reports a study in Frontiers in Oncology.

“CAR T therapy targeted against BCMA in MM is a promising new treatment for MM with high and rapid clinical efficacy, even in multiple refractory patients, and has produced rapid responses. However, despite high and deep responses, most patients eventually relapse,” the authors wrote. “In light of this new treatment, novel predictors of PFS are needed.”

Their retrospective study analyzed data from 5 clinical trials at the University of California, San Francisco, between November 1, 2017, and February 26, 2020; data cutoff was August 27, 2020. Fifty-four consecutive patients were included in their final analysis, all of whom were treated with BCMA-directed CAR T therapy. Serological disease measures were made at 15 days post CAR T infusion and monthly thereafter; bone marrow biopsies were performed at 1, 3, 6, 12, 18, and 24 months; PET-CT scans were done from 3 to 6 months after CAR T infusion; and overall response was measured via International Myeloma Working Group (IMWG) uniform response criteria.

At baseline, serologically measurable disease was defined as serum M-protein of at least 0.5 g/dL or a SFLC measure of at least 100 mg/L.

Overall, 92.5% of the 54 patients had refractory disease, 48.1% relapsed following CAR T infusion, and 51.9% had going responses—all by data cutoff. Both those with relapsed disease and ongoing responses received a median 6 prior lines of therapy, but the relapsed cohort had a higher median iSFLC measure.

The median PFS for both groups was 12.7 months and the median overall survival (OS) was 25.2 months. Follow-up was a median 8.8 (range, 5.6-12.6) months.

Following CAR T infusion, iSFLC levels dropped faster than M-protein levels for those who responded to the treatment; however, these levels did converge between 3 and 6 months post infusion. In addition, drop in detectable M-protein did not correlate with PFS at 0.5 (P = .9), 1 (P = .8), and 3 (P = .5) months.

For this study, better than a partial response (PR) was defined according to IMWG criteria of 87%. This was seen in 52% of participants with at least a complete response (CR), 35% who had a very good PR/PR, and 13% who had less than a PR. PFS was also shown to be significantly different in those with at least a PR vs less than a PR (HR, 63.0; 95% CI, 13.9-285.0; P < .0001).

Additional study findings included the following:

• iSFLC levels remained nonelevated in 94% of patients by 1 month after CAR T initiation; this was up from 82% at the 15-day mark
• Nonelevated iSFLC levels at 15 days and 1 month after CAR T correlated with prolonged PFS vs patients with persistent high iSFLC levels
• MRD negativity at 10^-6 at any point had a positive correlation with prolonged PFS vs those with MRD negativity at 10^-5
• Prolonged PFS was seen in patients who achieved MRD at 10^-6 or less at 1 month vs MRD of at least 10^-6

The principal limitation to extrapolating these findings to a larger patient population, the authors noted, may be that all of the included participants had normal or near-normal kidney function. Individuals with impaired renal function in a real-world setting may not see similar results.

“For MM patients treated with BCMA CAR T therapy, achieving a nonelevated iSFLC as early as 15 days or 1 month, and MRD negativity with PET/CT negativity were strongly associated with a favorable PFS,” they wrote. “However, larger studies are needed to establish the role of these markers in relation to the conventional IMWG criteria for response assessment in MM patients on CAR T therapies.”

Reference

Wong SW, Shah N, Ledergor G, et al. Early dynamics and depth of response in multiple myeloma patients treated with BCMA CAR-T cells. Front Oncol. Published online December 6, 2021. doi:10.3389/fonc.2021.783703