Minimal Residual Disease Measured after Treatment with Bispecifics in Relapsed Multiple Myeloma: Experience from an Academic Medical Center
Authors: Blanco Alberto , Chari Ajai , Martin Thomas G , Arora Shagun , Chung Alfred , Kumar Anupama Deepa , Shah Nina , Wong Sandy W. , Takamatsu Hiroyuki , Martínez-López Joaquin , Wolf Jeffrey Lee 
Published: December 2024

Introduction
Bispecific T cell engagers (TCEs) have emerged as an appealing therapy for relapsed or refractory multiple myeloma (MM), achieving a high rate of deep and durable responses. In these patients, the role of minimal residual disease (MRD) has not yet been established, but it could have prognostic value as it has demonstrated in other settings. Additionally, some patients seem to maintain persistent responses even after halting treatment. MRD may help identify the patients who could benefit from this strategy.
Methods
Clinical records of 716 consecutive patients (pts) with MM at UCSF who had MRD assessment between November 2017 and May 2024 were reviewed. Of these, 31 pts had been treated with TCE, either in a clinical trial or with commercial supply. MRD was evaluated in bone marrow samples with the ClonoSEQ® assay. A cutoff of 10-6 was used to define negative MRD (MRD-). High-risk (HR) cytogenetics was defined as t(4;14), t(14;16), del17p, gain or amplification of 1q.
Results
Median age at the time of treatment was 66 years (interquartile range, IQR, 60-72). Over half of the pts had IgG MM (51.6%), followed by IgA (22.6%), light chain (22.6%) and non-secretory (3.2%). Cytogenetic analysis by FISH was available in 24 pts (77.4%) prior to treatment, showing HR disease in 17 (70.8%); 77.4% and 25.8% were triple-refractory and penta-refractory, respectively. Twenty-one had ISS evaluation prior to treatment: 33.3% / 57.1% / 9.5% for stages I, II and III. PET/CT was performed in 17 (54.8%), revealing extramedullary disease (EMD) in 5 pts (unknown EMD status in 14 cases). Median number of prior lines was 4 (range 1-13), 19.4% had received CAR-T previously, and 12.9% had been previously exposed to another TCE.
Twenty-three pts (74.2%) were enrolled in clinical trials (7 with teclistamab, Tec, 6 with talquetamab, Tal, and 10 with investigational agents). Twelve of these pts received TCE in combination with daratumumab and/or pomalidomide. Five and three pts received commercial Tec or Tal, respectively.
Regarding MRD, 27 pts (87.1%) attained MRD- in the 1st evaluation, after a median of 2 months from the 1st dose of TCE (IQR 1-3). Fourteen pts underwent &gt;1 MRD testing, with 1 showing loss of MRD-. MRD conversion predicted serum relapse in this case (occurring 4 months later). Two pts with positive MRD at 1st evaluation (both within the first two months of treatment) reached MRD- 6 months after TCE start. Among the remaining 11 cases with MRD monitoring, 100% kept sustained MRD-, but 2 relapsed (13 and 15 months after the last MRD assessment).
Interestingly, at the time of 1st MRD evaluation, only 18 pts (58.1%) had serum complete response (CR). Very good partial response was detected in 16.1%, partial response in 16.1% and 6.5% had minor response or stable disease (SD). Of responding pts, all light chain pts attained a CR, and all but one underwent BM biopsy in the first 2 months of treatment. This suggests that serum markers, except light chains, may not reflect the rapid kinetics of marrow clearance achieved with these drugs.
For MRD, no differences were found in subgroups according to high cytogenetic risk (88.2% vs 100%, p=0.9), ISS (I, II or III) (85.7% vs 100% vs 100%, p=0.3) or proven EMD (100% vs 92.3%, p=1).
After a median follow-up of 35 months, median progression-free survival (PFS) was not reached. Among the pts reaching MRD-, 8 (27.6%) relapsed. Pts with EMD showed a median PFS of 26 months (not reached in the group without EMD), but the difference did not reach statistical significance (p=0.1). No differences of PFS were found according to the presence of other HR features (cytogenetics and ISS).
Eleven pts (35.5%) discontinued therapy due to study protocol (36.4%), toxicity (54.5%) or patient's choice (9.1%). All of them had reached MRD- by that time. The median duration of treatment was 24.3 months (range 8.2-60.7). Only one patient relapsed, 25 months after the last dose (ISS II, unknown cytogenetics or EMD). With a median follow-up of 34.8 months, the rest remain in remission (with a median time from discontinuation of 5.5 months, range 3-26). Three of them had HR cytogenetics, none had EMD or ISS III.
Conclusions
In our cohort, treatment with TCE achieved a high rate of MRD-, even in heavily pretreated patients with HR features. MRD- seems to translate into long PFS, regardless of HR disease. Prospective studies on fixed duration treatment with TCE based on baseline risk and treatment response are needed.