Minimal Residual Disease Measured after Treatment with Bispecifics in Relapsed Multiple Myeloma: Experience from an Academic Medical Center

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 1^st evaluation, after a median of 2 months from the 1^st dose of TCE (IQR 1-3). Fourteen pts underwent >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 1^st 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 1^st 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.

Chari:Antengene: Honoraria; Janssen: Research Funding; AbbVie; Adaptive; Amgen; Antengene; Bristol Myers Squibb; Forus; Genetech/Roche; GSK; Janssen; Karyopharm; Millenium/Takeda; and Sanofi/Genzyme: Consultancy. Martin:Janssen: Research Funding; Poseida: Research Funding; GSK, Pfizer, Roche: Honoraria; BMS: Research Funding; Sanofi: Research Funding. Chung:CarsGen Therapeutics: Research Funding; Abbvie: Research Funding; K36 Therapeutics: Research Funding; Cellectis: Research Funding; Caelum Biosciences: Research Funding; Merck: Research Funding; Johnson & Johnson Innovative Medicine: Membership on an entity's Board of Directors or advisory committees, Other: travel reimbursement, Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Research Funding. Shah:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Takamatsu:Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy; Sanofi: Honoraria; SRL: Consultancy. Martínez-López:Altum Sequencing: Current equity holder in private company; Pfizer: Honoraria; Janssen: Honoraria. Wolf:Adaptive: Consultancy.

TNB-383B (CC197011) and CC 18704 Celgene CC-93269 BCMA BiTE, bispecifics for RRMM, still off-label.