(PA-194) Detectable Peripheral Blood Measurable Residual Disease (PBMRD) Is Strongly Associated with Early Progression in Newly Diagnosed Multiple Myeloma (NDMM)

Bone marrow (BM) measurable residual disease (MRD) is a key biomarker in multiple myeloma (MM), but its invasive/painful nature limits serial monitoring. It also risks false negatives from haemodilution, patchy disease, or extramedullary involvement. Peripheral blood MRD (PBMRD) offers a minimally invasive, and convenient alternative, though its clinical relevance in newly diagnosed MM (NDMM) remains unclear. We assessed the clinical value of PBMRD alongside BMMRD post-initial therapy in NDMM.

Methods:

We prospectively enrolled 94 NDMM patients who completed 8 VRd cycles followed by BM/PB MRD assessment. Post-induction, patients were randomized to MRD-guided consolidation (VRd/KPd) or standard maintenance (Lenalidomide or Bortezomib-Lenalidomide; CTRI/2021/11/037702). MRD was evaluated using a highly sensitive 13-color flow cytometry method. Any detectable MRD was defined as positive. Levels of M-protein,  FLC and Serum immunofixation (sIF) were measured.

Results:

Of 94 patients (age: median-53.5 years; range-32-75 years; M:F-3), ISS-I, II and III included 21 (22.34%), 26(27.6%), and 47(50%), respectively. RISS staging was available in 86 patients where RISS-I, II and III included 11(12.8%), 48(55.8%), and 27(31.4%), respectively. Best response at the end of 8-cycles of VRd included stringent-CR-29.03%, CR-31.33%, VGPR-26.88%, PR-10.75%, patients. The sIF was done in 92 patients with sIF(+) in 59(64.13%) at 8 cycles of VRd. BMMRD was detectable in (median-0.019%; range-0.0002-4.5%) in 60/94(63.8%) patients. PBMRD was detectable (median-0.0016%; range-0.00007-0.09%) in 18/94(19.15%) patients and 18/60 (30%) of BMMRD-positive patients.

Median follow-up was 36 weeks (25-92 weeks) and 14 of 94 patients progressed after 8 cycles of VRd during this follow-up. On Kaplan Meier analysis, detectable PBMRD was strongly associated with PFS (26 weeks vs. not reached; HR-14; p< 0.0001). Detectable BMMRD also demonstrated an association with PFS with HR-5.9 (p=0.0076), and sIF+ status with HR-2.6 (p=0.047), but the median was not reached for both i.e. positive versus negative patients for BMMRD and sIF.  ISS, R-ISS, high-risk cytogenetics and the best initial response did not reveal any association with early progression on univariate analysis. PBMRD status showed a strong independent association (HR-12; p=0.0012), with early progression in multivariate analysis.

Conclusions:

PBMRD using highly sensitive flow cytometry is detectable in one-third of NDMM patients with detectable BMMRD. Thus, PBMRD positivity serves as a surrogate for BMMRD and can help to design a staged approach to reduce number of BM procedures thereby improving its acceptance. Most importantly, positive PBMRD is strongly associated with early myeloma progression and identifies ultra-high-risk NDMM patients, providing a rationale for immediate therapeutic intervention.