Induction Quadruplet Therapy and Minimal/Measurable Residual Disease (MRD)-Informed Treatment Adaptation in Newly Diagnosed Multiple Myeloma (NDMM): Results from an Academic-Community Pathway

Background: MRD is a strong predictor of progression free survival (PFS) and overall survival (OS) in NDMM patients (pts) especially in the setting of autologous stem cell transplantation (ASCT). While MRD is increasingly reported in clinical trials, its adoption in routine practice is hindered by logistical complexity and uncertainty regarding its role to modify therapy. We developed a clinical academic-community pathway for optimal treatment and MRD-based monitoring of patients with NDMM candidates for ASCT.

Methods: In March 2020 we adopted the institutional standard for induction therapy with subcutaneous daratumumab 1,800 mg SC (standard schedule), bortezomib 1.3 mg/m2 SC days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO days 1,8,15,22 of each 28-day cycle (mDara-VRd). We assessed response after 4 cycles of induction including bone marrow MRD by next-generation sequencing (NGS- ClonoSEQ®). All transplant eligible patients irrespective of post induction response were included and received standard high-dose Melphalan and ASCT followed by response reassessment including MRD 60-80 days after ASCT. Patients subsequently underwent 4-8 additional cycles of mDara-VRd consolidation followed by MRD assessment. Patients with two consecutive MRD negative (<10^-5) at any point were offered the possibility of treatment cessation with MRD surveillance (MRD-SURE). Otherwise, patients received maintenance with lenalidomide until progression. The institutional pathway was disseminated to community-based partner practices where patients could receive induction and consolidation therapy while response assessment, including MRD and ASCT was performed at the academic center. The primary objectives of this analysis are to report the feasibility of this approach and its clinical results, including achievement of MRD negativity (<10^-5). All efficacy results are reported by intention to treat.

Results: In total 69 consecutive patients were included in this analysis with sufficient follow up to complete induction. Of those, 59 have reached post ASCT response assessment. Median follow up is 15.5 mo (range 3.7-27.6). Median age of pts was 62 years (range 33-78),24 (35%) were of racial-ethnic minorities and 41 (59%) were treated primarily in the community setting (Table). MRD testing by NGS was trackable (i.e a baseline sample could be retrieved with the identification of one or more clonogenic sequences) for 61 (88%) pts. Overall response rate was 97%, 29% achieved sCR/CR after induction, 63% after ASCT and 78% as best response on therapy. Among the 61 patients with MRD trackable by NGS, 21% (95% C.I. 12-34%)-achieved MRD negativity <10^-5 post induction, 51% (95% C.I. 37-65%) post AHCT and 64% (95% C.I. 50-77%) with subsequent consolidation. Patients achieving MRD <10^-6 at the same milestones were 5% (95%C.I. 1-14%), 34% (95%C.I. 22-48%) and 47% (95%C.I. 33-61%) respectively (Figure). Among the 42 patients with MRD trackable by NGS and with >12 months from initiation of therapy, 16 (38%) have reached 2 consecutive MRD negative (<10^-5) assessments and only 1 had resurgence of MRD (yet without clinical or biochemical progression) during MRD-SURE. At 18-month, PFS was 94% and OS 96%. In multivariable analysis neither age, race/ethnicity, staging or number of high-risk cytogenetic abnormalities predicted MRD negativity at <10^-5 post induction or post ASCT.

Conclusion: A real-world academic-community clinical pathway for quadruplet induction/consolidation therapy, ASCT and MRD-informed treatment modification is feasible, and yields results similar to obtained in clinical trials. While no patient or disease characteristic was predictive of achievement of MRD negativity, longer follow up will be needed to understand the interplay of disease features, depth of response and outcomes.