Paper Details

ABSTRACT

BACKGROUND AND SIGNIFICANCE. The incorporation of proteasome inhibitors, immunomodulatory drugs, and CD38-targeting antibodies has progressively increased the depth and durability of response in newly diagnosed multiple myeloma (NDMM). Contemporary quadruplet regimens achieve high rates of minimal residual disease (MRD) negativity, prompting prospective evaluation of whether autologous stem-cell transplantation can be deferred in selected patients who achieve deep responses and lack established high-risk features.

Nevertheless, treatment selection in NDMM remains heterogeneous. Some patients are candidates for four-drug therapy, whereas others may not tolerate the toxicity associated with an additional agent or may prefer to avoid the added treatment burden and inconvenience of a quadruplet regimen. Thus, classification based on quadruplet eligibility may become increasingly relevant as the historical distinction between transplant-eligible and transplant-ineligible disease evolves.

BCMA×CD3 bispecific antibodies have demonstrated substantial activity and high rates of MRD negativity in relapsed or refractory multiple myeloma. Their incorporation into frontline therapy provides an opportunity to investigate whether T-cell-redirecting immunotherapy can produce rapid and deep responses without routine exposure to conventional induction and high-dose melphalan. ADVANCE 2.0 is evaluating elranatamab-based therapy in both quadruplet-eligible and quadruplet-ineligible/quadruplet-deferred patients with NDMM.

AIMS. To evaluate the safety and efficacy of elranatamab, lenalidomide, and dexamethasone, with or without carfilzomib, as frontline therapy for patients with NDMM.

METHODS. ADVANCE 2.0 (NCT06997081) is an investigator-initiated, single-center, phase II clinical and correlative study with a planned enrollment of approximately 130 patients. Participants are assigned to treatment according to their eligibility for quadruplet therapy. Quadruplet-eligible patients receive carfilzomib, elranatamab, lenalidomide, and dexamethasone (Car-ERd), whereas quadruplet-ineligible/quadruplet-deferred patients receive elranatamab, lenalidomide, and dexamethasone (ERd).

Quadruplet-eligible patients receive on 28-day cycles: (cycle 1) elranatamab step-up-dosing and thereafter weekly dosing; (cycles 2-6) elranatamab, carfilzomib and dexamethasone days 1 and 15 and lenalidomide days 1-21; followed by (cycles 7-24) elranatamab day 1 and lenalidomide days 1-21. Quadruplet-ineligible patients receive on 28-day cycles: (cycle 1) elranatamab step-up-dosing and thereafter weekly dosing; (cycles 2-6) elranatamab and dexamethasone days 1 and 15 and lenalidomide days 1-21; followed by (cycles 7-24) elranatamab day 1 and lenalidomide days 1-21. The primary endpoint is MRD negativity 10^-5 at completion of 12 cycles. Secondary endpoints include clinical response rates per IMWG criteria, MRD^-6 negativity, sustained MRD negativity, progression-free survival, overall survival, and safety. Correlative studies will evaluate bone marrow, immune, genomic, and/or spatial biomarkers associated with response, resistance, and treatment-related toxicity. Enrollment began in August 2025, and the study is currently recruiting.

ADVANCE 2.0 is the first prospective study to evaluate frontline elranatamab-based therapy using treatment intensity determined by quadruplet eligibility. The study will define the safety, depth of response, and biological effects of incorporating BCMA-directed T-cell engagement into initial therapy for NDMM.