Response adaptive salvage treatment with daratumumab-lenalidomide-dexamethasone for newly diagnosed transplant-eligible multiple myeloma patients failing front-line bortezomib-based induction therapy-ALLG MM21.

In Australia, bortezomib-based induction (V-IND) is used in >90% of newly diagnosed transplant-eligible multiple myeloma (MM) patients. Four cycles of V-IND with bortezomib-cyclophosphamide-dexamethasone or bortezomib-lenalidomide-dexamethasone are available via the Pharmaceutical Benefits Scheme prior to autologous stem cell transplantation (ASCT). Patients who demonstrate suboptimal response or who are refractory to V-IND demonstrate inferior survival, representing a subgroup of MM where an unmet need persists. We evaluated an early, response-adapted approach in these patients by switching to an intensive sequential therapeutic strategy incorporating daratumumab-lenalidomide-dexamethasone-based (DRd) salvage, high-dose melphalan ASCT followed by DRd consolidation and R maintenance. The overall response rate following four cycles of DRd salvage was 72% (95% credible interval: 57.9-82.4); prespecified, dual, Bayesian proof-of-concept criteria were met. Euro-flow minimal residual disease (MRD) negativity was 46% in the intention-to-treat population and 79% in the evaluable population following 12 cycles of DRd consolidation. At the 24-month follow-up, median progression-free survival and overall survival were not reached. DRd salvage was well tolerated with grade 3 and 4 events reported in 24% and 8% respectively. Response-adapted DRd combined with ASCT achieves high rates of MRD negativity and durable disease control in this functional high-risk group.