Phase 3 trial: Investigators report higher MRD-negativity with KRd, daratumumab-KRd versus VMP-Rd in transplant-ineligible myeloma

Evidence before this study

We searched PubMed on Jan 15, 2017, with no date restrictions, for literature published in English about treatment of transplant-ineligible patients with newly diagnosed multiple myeloma. We complemented our search by including the abstracts of meetings of the American Society of Hematology, the American Society of Clinical Oncology, and the annual meetings of the European Hematology Association. Our search terms were “multiple myeloma”, “new diagnosis”, “transplant ineligible”,” “frailty-adapted therapy”, and “treatment options”. Our search identified clinical trials in patients with newly diagnosed multiple myeloma and not eligible for autologous stem cell transplantation. The most cited studies included regimens containing VMP (bortezomib, melphalan and prednisone) alongside Rd (lenalidomide and dexamethasone). Preliminary reports about addition of daratumumab to the previous standards of care were also found among highly cited studies. Although there were several publications addressing patient frailty in myeloma, we could not find prospective studies planning frailty-adapted therapy for patients with multiple myeloma. We considered these results when designing the present study focusing on patient fitness and its effect on therapy adaption for transplant-ineligible patients with a recent diagnosis of multiple myeloma.

Added value of this study

Our findings showed that triplet and quadruplet combinations based on carfilzomib, lenalidomide, and dexamethasone (KRd) and daratumumab–KRd are superior to the conventional approach based on VMP-Rd in terms of undetectable measurable residual disease after 18 induction cycles. Additionally, frailty assessment aids in selecting triplet or quadruplet regimens to best adapt therapy to patient fitness and mitigate toxicity and mortality. This phase 3 clinical trial complements the current treatments for patients with transplant-ineligible multiple myeloma and shifts focus towards frailty-adapted therapy. Furthermore, our results support integration of measurable residual disease into management of patients with myeloma.

Implications of all the available evidence

This study is complementary to the results reported by three additional phase 3 clinical studies in transplant-ineligible fit patients newly diagnosed with myeloma, in which triplets were compared with quadruplet regimes. In contrast to our study, the previous phase 3 studies included bortezomib as proteasome inhibitor. Patient fitness was evaluated based on chronological age up to 80 years and, in one of the studies, the International Myeloma Working Group frailty scale was used. In our study, fitness evaluation included a Comprehensive Geriatric Assessment according to the recommendations of the International Society of Geriatric Oncology. The main implication of our study is support for incorporating quadruplet regimens into new guidelines for the management of transplant-ineligible patients newly diagnosed multiple myeloma. Importantly, our findings highlight the need for frailty-based treatment selection, ensuring that therapeutic intensity is matched to patient fitness. Additionally, the study reinforces the value of measurable residual disease assessment as a foundation for designing response-adapted treatment strategies in future trials. Together, these insights pave the way for next-generation studies aimed at integrating quadruplets with T-cell redirecting therapies, further advancing personalised treatment in this patient population.

Source: The Lancet Haematology