Extended Daratumumab-KRd Therapy Achieves 85% Three-Year PFS in Newly Diagnosed Multiple Myeloma Without Transplant
Key Insights
A phase II trial of extended daratumumab-carfilzomib-lenalidomide-dexamethasone (Dara-KRd) for 24 cycles achieved 75% stringent complete response and/or minimal residual disease negativity in newly diagnosed multiple myeloma (search) patients.
The treatment demonstrated an impressive 85% three-year progression-free survival rate without autologous stem cell transplant, including 100% for standard-risk patients and 92% for those with one high-risk cytogenetic abnormality.
Extended quadruplet therapy showed deepening responses over time, with minimal residual disease negativity rates increasing from 35% after 8 cycles to 53% as best response, suggesting potential to defer transplant in select patients.
A phase II clinical trial has demonstrated that extended treatment with daratumumab-carfilzomib-lenalidomide-dexamethasone (Dara-KRd) can achieve deep, durable responses in newly diagnosed multiple myeloma (search) (NDMM) patients without requiring autologous stem cell transplant (ASCT). The study, conducted across two Multiple Myeloma Research Consortium sites, enrolled 42 patients and achieved its primary endpoint with a 75% rate of stringent complete response (sCR) and/or minimal residual disease (MRD) negativity.
Treatment Protocol and Patient Population
The open-label, single-arm study treated patients with 24 cycles of Dara-KRd, representing an extended approach compared to the traditional 8-cycle induction standard. The regimen included intravenous daratumumab 16 mg/kg, intravenous carfilzomib 20/36 mg/m², oral lenalidomide 25 mg, and oral dexamethasone with age-adjusted dosing.
The patient population included a median age of 58 years, with 57% harboring high-risk cytogenetic abnormalities (HRCA). Notably, 24% of patients had two or more HRCA, representing a particularly challenging subset typically recommended for early ASCT. High-risk features included t(4;14) in 24% of patients, deletion 17p in 19%, and 1q copy number abnormalities in 33%.
Efficacy Outcomes
Following 8 cycles of therapy, 30 of 40 evaluable patients (75%, 95% CI 61-89%) achieved sCR and/or MRD negativity at the 10⁻⁵ threshold, meeting the statistical threshold for efficacy. The overall response rate reached 95%, with 68% achieving sCR and 70% achieving at least complete response.
The study revealed significant deepening of responses over extended treatment duration. MRD negativity at the 10⁻⁶ threshold increased from 35% after 8 cycles to 53% as best response. Among 33 MRD-evaluable patients from cycle 8 onward, 11 of 27 patients (41%) achieved sustained MRD negativity with two consecutive negative results at least one year apart.
Survival Outcomes
With a median follow-up of 27 months, the estimated 3-year progression-free survival (PFS) was 85%. Results varied by cytogenetic risk: 100% for standard-risk disease, 92% for patients with one HRCA, and 60% for those with two or more HRCA. The estimated 3-year overall survival reached 95%.
Importantly, none of the 11 patients with sustained MRD negativity below 10⁻⁵ experienced disease progression, reinforcing the prognostic value of sustained MRD negativity. Among the 7 patients who experienced progression, 6 had at least one high-risk feature including extramedullary disease, multiple HRCA, or circulating plasma cells.
Mass Spectrometry Analysis
The study incorporated mass spectrometry analysis using both EXENT® and liquid chromatography-mass spectrometry (LC-MS) methods. EXENT® negativity as best response was associated with superior PFS (p = 0.03), with only one patient achieving EXENT® negativity experiencing disease progression. None of the patients who reached LC-MS negativity experienced disease progression, suggesting this highly sensitive method may serve as an optimal predictor of durable response.
Safety Profile
Extended Dara-KRd demonstrated a favorable safety profile with no treatment-related deaths. Dose reductions occurred in 26% of patients for carfilzomib, 55% for lenalidomide, and 52% for dexamethasone. Common hematologic adverse events included thrombocytopenia (64% all grades, 26% grade 3+) and neutropenia (26% all grades, 21% grade 3+).
Non-hematologic toxicities included hyperglycemia (76% all grades), diarrhea (71%), and hypertension (57% all grades, 17% grade 3+). Upper respiratory infections occurred in 67% of patients, including 38% with COVID-19 infections, though no patient died from COVID-19. Cardiac events were rare, with no venous thromboembolic events reported.
Stem Cell Collection
Stem cell mobilization remained feasible during extended quadruplet therapy. Collection was performed in 88% of patients using G-CSF and upfront plerixafor, achieving a median yield of 8.26 × 10⁶ CD34 (search)+ cells/kg. This yield exceeded that reported in the MASTER trial (6.0 × 10⁶ CD34+ cells/kg), potentially due to the upfront plerixafor use and higher target stem cell dose.
Clinical Implications
The study represents the first demonstration that extended Dara-KRd can induce and sustain deep responses without ASCT. The 85% three-year PFS compares favorably with historical controls and approaches the 90% three-year PFS achieved with Dara-VRd plus ASCT in the phase 3 PERSEUS trial.
However, the results highlight ongoing challenges in treating patients with multiple HRCA, where the 60% three-year PFS remains suboptimal. The authors suggest this population may benefit from earlier incorporation of CAR-T cell therapy and bispecific antibodies.
The extended treatment approach challenges the arbitrary 8-cycle induction standard and suggests that prolonged quadruplet therapy may compensate for deferring ASCT in select patients. The deepening responses over time support this strategy, though the approach carries cost implications and time toxicity considerations.
Study Limitations and Future Directions
Study limitations include the small sample size of 42 patients and use of twice-weekly carfilzomib, which has become less common in practice. The authors note that once-weekly carfilzomib 56 mg/m² has achieved similarly high MRD negativity rates in other studies.
Ongoing phase III trials, including comparisons of VRd versus extended KRd and studies in transplant-deferred settings, will provide additional data on optimal treatment duration and the role of ASCT in the era of effective quadruplet therapy. The results suggest that for carefully selected patients, particularly those with standard-risk or single HRCA, extended quadruplet therapy may offer an alternative to immediate ASCT while preserving this option for future use.