Phase II Study of Daratumumab-KRd Without Transplant in Newly Diagnosed Myeloma

Overview

This phase II study evaluated 24 cycles of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM). Among 42 patients, high rates of stringent complete response (sCR) and minimal residual disease (MRD) negativity were observed, demonstrating deep and durable responses with an ASCT-free approach.

Background

Standard frontline therapy for NDMM typically includes a proteasome inhibitor, an immunomodulatory drug, and corticosteroids, often followed by ASCT and maintenance. While ASCT improves progression-free survival, its impact on overall survival remains unclear. Quadruplet regimens adding daratumumab to PI-IMiD-steroid combinations have shown high MRD negativity rates, especially when combined with ASCT. This study investigates the efficacy of prolonged Dara-KRd without ASCT to establish the durability of response in transplant-ineligible or -deferred patients.

Data Highlights

Key Findings

• At the end of 8 cycles, the primary endpoint of sCR and/or MRD negativity (10−5 threshold) was assessed in 40 evaluable patients.
• High rates of deep responses were achieved with 24 cycles of Dara-KRd without ASCT.
• MRD testing by next-generation sequencing showed sensitive detection with a limit of 6.8 × 10−7, supporting durable remission assessment.
• Peripheral blood mass spectrometry was used as an exploratory endpoint to complement MRD evaluation.
• Adverse events were monitored and graded per NCI CTCAE v4.0, with treatment generally well tolerated.
• Patients had the option to harvest stem cells after 4–6 cycles to allow future ASCT if needed.

Clinical Implications

This study supports the use of prolonged Dara-KRd quadruplet therapy as an effective frontline regimen for NDMM patients who are ineligible for or defer ASCT. The high rates of sCR and MRD negativity suggest that durable disease control can be achieved without immediate transplant. MRD monitoring by sensitive NGS and mass spectrometry techniques may guide treatment duration and intensity in this setting.

Conclusion

Dara-KRd administered for 24 cycles without upfront ASCT yields deep and durable responses in NDMM, including patients with high-risk cytogenetics. This ASCT-free approach represents a promising treatment paradigm warranting further investigation.

References

1. 1,2 -- ASCT impact on PFS and OS in NDMM
2. 3 -- PERSEUS trial: Dara-VRd with ASCT outcomes
3. 4 -- MASTER trial: Dara-KRd with MRD-adapted therapy and ASCT
4. 5,6 -- MANHATTAN trial: Dara-KRd without ASCT
5. 7 -- Mass spectrometry MRD assessment methods
6. 8 -- IMWG response criteria
7. 9 -- International consensus on MRD reporting
8. 10 -- IMWG criteria for high-risk cytogenetics