MRD-Guided Transplant Deferral Remains Feasible at Nearly 4 Years in MILESTONE Study

Minimal residual disease (MRD)–guided deferral of autologous stem cell transplantation (ASCT) remained feasible after nearly 4 years of follow-up in the phase 2 MILESTONE study (NCT04991103). Among 20 transplant-eligible patients with newly diagnosed multiple myeloma, 5 achieved MRD negativity following induction and deferred ASCT according to the study protocol. After a median follow-up of about 42.3 months, 2 of these patients had experienced disease progression and none had died.¹

The results, presented at the 23rd International Myeloma Society Annual Meeting, offer early evidence that response following modern quadruplet induction could help individualize the timing of transplantation. The small, single-center study does not establish that ASCT can be omitted permanently.

Using MRD to Guide Transplant Timing

High-dose therapy followed by ASCT remains an important consolidation strategy for eligible patients with newly diagnosed multiple myeloma. Modern quadruplet regimens have increased the proportion of patients achieving deep responses before transplantation, prompting research into whether upfront ASCT is necessary for every eligible patient.²

MILESTONE enrolled 20 patients who received 6 cycles of induction with daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd). MRD status after induction determined whether patients proceeded to ASCT or deferred the procedure. Five patients (25%) achieved MRD negativity below the 10^-5 threshold and qualified for transplant deferral.¹

Across the broader analysis population, the cumulative rate of MRD-negative complete response reached approximately 85% and 55% at sensitivities of 10^-5 and 10^-6, respectively. Sustained MRD negativity was observed in 60% and 35% of patients at those respective thresholds.¹

The difference between the 2 thresholds matters when treatment decisions depend on the absence of detectable disease. Testing at 10^-6 can detect about 1 malignant cell among 1 million nucleated cells, making it more stringent than assessment at 10^-5. Whether either threshold can independently identify patients who will receive the same long-term benefit without upfront ASCT remains unresolved.

Extending the MRD-Adapted Treatment Model

MILESTONE builds on the response-adapted framework evaluated in the phase 2 MASTER trial (NCT03224507). MASTER administered daratumumab, carfilzomib, lenalidomide, and dexamethasone followed by ASCT and MRD-directed consolidation. Patients who achieved MRD negativity during 2 consecutive assessments entered treatment-free MRD surveillance.³

MILESTONE moves the decision point earlier. Instead of using MRD to determine when treatment can stop after transplantation, the study uses postinduction MRD status to determine whether transplantation can be deferred. This distinction is clinically important because in MASTER, ASCT remained part of initial therapy before patients became eligible for treatment-free surveillance. In MILESTONE, however, only 5 patients met the postinduction threshold required to defer ASCT. The findings therefore support the feasibility of a selective approach rather than broad transplant avoidance.

The phase 3 PERSEUS trial provides additional context for the depth of response achievable with D-VRd. In transplant-eligible patients, adding subcutaneous daratumumab to VRd induction and consolidation, followed by daratumumab plus lenalidomide maintenance, significantly improved PFS and increased MRD negativity compared with VRd and lenalidomide maintenance.⁴ PERSEUS did not test MRD-guided transplant deferral, but its findings support the use of potent quadruplet induction to generate deeper responses.

Immune Markers Could Refine Patient Selection

MILESTONE also included exploratory immune profiling. The baseline ratio of soluble B-cell maturation antigen (sBCMA) to B-cell activating factor correlated with bone marrow plasma cell burden and performed better than either marker assessed alone. An increasing ratio of CXCL9 to sBCMA after consolidation was associated with lower MRD burden following ASCT.¹

These findings suggest that immune biomarkers could eventually supplement bone marrow MRD testing when selecting patients for treatment deescalation. They are not ready for routine clinical use and require validation in larger populations.

Implications for Pharmacy Practice

For oncology pharmacists, MRD-directed treatment introduces new counseling and care-coordination needs. Patients may interpret an MRD-negative result as proof that the disease has been eliminated, although MRD negativity reflects the sensitivity and timing of the assay. Deferring ASCT also preserves transplantation as a later option rather than removing it from the treatment plan.

Pharmacists can help ensure that MRD results, treatment exposure, stem-cell collection status, and surveillance plans remain clearly documented across care settings. Continued monitoring is essential because 2 of the 5 patients who deferred transplantation eventually experienced progression.

MILESTONE provides hypothesis-generating evidence that postinduction MRD negativity can inform the timing of ASCT. Larger randomized studies with longer follow-up are needed before MRD-guided transplant deferral becomes a routine strategy for transplant-eligible patients.^1,5

REFERENCES

1. Bal S, Zumaquero E, Ravi G, et al. Feasibility of MRD-adapted deferral of autologous stem cell transplantation in newly diagnosed multiple myeloma: clinical and translational results from the phase II MILESTONE study. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.

2. ClinicalTrials.gov. Minimal residual disease response-adapted deferral of transplantation in multiple myeloma: MILESTONE. ClinicalTrials.gov identifier: NCT04991103. Updated December 31, 2025. Accessed September 25, 2026. https://clinicaltrials.gov/study/NCT04991103

3. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935

4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

5. Mo CC, Hartley-Brown MA, Midha S, Richardson PG. Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy. Cancers (Basel). 2023;15(24):5709. doi:10.3390/cancers15245709