Introduction Daratumumab (Dara) plus melphalan, prednisolone, and bortezomib (Bor) (D-MPB), followed by Dara maintenance therapy, has become one of the standard of care for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) based on the ALCYONE trial. However, a steep decrease in progression-free survival (PFS) during Dara maintenance therapy has been reported. Although Bor maintenance therapy may offer benefits in patients who respond to Bor-containing induction, this has not been validated in randomized trials.

We conducted a randomized phase III study evaluating the efficacy of adding Bor to Dara maintenance therapy after D-MPB induction in TI-NDMM (JCOG1911/B-DASH study, jRCTs031200320). Here, we report the results of a pre-specified interim analysis.

Methods Patients with NDMM aged ≥65 years, or 20–64 years who declined autologous stem cell transplantation, were eligible for first registration. In this study, D-MPB therapy was administered using a 3-week cycle definition up to 18 cycles, corresponding to a 6-week cycle up to nine cycles used in the ALCYONE trial. Patients who achieved a partial response (PR) or better after at least 12 cycles of D-MPB therapy were eligible for the second registration and were randomized 1:1 to receive either Dara alone (arm A) or Dara (day 1) plus Bor (1.3 mg/m², days 1 and 15) (arm B) in a 28-day cycle up to 24 cycles. Randomization was adjusted for institution, age, cytogenetic risk, and response to induction therapy. The primary endpoint was PFS after the second registration. We assumed a 2-year PFS rate of 65% in arm A and expected a 11% improvement in arm B. The planned total sample size for second registration was set at 166 patients with a one-sided α level of 5% and power of 70%. The secondary endpoints included overall survival (OS) after the second registration, PFS and OS after the first registration, response rate, and adverse events (AEs). An interim analysis was pre-specified upon the occurrence of at least 20 PFS events to determine whether continuing patient accrual was reasonable.

Results Between January 2021 and August 2024, 224 patients (median age, 74 years; range, 62–86) were enrolled and completed the planned first registration. The ECOG PS score was 2–3 in 21% of patients. The Revised International Staging System was stage I in 17%, II in 69%, III in 10%, and unknown in 4% of the patients.

A pre-specified interim analysis was conducted on 135 patients (69 in arm A and 66 in arm B) in March 2025. Baseline characteristics at the second registration were balanced between arms: age ≥75 years (37% vs. 35%), high-risk cytogenetics (23% vs. 20%), very good PR (28% vs. 22%), and complete response or better (51% vs. 58%) in arms A and B, respectively.

At the interim data cutoff on November 28, 2024, the median number of maintenance cycles was 19.5 (IQR, 8.5–24) in arm A and 12 (IQR, 6–21) in arm B. Protocol treatment was discontinued because of AEs in four patients in arm A and 12 in arm B. With a median follow-up of 1.3 years (range, 0.0–2.9) after second registration, 24 PFS events (20 progressive diseases and four deaths) had occurred. The 2-year PFS rates were 80.2% (95% CI, 63.2–89.9) in arm A and 72.5% (95% CI, 56.9–83.2) in arm B, yielding an Hazard ratio of 1.53 (95% CI, 0.68–3.45). As secondary endpoints, the 2-year PFS and OS among all first-registered patients were 83.6% (95% CI, 76.4–88.7) and 94.8% (95% CI, 89.7–97.4), respectively.

Grade ≥2 AEs occurring in ≥5% of patients during maintenance therapy included lymphopenia (27.5% vs. 37.9%), upper respiratory infections (7.2% vs. 6.1%), sensory peripheral neuropathy (7.2% vs. 16.7%; all grade 2), diarrhea (0% vs. 6.1%), and hypertension (7.2% vs. 1.5%) in arms A and B, respectively. The interim analysis revealed that the predictive probability of arm B demonstrating statistical superiority at the final analysis was 5.5%. Accordingly, in March 2025, the JCOG's Data and Safety Monitoring Committee recommended early termination of the study.

Conclusion This phase III study revealed that adding Bor to Dara maintenance therapy did not improve PFS in patients with TI-NDMM. Tolerability issues, including a high incidence of AEs and frequent treatment discontinuation due to AEs in arm B, as well as favorable PFS exceeding our expectations in arm A, may have influenced the results of the JCOG1911.

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2025
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