Background: The phase 3 CEPHEUS trial showed that the daratumumab-based quadruplet regimen comprised of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) offers superior efficacy with a tolerable safety profile compared with VRd in patients with newly diagnosed multiple myeloma (NDMM) who are transplant-ineligible (TIE) or transplant-deferred. Patients treated with DVRd achieved significantly higher rates of minimal residual disease negativity (60.9% vs. 39.4%) and a significantly longer progression-free survival (PFS; hazard ratio: 0.57, median PFS not reached for DVRd) than those treated with VRd. This has led to an increased adoption of DVRd as frontline (FL) treatment for TIE patients with NDMM in real-world (RW) clinical practice. However, the RW implementation of DVRd is slightly modified from the CEPHEUS protocol. In particular, bortezomib is typically dosed once weekly instead of the twice weekly schedule to help optimize side effect management, decrease patient burden, and enhance quality of life. The objective of this study was to characterize the use and evaluate the RW outcomes of DVRd with weekly bortezomib dosing among non-transplanted NDMM patients.

Methods: This retrospective study utilized data from the Flatiron Health Research database. Patients with NDMM aged >18 years who were treated with DVRd between January 1, 2019, and December 31, 2024, were included. The date of initiation of DVRd was defined as the index date. Due to the absence of transplant eligibility status in the Flatiron database, this analysis excluded all individuals who underwent hematopoietic stem cell transplantation during the study period. Patients who were enrolled in a clinical trial, had presence of other cancers, received chimeric antigen receptor T-cell therapy, or were diagnosed with amyloid light-chain amyloidosis prior to the index date were also excluded. Patients were considered to have received a once-weekly bortezomib dosing schedule if bortezomib was initiated and maintained for a minimum of 6 weeks with an interval of 5-9 days between all doses. Frailty score was calculated based on age, Charlson-comorbidity index, and Eastern Cooperative Oncology Group performance status (ECOG PS). PFS was measured from the index date to either disease progression or death, whichever occurred first. Patient characteristics were summarized using descriptive statistics, and clinical outcomes were analyzed using Kaplan-Meier methods.

Results: A total of 704 non-transplanted patients with NDMM receiving FL DVRd were identified; of these, 462 (65.6%) received bortezomib once weekly or less frequently, of which 113 patients were treated with once-weekly bortezomib for a minimum of 6 weeks and were included in this analysis. Among these 113 patients, the median duration of once-weekly bortezomib was 14 weeks (range: 6-58 weeks). Median age was 67 years, 55.8% of patients were male, most were White (62.8%), and 18.6% were African American. Most patients (66.3%) were considered non-frail (frailty score <2). Among patients with available data (n=92), 82.6% had an ECOG PS of 0-1, and 17.4% had an ECOG PS of 2. In terms of disease risk status among patients with available data (n=98), more than half (54.1%, 53/98) of the patients had at least 1 of the high-risk cytogenetic biomarkers, defined as the presence of t(4;14), t(14;16), t(14;20), del(17p), and 1q gain/amplification, and 13.3% (13/98) had ≥2. Among patients with documented staging information, 23.7% (18/76) had International Staging System stage III disease. The median duration of follow-up was 19.1 months. Median PFS was not reached (95% confidence interval: 36.1 months, not reached), with 18 disease progression or death events observed. The PFS rate at 12 and 24 months was 87.4% and 80.6%, respectively.

Conclusions: Data from this analysis indicate that the once-weekly bortezomib dosing schedule as part of the daratumumab-based quadruplet regimen, DVRd, is effectively used in the RW setting and has similar long-term efficacy outcomes to those observed in the CEPHEUS trial. This practice of weekly bortezomib dosing frequency among FL DVRd-treated patients was observed regardless of age and disease risk and is feasible for the treatment of frailer patients. In summary, these data suggest that once-weekly bortezomib dosing is an effective treatment option for a broad range of non-transplanted patients with NDMM treated with the CEPHEUS DVRd regimen.

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2025
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