Daratumumab With Bortezomib and Dexamethasone Improves Survival in RRMM

Patients with multiple myeloma administered daratumumab in combination with bortezomib and dexamethasone demonstrated improvements in overall survival compared with those given bortezomib and dexamethasone alone.

The combination of daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone significantly prolonged overall survival (OS) in patients with relapsed/refractory multiple myeloma (RRMM), according to findings from the phase 3 CASTOR study (NCT02136134).

At a median follow-up of 72.6 (0.0-79.8 months), there was a significant OS benefit for patients given daratumumab combined with bortezomib and dexamethasone (hazard ratio [HR], 0.74; 95% CI, 0.59-0.92; P = .0075) and the median OS was 49.6 months with this combination compared with 38.5 months for the arm without daratumumab.

Additionally, patients with RRMM who had received 1 prior line of therapy had the greatest OS benefit. These data show the promise of early use of daratumumab to improve patient benefit.

“It is our understanding that these long-term results from the CASTOR study represent the first OS data with daratumumab in the RRMM population and provide further support of a survival advantage with a daratumumab-containing regimen in multiple myeloma. For the first time to our knowledge, the combination of daratumumab and a standard-of-care regimen significantly improved OS in patients with RRMM,” wrote the study authors in findings published in the Journal of Clinical Oncology.

The multicenter, randomized, active-controlled, phase 3 CASTOR trial enrolled patients with RRMM who had ≥ 1 line of prior therapy. Patients were randomly assigned 1:1 to receive bortezomib 1.3 mg/m2 subcutaneously once on days 1, 4, 8, and 11, and dexamethasone 20 mg orally or intravenously once on days 1, 2, 4, 5, 8, 9, 11, and 12 for up to 8 cycles with or without daratumumab at 16 mg/kg intravenously once a week. Treatment continued until disease progression.

Those administered bortezomib and dexamethasone were then offered daratumumab monotherapy after disease progression after a positive primary analysis and protocol amendment.

Enrollment in the trial was open to patients with multiple myeloma who had documented evidence of progressive disease as defined based on Investigator's determination of response of International Myeloma Working Group criteria on or after their last regimen, an ECOG performance status of 0-2, and have achieved a response to at least 1 prior regimen in the past.

Investigators assessed the primary end point of progression-free survival (PFS) with secondary end points including disease progression, overall response rate, MRD negativity, and OS.

A total of 498 patients were enrolled and randomly assigned to receive bortezomib, dexamethasone, and daratumumab (n = 251) or bortezomib and dexamethasone (n = 247). The median age of patients was 64 (range, 30-88) years, and the median number of prior lines of therapy was 2 (range, 1-10), including bortezomib (65.5%), thalidomide (49.4%), lenalidomide (42.0%), and both a proteasome inhibitor and an immunomodulatory drug (48.4%).

Eighty-seven patients given bortezomib and dexamethasone then received single-agent daratumumab after disease progression. During monotherapy, the median number of daratumumab cycles received was 11 (range, 1-63). The median duration of daratumumab monotherapy was 9.2 months (range, 0.2-57.1). Additionally, 38 patients were administered daratumumab as subsequent therapy not provided in the study.

At the time of the data cutoff of June 28, 2021, the median follow-up was 72.6 months (range, 0.0-79.8). Among patients given the combination of bortezomib, dexamethasone, and daratumumab, significant OS benefit was observed (hazard ratio [HR], 0.74; 95% CI, 0.59-0.92; P = .0075). The median OS was 49.6 months vs 38.5 months for those given bortezomib, dexamethasone, and daratumumab and bortezomib and dexamethasone.

Then, 161 patients (66.3%) of the 243 given the combination which included daratumumab and 200 (84.4%) of 237 patients in the bortezomib and dexamethasone group received subsequent therapy. The median number of subsequent lines of therapy was 2 (range, 1-9) vs 3 (range, 1-10), respectively. There was a significant increase in the median time to subsequent therapy for those given daratumumab vs those without (25.4 vs 9.7 months; HR, 0.27; 95% CI, 0.21-0.34; P < .0001).

PFS2 was significantly prolonged with the bortezomib, dexamethasone, and daratumumab arm (37.7 months) versus the bortezomib and dexamethasone (19.9 months; HR, 0.43; 95% CI, 0.34-0.54; P < .0001). Median PFS for patients who started the first-line of subsequent therapy was 13.2 months (95% CI, 10.1-15.4) in those given daratumumab and 9.2 months (95% CI, 7.4-10.6) for the combination without daratumumab.

Additionally, the median time to crossover to daratumumab subsequent therapy for patients given just bortezomib and dexamethasone was 20.5 months (5.7-68.3) after disease progression. Thirty-five (40.2%) of the 87 patients given bortezomib and dexamethasone who received subsequent daratumumab monotherapy after disease progression are still alive. The median OS observed in patients is 63.4 months (95% CI, 51.2-72.4).

Regarding safety, the most common grade 3/4 treatment-emergent adverse events (TEAEs) with the combination including daratumumab vs the combination without daratumumab were thrombocytopenia (46.1% vs 32.9%), anemia (16.0% vs 16.0%), neutropenia (13.6% vs 4.6%), lymphopenia (10.3% vs 2.5%), and pneumonia (10.7% vs 10.1%). For patients administered the combination daratumumab vs those without, serious TEAEs occurred in 134 (55.1%) patients vs 81 (34.2%). The most common serious TEAEs was pneumonia (10.7% vs 10.1%, respectively), and the percentage of patients with TEAEs which led to discontinuation were similar between groups at 10.7% vs 9.3%.

Another 7 (2.9%) patients were given the combination with daratumumab and 5 (2.1%) patients in the arm without discontinued treatment because of infections. TEAEs which led to death were reported in 17 (7.0%) patients given the combination with daratumumab and 14 (5.9%) for the group without daratumumab and the most common were pneumonia (0.8% each) and general physical health deterioration (0.4% v 1.3%, respectively). During the study, 3 patients died due to COVID-19, including 1 in the arm with daratumumab and 2 in the arm without daratumumab.

These findings, combined with the OS results from the phase 3 POLLUX study (NCT02076009), show OS benefit with daratumumab-containing regimens in patients with RRMM for the first time. With the combination of daratumumab, bortezomib, and dexamethasone, patients with RRMM had a significant reduction in the risk of death vs patients given bortezomib and dexamethasone alone. Overall, these data provide strong rationale for use of daratumumab in early lines to maximize patient benefit.

REFERENCES:
  1. Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-Label, phase III Trial [published online ahead of print, 2022 Nov 22]. J Clin Oncol. 2022;JCO2102734. doi:10.1200/JCO.21.02734
  2. Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. ClinicalTrials.gov. Updated November 4, 2022. Accessed November 30, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02136134