Phase 3 DREAMM-8 Trial Data Show Superior Efficacy of BPd vs PVd in Relapsed/Refractory Multiple Myeloma

The phase 3 DREAMM-8 study (NCT04484623) showed belantamab mafodotin (Blenrep; GlaxoSmithKline) plus pomalidomide (Imnovid; Bristol Myers Squibb) and dexamethasone (BPd) vs pomalidomide plus bortezomib (Velcade; Takeda Oncology) and dexamethasone (PVd) demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit in relapsed/refractory (R/R) multiple myeloma (MM) following 1 or more prior lines of therapy, explained Suzanne Trudel, MSc, MD, a clinician scientist at Princess Margaret Cancer Centre at the University Health Network, during a plenary session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Treatment with BPd also led to deeper and more durable responses and a favorable overall survival (OS) trend compared to PVd, as well as a manageable safety profile.^1,2

“It is clear these days that treatment for patients with newly diagnosed [MM] involves the use of triplet and/or quadruplet regimens, incorporating proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies,” Trudel said during the ASCO presentation.¹

However, after first relapse, Trudel explained that a majority of patients will be exposed to, and many will be refractory to, these 3 primary MM drug classes. Belantamab mafodotin, which is a first-in-class anti-BCMA antibody drug conjugate, may help address this challenge.¹

However, after first relapse, Trudel explained that a majority of patients will be exposed to, and many will be refractory to, these 3 primary multiple myeloma drug classes. Image Credit: © Saiful52 - stock.adobe.com

“We need treatment strategies that incorporate new agents with novel mechanisms of action for first relapse and beyond. DREAMM-8 is an ongoing, global, randomized, open-label study that accrued patients who had progressed on their last line of therapy, had received 1 or more prior lines of therapy (including lenalidomide or anti-BCMA therapy), were pomalidomide-naïve, and not intolerant or refractory to bortezomib,” Trudel said.¹

During the trial, 302 patients were randomly assigned 1 to 1 to receive BPd (n=155) or PVd (n=147). In the BPd arm, cycles were 28 days with patients receiving belantamab mafodotin at 2.5 mg/kg intravenous (day 1, cycle 1), then 1.9 mg/kg (day 1, cycle 2+), with pomalidomide at 4 mg (day 1-21, all cycles) and dexamethasone at 40 mg (day 1, weekly, all cycles). In the PVd arm, cycles were 21 days, with patients receiving pomalidomide at 4 mg (day 1-14, all cycles), with bortezomib at 1.3 mg/m2 subcutaneous (day 1, 4, 8, 11 [cycles 1-8]; and day 1, 8 [cycles 9+]) and dexamethasone at 20 mg (day of and 1 day after bortezomib dose).¹

“Treatment was continued until disease progression, death, unacceptable toxicity, end of study, or withdrawal of consent. Patients were stratified based on prior lines of therapy and prior exposure to bortezomib or anti-CD38 monoclonal antibodies,” Trudel said.¹

The primary end point of the study was PFS, with key secondary end points including overall survival (OS), minimal residual disease (MRD) negativity rates, duration of response (DoR), overall response rate (ORR), complete response rate (CRR), as well as 19 other secondary end points. The study met its primary endpoint of PFS, with a median (range) follow-up of 21.78 months (0.03-39.23). Median PFS (95% CI) was not reached (NR; 20.6-NR) in the BPd arm, while median PFS was 12.7 months (9.1-18.5) in the PVd (HR, 0.52; 95% confidence interval [CI], 0.37-0.73; P<0.001) arm. Further, the 12-month PFS rate (95% CI) was 71% (63-78%) in the BPd arm vs 51% (42-60%) in the PVd arm.¹

“The 12-month PFS of 71% vs 51% for BPd vs PVd, respectively, represents a clinically meaningful and statistically significant reduction in the risk of death,” Trudel said. “The treatment benefit was consistent across all efficacy end points, including [CRR], MRD negativity at 10-5,[DoR], investigator-assessed [PFS], and [OS], noting that the survival data still needs to mature, but the hazard ratio was .77, and the [OS] benefit came despite the use of effective anti-myeloma therapies, including anti-BCMA targeted therapy and anti-CD38s for patients who progressed on the PVd arm.”¹

Among the secondary end points, the trial results showed that ORR (95% CI) was 77% (70.0-83.7%) with BPd vs 72% (64.1-79.2%) with PVd, with a CRR (95% CI) of 40% (32.2-48.2%) in the BPd arm vs 16% (10.7-23.3%) in the PVd arm. Median DoR (95% CI) was NR (24.9-NR) among the BPd cohort, while median DoR in the PVd cohort was 17.5 months (12.1-26.4). Further, OS (hazard ratio, 0.77; 95% CI, 0.53-1.14) showed a positive trend favoring BPd, with OS follow up ongoing, according to Trudel.¹

Adverse events (AEs) were reported in over 99% and 96% of patients in the BPd and PVd arms, respectively, Trudel exaplined. Among patients treated with BPd, 89% had ocular AEs (Common Terminology Criteria for Adverse Events grade 3/4, 43%) vs 30% (grade 3/4, 2%) in the PVd arm. The AEs were shown to be generally manageable and broadly consistent with the known safety profiles of the individual agents.¹

“Although there were numerically more patients who had grade 3/4 [AEs] or serious [AEs] in the BPd arm, when we adjust for time on treatment, the AES were actually similar or lower in the BPd arm,” Trudel said. “The discontinuation profile or fatal events was 11% in both arms, while discontinuation due to [AEs] of any cause was also similar in both arms. Ocular events were managed with dose delays or modification, and these protocol pre-specified dose modifications led to lower discontinuation rates for ocular [AEs] at 9%.”¹

Treatment with BPd significantly reduced the risk of progression events vs PVd with a hazard ratio of .52 in patients with R/R MM who have 1 or more prior lines of therapy, including lenalidomide, according to Trudel. In addition, BPd was associated with an early trend in OS and a greater depth in durability of responses.¹

“Taken together with the results of DREAMM-7 [NCT04246047], which combined belantamab mafodotin with bortezomib and dexamethasone, these data highlight the potential of belantamab mafodotin containing triplets to address the unmet need of novel regimens to treat patients in myeloma with first relapse,” Trudel said.^1,3

Oreofe O. Odejide, MD, MPH, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School of Medicine, commented on the findings of the DREAMM-8 trial, noting that BPd was significantly more effective at stopping relapse in myeloma compared to the current standard of care.¹

“There have been several advances in the care of patients with myeloma over the past several years that involve the inclusion of multiple agents as front-line treatment for myeloma, so we have triplets or quadruplets treatments that have really improved outcomes for patients with myeloma,” Odejide said. “It also means that when patients relapse, they've often been exposed and may not respond as well to many anti-myeloma treatments [sic]. Belantamab mafodotin, based on these findings, are meeting these needs squarely. Based on the findings of this study, [BPd] is poised to be a new treatment option potentially for patients who have [R/R MM].”¹

REFERENCES

1. Trudel S. On-Site Briefing on Plenary Abstracts. 2024 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2024; Chicago, Illinois.
2. Belantamab Mafodotin Plus Pomalidomide and Dexamethasone (Pd) Versus Bortezomib Plus Pd in Relapsed/Refractory Multiple Myeloma (DREAMM 8). ClinicalTrials.gov. Updated May 28, 2024. Accessed June 3, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04484623
3. Evaluation of Efficacy and Safety of Belantamab Mafodotin, Bortezomib and Dexamethasone Versus Daratumumab, Bortezomib and Dexamethasone in Participants With Relapsed/​Refractory Multiple Myeloma (DREAMM 7). ClinicalTrials.gov. Updated December 13, 2023. Accessed June 3, 2024. https://clinicaltrials.gov/study/NCT04246047