Belantamab mafodotin (Blenrep, GSK) appears to be a phoenix rising from the ashes with positive data from two multiple myeloma clinical trials presented at this week's recent American Society of Clinical Oncology (ASCO) meeting. (What is the ASCO conference?) 

Blenrep was granted FDA accelerated approval on August 5, 2020, based on results from the DREAMM-2 clinical trial. The FDA required GlaxoSmithKline (GSK) to provide confirmatory data in order to receive full approval. When the DREAMM-3 Phase III study results were published, the data didn't meet the FDA's requirements for approval, so the company began withdrawing the drug from the market in November of 2022. The market withdrawal was not made for safety reasons. 

The company chose to continue existing clinical trials that were already in progress. Results from two of these trials were reported at this week's ASCO conference, and the data is proving to be positive. 

Blenrep is the only BCMA antibody-drug conjugate, a type of treatment that targets BCMA on the surface of myeloma cells and uses the immune system to deliver a toxic payload to them. The treatment is administered via an intravenous infusion (IV). 

DREAMM-7 Trial: Blenrep Combination Achieves Better Results Than Daratumumab-based Triplet Therapy Even in Patient with Poorer Prognosis

The DREAMM-7 study is a Phase III study comparing belantamab mafodotin, bortezomib, and dexamethasone (BVd) against daratumumab, bortezomib, and dexamethasone (DVd). Directly comparing a new therapy with daratumumab is a bold decision, given the potency of daratumumab in treating myeloma. Patients in the study had received at least one prior line of therapy. 

At a median follow-up of 28.2 months with 243 patients in the BVds arm and 251 patients in the DVd arm, the results were: 

• Progression Free Survival: 36.6 months (BVd) vs. 13.4 months (DVd) 
• Overall Survival at 18 months: 84% (BVd) vs. 73% (DVd)
• Complete response and MRD negative status: 25% (BVd) vs. 10% (DVd)
• Incidence of severe side effects: 82% (BVd) vs. 49% (DVd)
  • Eye-related side effects, including blurred vision, visual impairment, dry eye, and eye irritation, were reported with BVd treatment.

Maria Victoria Mateos, MD from the University of Salamanca, presented the results at the ASCO meeting and noted that for patients who had exhausted the use of lenalidomide (refractory), the differences were even more pronounced: 

• Median progression-free survival of 25 months for the BVd patients compared to 8.6 months for the DVd patients
• Overall response rate: 84% for BVd vs. 61% for DVd
• Patients achieving complete response or better: 35% for BVd vs. 11% for DVd
• Patients with a complete response who become MRD negative: 25% for BVd vs. 6% for DVd 

Dr. Mateos also noted that for patients with high-risk cytogenetics (translocations of 4;14 or 14;16, or deletion 17p), the BVd group tripled the median progression-free survival (33.2 months) compared to the DVd group (10.5 months). The high-risk patients in the BVd arm also had a higher complete response rate (45% BVd vs. 13% for DVd) and MRD negativity rates (31.3% BVd vs. 7.2% for DVd). 

DREAMM-8 Trial: Blenrep Combined with Pomalidomide and Dexamethasone Improves Outcomes in Relapsed/Refractory Myeloma

The DREAMM-8 study is a Phase III study comparing belantamab mafodotin, pomalidomide, and dexamethasone (BPd for 155 patients) against bortezomib, pomalidomide and dexamethasone (VPd for 147 patients). Patients in the study had received more than one prior line of therapy. Suzanne Trudel, MD of Princess Margaret Cancer Center, presented the results at the ASCO meeting.

At a median follow-up of 21.8 months, the results were: 

• Overall Response Rate: 77% (BPd) vs. 72% (VPd)
• Complete Response or better: 40% (BPd) vs. 16% (VPd)
• MRD negativity rate: 24% (BPd) vs. 5% (VPd)

After one year, 71% of patients treated with BPd hadn't progressed (compared to 51% in the VPd group), and 83% were still alive (compared to 76% with VPd). This trial is currently still monitoring patients for longer-term outcomes, but it already is the longest progression-free survival that has been seen in any treatment combination using pomalidomide and dexamethasone as a backbone. 

This positive trend in all outcomes was also seen in patients with poor prognoses, like those refractory to lenalidomide or with high-risk cytogenetics.

More patients treated with BPd experienced side effects: 94% of patients with BPd vs. 76% with VPd. Dr. Trudel noted in her presentation that the safety results were consistent with previous studies:

• Frequent side effects included low counts of white blood cells and platelets, and pneumonia
• Discontinuation of therapy due to side effects for both arms was relatively similar (15% for BPd and 12% for VPd)
• Eye-related side effects were more common in the BPd group, with 43% of patients experiencing severe side effects. Although in most cases, these are resolved with dose modifications, 9% of patients had to discontinue Blenrep for this reason.

Sometimes, Less is More in Myeloma Treatment

Sagar Lonial, MD of Emory University, provided context at the end of the presentation on how to apply antibody-drug conjugates in clinical practice. There are 13 antibody-drug conjugates approved for a variety of types of cancers today. In myeloma, Blenrep targets BCMA. Why is this a good target? As Dr. Lonial tells his fellows, "Everything bad that a myeloma cell wants to do is mediated by BCMA." 

Dr. Lonial showed how long and durable the responses were in all of the Blenrep trials and suggested that the administration schedule could still be optimized by adjusting the quantity and frequency of the dose. This could lead to maintained or even improved benefits lowering eye-related side effects. "Less is more" was first coined by architect Ludwig Mies Van der Rohe in ancient Greece, and the phrase seems to apply to this situation. Dr. Lonial suggested that physicians should consider lowering the dose and spacing out the administration frequency to achieve an equal impact with fewer side effects. 

The data from these two studies suggest that Blenrep will continue on its path to regain regulatory approval in the US as another way to target BCMA that is completely different from CAR T-cell therapy and bispecific antibody approaches. For patients who need effective therapy after their first line of treatment or are unable to receive CAR T or stay on bispecifics long-term due to infections or other side effects, it would be a welcome option. 

Patients will always celebrate new tools in the myeloma toolbox, which will allow doctors and patients to be as flexible as possible in individualizing their best path forward with myeloma.

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Sources: 

• DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM).
• Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM).
• Belantamab Mafodotin combination reduced the risk of disease progression or death by nearly 50% versus standard of care combination in relapsed/refractory multiple myeloma