FDA Advisory Committee Rejects Blenrep Combo Therapies—But a Positive Vote is Possible for Myeloma Patients Seeking New Options

The road for the first BCMA-targeting antibody drug conjugate (ADC) in myeloma hit a pothole today when a majority of FDA committee advisors voted negatively against the approval of belantamab mafodotin (Blenrep, GSK) both in combination with bortezomib and dexamethasone (3 positive to 5 negative votes) and with pomalidomide and dexamethasone (1 positive to 7 negative votes).

These committee meeting votes are never the final vote. They are advisory votes that the FDA takes under consideration when making their final decision.

The FDA committee had a hard time seeing the forest for the trees—addressing detailed dosing questions they were given while losing sight of the overarching goal of serving myeloma patients and determining whether a product is safe and effective.

I attended the meeting in person and felt the dosing discussion could be reasonably managed through shared decision-making between doctor and patient. The data from these studies show the product to be effective and safe when managed according to plan. As both a patient and a patient advocacy leader, I encourage the FDA team to approve this drug.

A Little History

Belantamab mafodotin was the first ADC targeting BCMA developed to treat multiple myeloma. It was developed by GlaxoSmithKline.

One of their earliest clinical trials was the DREAMM-2 study that compared two different doses in two treatment arms (3.4 mg/kg vs. 2.5 mg/kg). The overall response rate was about 31%.

This is in line with other prior single-agent myeloma FDA approvals for overall response rate (ORR) like daratumumab (29%), selinexor (26%), and carfilzomib (23.7%).

Clearly, CAR-T and bispecific antibody therapies are advancing science as single agents with a 60-95% ORR, however, the data in future Blenrep studies show that when used in combination, it competes well against these modern treatments.

Belantamab mafodotin received FDA accelerated approval based on this data and went on the market in August 2020 with a Risk Evaluation and Mitigation Strategy (REMS) program to alert doctors and patients about potential eye side effects. This was a new side effect for myeloma patients and patients needed to meet with an ophthalmologist or optometrist before each belantamab mafodotin dose.

The side effects were described as “keratopathy” which sounded scary, but mainly meant dry eyes and blurry vision which was manageable and reversible.

To slow these side effects, doctors quickly learned that they could reduce the dose or space out the dose. Remarkably, some patients remained in remission even after discontinuing treatment—an outcome that surprised many physicians. With the accelerated approval, the FDA also set the expectation that a future study would need to confirm the benefit to make the approval permanent.

All eyes were on the confirmatory DREAMM-3 study, which compared belantamab mafodotin alone vs. pomalidomide and dexamethasone. Although the single drug belantamab mafoditin showed longer progression-free survival than the double combination (11 months vs. 7 months), the results were not statistically significant enough, so the drug was voluntarily pulled from the US market in February of 2023. The pull of approval had nothing to do with safety.

DREAMM-7 and DREAMM-8 studies were already underway and GSK chose to continue those studies. Once the data became available years later, it was clear that belantamab mafodotin had legs. It was both safe (with known side effects) and effective.

In the DREAMM-7 study, the progression-free survival (how long patients stayed in remission before relapsing) of belantamab mafodotin with bortezomib and dexamethasone (BVd) combination (36.6 months) was better than daratumumab with bortezomib and dexamethasone (DVd) combination (13.6 months).

This means the BVd patients had 23 more months of remission compared to the DVd group. The dose used was 2.5 mg.

In the DREAMM-8 study, belantamab mafodotin with pomalidomide and dexamethasone (BPd) was compared to pomalidomide with bortezomib and dexamethasone (PVd) and also showed superior progression-free survival (32.6 vs. 12.5 months).

This means that patients on BPd lived 20.1 months longer than the PVd group. The initial dose used was 2.5 mg and was lowered to 1.9 mg over time.

The data confirming drug effectiveness were strong from both studies.

The FDA ODAC Meeting: Asking the Wrong Questions

The FDA ODAC meeting should have answered the important questions about whether the drug was effective, better than the comparator arms and safe, the traditional criteria for market approval. However, the meeting was too heavily focused on a risk vs. benefit analysis - was the risk of eye-related issues (which was high in both studies) worth the benefit with the 2.5 mg dose?

The FDA argued that the 2.5 mg starting dose should have been lowered in both trials, as many patients in the study either delayed or reduced their doses due to side effects. The company explained that the higher starting dose was intended to help get the myeloma under control quickly.

However, even with ad hoc dose reductions given when necessary, the drug retained its effectiveness and performed better than the comparator treatment arms.

This question was asked for each belantamab mafodotin combination (BVd and BPd) to a committee of physicians who had medical experience outside of myeloma. We understand the FDA's need to select unrelated disease committee members to prevent bias or conflict of interest, but also know that they may lack a complete and contextual understanding of the myeloma patient landscape and experience. I call on the FDA to listen more closely to the expert myeloma voices in the room.

Expert Voices in the Room

Several myeloma physicians, including Sagar Lonial, MD, Emory University, Paul Richardson, MD, Dana Farber Cancer Institute, Craig Cole, MD, Karmanos Cancer Center, Saad Usmani, MD, Memorial Sloan Kettering Cancer Center and Hans Lee, MD, Sarah Cannon Research Institute advocated for the approval of belantamab mafodotin because they see a great unmet need for patients. 

They see BCMA as a strategic target and know that most patients across the country can’t or won’t be able to receive a CAR-T or bispecific antibody because they don’t live near an academic medical center. This represents an off-the-shelf option for community center patients.

The experts acknowledged that CAR-T is wonderful, but frail patients aren’t fit enough, it has potentially serious side effects, and some patients just can’t travel to an academic center. Belantamab mafodotin can safely be given in local oncology practices and rural settings.

They shared that this drug solves a critical access issue, since some patients are not willing or are unable to travel. Belantamab mafodotin is an excellent option for patients being treated in nearby community hospitals.

The experts stressed that side effects exist for all myeloma therapies, and they work with their patients to mitigate them. They noted that although the FDA meeting questions focused on dosing, doctors always manage myeloma with dose reductions or treatment holds for each individual patient. Essentially, every myeloma drug we use today has a different dosage or administration schedule than when it was first FDA-approved. Blenrep isn’t different from any other myeloma therapy in that way.

They also shared how they work in tandem with local eye care providers to ensure patients' vision is closely monitored. With over 15 antibody drug conjugates now on the market for other cancers (that also have eye side effects), doctors are becoming more familiar with the management of this side effect.

Patient Voices in the Room

Over an hour of the meeting was dedicated to patient comments and comments from leading advocacy groups like HealthTree, the International Myeloma Foundation, and the Multiple Myeloma Research Foundation, which favored an approval.

Patients who had been on belantamab mafodotin for years shared how this became a lifesaving drug for them when they had run out of options. They talked about how they had been on the drug for four or more years and managed the side effects well. For some, the side effects were minimal. Some shared that compared to their past lines of therapy, this was a treatment that had the most tolerable side effects.

It was clear that the committee's interpretation of the eye side effect data from the clinical trials didn't match the actual patient experience.

The vote at the end of the meeting did not represent the voices of myeloma experts or patients. The committee was laser-focused on answering the limited and highly specific dosing scientific question in front of it. The only committee member who voted yes to both BVd and BPd treatment combinations was John DeFelice, MD, the only myeloma patient.

Risk vs. Benefit—Let Patients Decide

The meeting was mystifying to me as a patient. This drug has been used globally by patients in the real world. It has been successfully used as a last resort for certain patients, giving them years of extra life.

Yes, it has some side effects, but what myeloma drug doesn’t? I respectfully urge the FDA to vote in favor of my ability to choose this therapy with my doctor if I need it, and work with my doctor to manage any side effects carefully.

We know that this drug has been used for over five years, both in the US and in Europe, by over 7,500 patients. Myeloma experts have practical experience with it and favor it. Patients appreciate having the option to use it.

If the side effects become intolerable, they will reduce the dose, space out the dose, or stop the treatment completely, just like they would for any other myeloma drug.

Patients make these risk vs. benefit decisions every day. We ask ourselves if we are willing to tolerate neuropathy with Velcade, anger on dexamethasone, diarrhea on Revlimid, cytokine release syndrome or neurotoxicity on CAR-T, skin peeling and nails falling off on a bispecific antibody.

Are we willing to tolerate specific side effects? It depends.

When I make decisions with my doctor, I consider everything. How effective is the therapy? How bad are the side effects? Do I have to travel? Do I need a caregiver? How long will I be on therapy? How often do I need to be in the clinic? Is the squeeze worth the juice?

This drug passed the efficacy test and met its clinical trial endpoint in two studies. Its side effects are known, manageable, and reversible. Additional steps have been taken to observe patients carefully.

I urge the FDA to allow this treatment to advance. Blocking promising therapies over manageable concerns risks leaving patients with fewer - and sometimes no - viable options left.

As a patient advocate, I am not advocating on behalf of a specific company or a single drug. This issue isn’t related only to these studies.

I am advocating for patients to have choices. I know patients who have relapsed after CAR-T and bispecifics. We still have no myeloma cure. So with the proper guardrails of information and follow-up in place, I implore the FDA to grant access to additional choices, especially those that are helpful for underserved patients.

We are grateful to the FDA for their prior myeloma approvals that have given us CAR-T, bispecific antibodies, monoclonal antibodies, proteasome inhibitors, immunomodulators, and so much more.

My hope and request is that the FDA approves the two treatment combinations based on each study's proven efficacy and safety.

If you’d like to watch the meeting to understand the full context, you can find the recording here.

Source: 

• GSK provides update on US FDA advisory committee review of Blenrep (belantamab mafodotin-blmf) combinations for patients with relapsed/refractory multiple myeloma