MC Community Event: Know Your Myeloma Therapy: BLENREP

On May 14th, 2021, Dr. Joshua Richter joined our Immunotherapy Treatment Chapter to explain how BLENREP (belantamab mafodotin-blmf) is being used in the clinic, who qualifies for it, and how to properly manage side effects. Dr. Richter is the director of the Multiple Myeloma program at the Blavatnik-Chelsea Medical Center at Mount Sinai Hospital in New York City, New York. Jenny Ahlstrom, founder of the Myeloma Crowd by HealthTree, joined us to moderate this event.

Both Dr. Ricther's informative presentation and the interactive Q&A session both educated and empowered those who watched. You can watch the recording of the session below and/or read the summary to learn more about one of the newest drugs in the myeloma arsenal, BLENREP, and see if it's right for you on your myeloma journey. 

Immunotherapy Treatment Chapter Intro

• Immunotherapy is taking front and center stage. While chemotherapy is still being used, we are shifting more towards an immunotherapy approach when treating myeloma. 
  • Classical chemotherapy looked at myeloma as an immune disorder and said, let's knock down all immune cells (good and bad). 
  • Immunotherapy treatments recognize that the immune cells that attack cancer should increase, while the cancer cells should be killed off. 

BCMA as a Target in Myeloma Treatment

• Classical chemotherapy was developed around the end of World War II was invented with the notion that cancer cells divide rapidly without following our bodies' cues that cancer cells should die, so it just killed things randomly. 
• Now we use targeted agents or agents that specifically targeted for something that is on the cancer cells and ideally nothing else. 
• BCMA is an antigen expressed specifically on plasma and myeloma cells. It's an easy target. There are three ways that we are currently targeting the BCMA antigen.
  • The first is belantamab, which is what we are going to talk about later. 
  • The second is with CAR T cells, training T cells to target BCMA
  • The third is called the bi-functional antibody, targeting both BCMA and CD3
• The BCMA can float off the cell and circulate,(soluble BCMA) research is being done to see if you can use it to monitor myeloma

Antibody-Drug Conjugates (ADCs) in Multiple Myeloma 

• BCMA is currently being used in BLENREP as an antibody-drug conjugate. This means it has part of the antibody that attaches itself to the BCMA, once it has found that cell it injects it with poison. 

Belantamab Mafodotin: BCMA-Targeted ADC 

• BLENREP is an IgG antibody, specifically engineered to target BCMA
• The toxin that the ADC drops into the cell is called MMAF, which ultimately triggers death within the cancer cell 
• BLENREP was approved by FDA in August 2020 as therapy for relapsed/refractory patients who have received at least 4 lines of previous therapy.
  • These previous therapies include a PI or proteasome inhibitors (such as Velcade), an IMiD or immunomodulatory drug (like REVLIMID), and an anti-CD38 monoclonal antibody (such as daratumumab) 

First ADC Approved in Multiple Myeloma 

• This is the first antibody-drug conjugate approved for multiple myeloma. There are other ADCs approved for other cancers such as leukemia and lymphoma that are extremely efficacious in those settings. 
• The starting dose is 2.5 mg/kg, given via IV for approximately 30 minutes once every 3 weeks. 
• It's approved without a steroid, so you can take this without one! 

Phase II DREAMM-2: Belantamab Mafodotin in Relapsed/Refractory Myeloma 

• The FDA approved this drug based on a study called the DREAMM-2 study. It looked at giving belantamab at two different doses (2.5 mg/kg and 3.4 mg/kg)
• Patients had an average of 6-7 lines of therapy in the study, while some patients even had 20+ lines of therapy 
• This drug is not approved for early relapsed patients
• The overall response rate is around 30%. At first glance, 30% might not seem like all that much. However, all the drugs approved at myeloma are approved at the end of the line and have an average of 30% overall response. 
• All drugs in the myeloma arsenal are approved at the end of the line for relapsed and refractory patients. As researchers and specialists learn how to properly administer the drug and with medications to combine it with, the drug advances further up the myeloma patient diagnosis timeline and the overall response rate improves significantly.
• The median progression-free survival was around 2-5 months, (time you are remission), the OSS or overall survival had not been reached, which is encouraging. 

Belantamab Mafodotin: Select AES in DREAMM-2

• The main issue with this drug is ocular or eye problems. It causes corneal events (abnormalities in the eyes) or keratopathy. 
• Corneal events occurred in 75% of the patients who participated in this trial. These effects could be small such as dry eye or small changes in visual activity, however, it could progress to something more concerning such as blurred vision or a decrease in the ability to see. 
• In general, it was reversible by holding the drug and allowing the body to heal itself. They tried to prevent it through eyedrops, but the main success in management came from holding the drug instead of every 3 weeks to be administered every 4-6 weeks. 
• As a result of this, the FDA approved BLENREP with something called a REMS (a risk evaluation and mitigation system). What this means is that your provider has to go through a variety of steps to give this to you. One of these steps is that every time you get a dose of the drug, within one week prior you need to be evaluated by an optometrist to make sure that you're not having any untoward side effects with the drug. 

Currently Available ADC Side Effects 

• The main side effect is the eye side effects. 
  • Solution: lubricant eye drops, frequent visits to the optometrist, spacing out the doses of the drug
• There is a small lowering of the platelets. 
  • Solution: monitoring, only give transfusions if need be. 
  • Infusion reactions are quite rare.

Ocular Toxicity Management  

• When the optometrist evaluates you, they will be looking for changes in the corneal epithelium (the outer lying of your eye), ulcers, dry eye, etc. 
• Weekly visits to the optometrist may be necessary until your symptoms have improved. 

DREAMM-6: Study Design (VD Arm)

• As we talked about earlier, myeloma drugs are originally approved by themselves near the end of the therapy lines. As time goes on, we learn how to use them in better combinations. 
• This DREAMM-6 study is the most mature of all of the combinations right now. This is combining BLENREP with bortezomib (Velcade) and dexamethasone. 
• When you give a drug earlier on in combination, the response rate changes quite a bit. The ORR (overall response rate) was at 78% instead of 30%.
• Half of the patients enrolled in the study have experienced a significant decrease in their myeloma, more than a 90% reduction. 
• This study is ongoing. 

Clinical Trials Currently Planned and/or Recruiting with Belamf in Multiple Myeloma 

• There are a variety of DREAMM clinical trials active right now looking to combine BLENREP with other well-known myeloma medications and therapies such as RVD or pomalidomide. This could potentially allow BLENREP to be approved with induction therapies. 
• There are also trials looking to combine BLENREP with other cancer-approved drugs that have not yet been successful in treating myeloma.
• There are also trials looking at the standard of care to answer general questions about the quality of life during treatments. 

Sample of the Question and Answer Session

• Q: Although it was approved by itself by the FDA, is the current real-world application of BLENREP usually in a combination with other drugs? 
  • A: It is being given in a combination with Velcade, or sometimes just by itself. Some patients find great success in just being treated with BLENREP. It's a split.
• Q: So for those patients who are having success being treated with just the BLENREP, is there a common patient profile that you are seeing? 
  • A: While we aren't sure yet what patient profiles have the most success when being treated by BLENREP, it is a great drug for people who have been through multiple lines of therapy that isn't extremely obvious. Right now in myeloma treatment, the three BCMA targeted therapies are BLENREP, CAR T Cell therapy, and bi-specific antibodies. While CAR T is great, it can often be toxic, so that leaves us with BLENREP (or something similar) and bispecific antibody treatments. The more treatments you have been on as a myeloma patient, the more tired your T-cells are. So while some people react positively to the bi-specific antibody treatments, others have T-cells that are just too tired. The great part about BLENREP is that it doesn't use the T-cells as much, but rather finds the cancer cells and kills them directly. 
  • We have a feeling that bi-specifics might be better earlier on in myeloma treatments, and that ADCs may do better later in treatment. 
• Q: We see through your presentation that when lowering the dose or spacing out the treatments, the drug still continues to have the same efficacy. Do you have any comments on this? 
  • We do a lot of our learning after the drug gets approved. Velcade used to be a totally intravenous drug and cause neuropathy in large amounts of people. Then we learned years after its approval that giving it subcutaneously was far better tolerated with the same efficacy. Selinexor when it was first approved was given twice a week and was very toxic. Now we give it once a week in combination where it is far better tolerated. The same thing will happen with BLENREP as we use it in the clinic, we gain experience as a community and see how to nuance it better or worse. I think the future of this drug will be in combinations and be administered every 4, 6, or even 8 weeks. If it gets approved in combination with RVD as induction therapy, because the backbone of the therapy is so good, I could see BLENREP being administered every 2 weeks, producing far fewer eye problems and much better responses. 
• Q: Why is eye toxicity common in ADC drugs? 
  • This isn't fully known, it has to do with the payload itself. Some of the poisons we give have a tropism where it just happens to go to certain areas and inject its toxicity. This is seen in other drugs that exist in other cancers. 

Watch the video for the entire Q&A Session and register for the Immunotherapy Treatment Chapter below in order to hear more educational sessions from experts such as this! 

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A special thanks to our Myeloma Crowd Community Sponsors, without whom this event would not have been possible: