As you are probably aware, there’s been tremendous progress in the world of multiple myeloma research, especially surrounding the new class of drugs referred to as "immunotherapy".
Dr. Omar Nadeem shared with the Boston Round Table audience the progress that immunotherapy has made in the myeloma world in recent years, as well as the future of immunotherapy products like CAR T-Cell therapy and bi-specific antibody therapy in front-line treatment for newly diagnosed myeloma patients.
Watch the video to learn more or read the summary below.
The Standard of Care in Myeloma Treatment
Over the past decade, multiple myeloma treatment has accelerated, providing many new and effective options for multiple myeloma treatments to use when facing this complicated disease.
In the late 90s, the standard of care for multiple myeloma patients was the autologous stem cell transplant, which is still commonly used and widely effective today.
Later, novel drugs like lenalidomide (REVLIMID) and bortezomib (VELCADE) entered the myeloma arsenal, providing physicians with better induction therapies and patients with longer longevity and higher quality of life.
Things only continued to improve from there, with pomalidomide (POMALYST), carfilzomib (Kyprolis), and daratumumab (DARZALEX), along with several other drugs being approved in the 2010s. With these new treatments, the standard 3-5 years of expected survival soon turned to closer to a decade.
Within this new decade, recently approved immunotherapies have improved myeloma treatment even further. CAR T-cell therapy and bi-specific antibody therapies produce extremely encouraging results in myeloma populations where patients are refractory (unresponsive) to other myeloma drugs.
Who Qualifies for CAR-T and Bi-specific Antibody Therapies In Today's Myeloma?
As of late September 2023, CAR T-cell therapy and bi-specific antibody therapy is currently only commercially available for those myeloma patients who have been through four prior lines of therapy.
Essentially, this means that most patients are only qualified to receive this promising treatment on their fifth relapse.
This is extremely frustrating for both myeloma physicians and patients alike, but because of safety precautions and ethical clinical trials, this is where the current FDA approval lies.
That being said, much is being done to move these immunotherapies up the line towards those who are on the first or second relapse and even being tested in the newly diagnosed and precursor (smoldering myeloma) settings.
Targets in Multiple Myeloma Immunotherapies
BCMA is a protein found on the surface of plasma cells, including mutated plasma cells. This is currently the most common target for immunotherapies used to treat multiple myeloma, although other targets are also being investigated.
Research is being done to test another protein as a target, called GPRC5D. A CAR-T cell therapy and at least one bi-specific therapy are being tested with this new target and are getting closer to possible FDA approval.
Other immunotherapies are being developed to target another protein called FcRH5.
Each of the respective treatments targeting different proteins has its own unique side effects due to the other cells that exist in the human body that share that protein on the surface of their cells (i.e. BCMA with other plasma cells, GPRC5D on quickly-dividing cells like hair and skin, etc.)
CAR-T Therapies for Multiple Myeloma Patients
Chimeric Antigen Receptor (CAR) T-cells are re-engineered T-cells from your own immune system that are put back into your body after a brief chemo-deleting treatment to target and kill myeloma cells that exist within you.
It does this by programming the CAR T-cells to recognize BCMA and attack cells with this protein on its surface.
CAR-T therapy is performed through the following steps:
- Apheresis (collection) of your T-cells
- A 4-8 week waiting game in which your cells are sent to the lab, re-engineered, and sent back
- Three days of low-dose chemotherapy to make room for the new T-cells
- Redistribution of T-cells into your body
The length of this process can be a challenge for those with a high disease burden and an urgent need for treatment.
As of September 2023, the FDA has approved two CAR T-cell therapies for myeloma.
They are Idecabtagene-Vicleucel (ide-cel), commercially known as ABECMA and Ciltacabtagene Autoleucel (cilta-cel), which is commercially known as CARVYKTI.
Though the two therapies have never gone head-to-head in a clinical trial, real-world data gives us a glimpse of how the two compare.
ABECMA did well with treating multiple myeloma and introduced the myeloma world to CAR-T. Typical responses last one year.
The results of CARVYKTI were even better, with almost 100% response rate within the clinical trial patient data.
CRS (cytokine release syndrome), a side effect of immunotherapies, presents one week out from CARVYKTI and only one day for ABECMA.
In some areas, because of the delayed CRS side effects, CARVYKTI is now being delivered as an outpatient with constant supervision instead of a whole week hospital stay. If there is a fever, they are then committed to the hospital. There are some known Parkinson’s like symptoms after CARVYKTI.
The Future of CAR-T Therapies in Myeloma
The predicted future of CAR T-cell Therapy is that it will become an option for myeloma patients on their first or second relapse, maybe even in the newly diagnosed setting.
One of the benefits of moving this therapy up is that patients' immune systems are much healthier.
There is also usually less urgency regarding patients needing to wait for their cells to be engineered.
T-cells are less exhausted in the earlier stages, and it's more cost-effective as most myeloma therapies work better in earlier lines, and maintenance drugs cost the patient and the company less money.
To learn more about current and future trials surrounding CAR-T Therapy, watch Dr. Nadeem's talk here.
Bispecific Antibody Treatment for Multiple Myeloma
Bispecific antibody therapies are a myeloma treatment that influences your T-cells by using an antibody drug to recognize and kill myeloma cells.
The mechanism of the CAR T-cell treatment and bispecific antibody treatment is similar, but bispecific antibody therapy does not require apheresis and is available off-the-shelf compared to the waiting game of CAR-T.
The overall responses are similar to those of CAR-T.
In general, the side effects of bispecific antibody therapy are a bit milder than CAR T cells, but the continuous therapy element of it complicates it.
Many infections are being seen, and dosing and frequency are changing in the real world, but more research is needed here.
The two bispecific antibody treatments that use BCMA-directed therapy are:
The two have been compared because of their similar mechanisms of action, but only real-world data will tell if one has the advantage over the other.
The other FDA-approved bispecific antibody therapy treatment targets GPRC5D.
It's called Talquetamab.
This bispecific has a different toxicity profile because it targets GPRC5D instead of BCMA. Thankfully, it gives another option for patients who have received several BCMA-directed therapies back-to-back.
When it comes to combining bispecific antibody therapies like teclistimab and talquetamab, the overall response rate was extremely promising.
From the data collected so far, the combination of bispecific therapies presents the same side effect profile as each individual bispecific, meaning the side effects don't double or become more adverse by combining the medications. Specifically combining talquetamab and teclistimab has shown very promising results.
Dr. Nadeem shared the possible benefits of moving immunotherapy to even the precursor stage, let alone the newly diagnosed stage of myeloma. Immunotherapy might make a lot more sense to those with smoldering myeloma. You could possibly cure the disease before it ever progresses.
Testing immunotherapies in clinical trials for high-risk smoldering myeloma patients. The first results will be presented at this year's ASH conference!
Immunotherapy is changing the game in myeloma treatment. Specialists expect immunotherapy to become the standard of care in earlier lines of therapy in the coming two years. Maybe there will be a role for immunotherapy within precursor myeloma treatment eventually.
Talk to your doctor if you think immunotherapy might be right for you!
about the author
Audrey is the Editor for the HealthTree Foundation for Multiple Myeloma. She originally joined the HealthTree Foundation in 2020 as the Myeloma Community Program Director. While not knowing much about myeloma initially, she worked hard to educate herself, empathize and learn from others' experiences. She loves this job. Audrey is passionate about serving others, loves learning, and enjoys iced chais from Dutch Bros. She also loves spending time with her supportive husband and energetic three-year-old.