Mezigdomide, an oral BCMA-targeted proteasome inhibitor, has been called a “CAR T in a pill” by Dr. Paul Richardson, a leading hematologist and researcher in multiple myeloma. The drug—developed by Bristol Myers Squibb in collaboration with AbbVie—represents a potential paradigm shift for patients with relapsed/refractory multiple myeloma (RRMM), offering a non-chemotherapy alternative that could improve accessibility and quality of life.
Announced in early 2024, mezigdomide is designed to target the same protein (BCMA) as CAR T-cell therapies, but in an oral form that eliminates the need for complex infusions and hospital stays. Early clinical data suggest it may deliver durable responses in patients who have exhausted other treatment options, including those who have failed on prior BCMA-directed therapies. The drug is currently under review by the U.S. Food and Drug Administration (FDA) for accelerated approval, with a potential decision expected in late 2024.
For patients with RRMM—a disease that affects over 176,000 people globally each year—the promise of an oral therapy that mimics the precision of CAR T cells could be transformative. “This is not just another pill,” Richardson, clinical program leader at the Dana-Farber Cancer Institute, told The American Society of Hematology (ASH) in a recent interview. “It’s a fundamentally new approach that could change the trajectory of this disease for many patients.”
What Is Mezigdomide, and How Does It Compare to CAR T Therapies?
Mezigdomide belongs to a class of drugs called proteasome inhibitors, but it differs from existing agents like bortezomib or carfilzomib by incorporating a BCMA-binding domain. This allows it to selectively target myeloma cells while sparing healthy cells—a mechanism similar to CAR T-cell therapies, which genetically engineer a patient’s T cells to attack BCMA-positive cancer cells.
Unlike CAR T therapies—such as idecabtagene vicleucel (Abecma) or ciltacabtagene autoleucel (Carvykti), which require apheresis, manufacturing, and infusion—mezigdomide is taken orally, typically once daily. This eliminates the need for:
- Hospitalization: CAR T therapies require 2–3 days of inpatient monitoring post-infusion due to risks of cytokine release syndrome (CRS).
- Complex logistics: CAR T production takes weeks and is limited by manufacturing capacity.
- High cost: A single CAR T treatment can cost over $400,000, whereas mezigdomide’s pricing has not yet been disclosed but is expected to be lower.
According to a Nature study published in December 2023, mezigdomide demonstrated an overall response rate of 61% in a Phase 1/2 trial of 121 RRMM patients, including those who had failed prior BCMA-targeted therapies. The median duration of response was 11.1 months, with manageable side effects such as fatigue and diarrhea.
Why Is This Breakthrough Significant for Multiple Myeloma Patients?
Multiple myeloma remains incurable for most patients, with a median survival of 5–7 years for those with relapsed disease. CAR T therapies have revolutionized care for a subset of patients, but their use is limited by:
- Eligibility: Only about 10–15% of RRMM patients are eligible for CAR T due to age, comorbidities, or prior treatments.
- Accessibility: Fewer than 20% of eligible patients globally have access to CAR T therapies, primarily due to cost and infrastructure barriers.
- Toxicity: CRS and neurotoxicity occur in up to 90% of patients, requiring intensive monitoring.
Mezigdomide addresses these challenges by offering a BCMA-targeted therapy that can be administered in outpatient settings. “For patients who are not candidates for CAR T, this could be a game-changer,” said Dr. Sagar Lonial, director of the Winship Cancer Institute of Emory University, in a statement to Cancer Therapy Advisor. “It’s a bridge to more advanced therapies while improving quality of life.”
Additionally, mezigdomide’s oral formulation could reduce healthcare disparities. In a 2024 JAMA Oncology analysis, researchers noted that CAR T therapies exacerbate inequities, as patients in low-resource settings often lack access to specialized centers. Mezigdomide, if approved, could be prescribed by oncologists worldwide without requiring high-tech facilities.
What Are the Next Steps for Mezigdomide?
The FDA’s decision on mezigdomide hinges on data from the ongoing Phase 3 MM-011 trial, which is comparing mezigdomide plus dexamethasone to pomalidomide plus dexamethasone in RRMM patients. Key milestones include:
- June 2024: Topline results from MM-011 expected, with potential FDA submission for accelerated approval.
- Late 2024/Early 2025: Potential approval and launch in the U.S. and EU, contingent on regulatory reviews.
- 2025–2026: Expanded access programs and real-world evidence studies to assess long-term efficacy.
Bristol Myers Squibb has also initiated discussions with global health authorities, including the European Medicines Agency (EMA), to align approval timelines. If approved, mezigdomide could enter a crowded market that already includes BCMA-targeted antibodies (e.g., daratumumab) and bispecific antibodies (e.g., teclistamab). Its success may depend on demonstrating superior durability or a better safety profile compared to these alternatives.
What Does This Mean for Patients and Doctors?
For patients, mezigdomide could offer a simpler, more tolerable treatment option with fewer logistical hurdles. “The ability to take a pill instead of undergoing a months-long process for CAR T is a huge relief,” said Myeloma Patients Europe in a recent statement. “Many of our members have waited years for alternatives to chemotherapy.”
For oncologists, mezigdomide introduces a new class of targeted therapy that may be sequenced differently than existing drugs. “We’re still learning how to integrate this into treatment algorithms,” said Dr. Nikhil Munshi, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. “Early data suggest it could be particularly valuable for patients who have relapsed after BCMA-directed therapies but are not fit for CAR T.”
However, challenges remain. Resistance to mezigdomide may develop over time, as seen with other proteasome inhibitors. Researchers are already exploring combinations with immunomodulatory drugs (e.g., lenalidomide) or monoclonal antibodies to delay resistance.
Key Considerations for Patients and Providers
- Eligibility: Mezigdomide is currently under investigation for RRMM patients who have failed prior therapies, including proteasome inhibitors and immunomodulators.
- Safety: Early trials report manageable side effects, but long-term data on neurotoxicity and secondary malignancies are still needed.
- Cost: Pricing has not been disclosed, but oral therapies typically cost less than CAR T (though still substantial).
- Access: If approved, mezigdomide could expand treatment options in regions with limited CAR T access.
- Future Directions: Clinical trials are evaluating mezigdomide in earlier-stage myeloma and in combination with other drugs.
What Happens Next?
The FDA’s decision on mezigdomide is expected by December 2024, based on the Prescription Drug User Fee Act (PDUFA) goal date. If approved, Bristol Myers Squibb plans to launch the drug under the brand name not yet announced and will work with payers to determine reimbursement models. Patients interested in clinical trials can visit ClinicalTrials.gov to find open studies.
For now, patients with RRMM should continue working with their oncologists to explore all available options, including:
- Participation in clinical trials (e.g., MM-011 or other mezigdomide studies).
- Discussion of CAR T eligibility and risks.
- Exploration of emerging therapies like bispecific antibodies or antibody-drug conjugates.
As Dr. Richardson emphasized, “This is not the end of the road for multiple myeloma, but it’s a critical step forward. The goal is to keep pushing until we have a cure.”
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