CAR-T for multiple myeloma: earlier treatment, new targets and ‘patient-friendly’ care
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Although chimeric antigen receptor T-cell therapy is approved for treatment of multiple myeloma, commercially available products are limited to patients who received at least four prior lines of therapy.
Given its impressive activity among heavily pretreated patients, commercial sponsors aim to test CAR-T as earlier therapy in clinical trials, while other researchers are developing novel CAR-T constructs with a wider array of targets for the disease.
It is never too early to consider the use of CAR T cells for multiple myeloma, according to Nina Shah, MD, professor of clinical medicine at University of California, San Francisco, and chair of Society for Immunotherapy of Cancer’s (SITC’s) Multiple Myeloma Immunotherapy Guideline Expert Panel.
In this installment of In Practice, Shah reviews the CAR-T landscape for multiple myeloma, including commercially available therapies, investigational options and what the clinical community can do to provide these treatments to more patients.
Healio: When should a community-level physician consider referring a patient with multiple myeloma to a CAR-T center?
Shah: Referrals as early as possible are preferred. Most patients with multiple myeloma can benefit from referral to a CAR-T center or a center with myeloma expertise because the patient might be eligible for a clinical trial or have the option of doing either hematopoietic stem cell transplantation or CAR-T, which typically requires treatment at a specialized care center. One positive aspect of the current CAR-T process is the relationships that have developed between community-level physicians and academic physicians. This collaboration means two people are on the case, which reassures academic center clinicians, community-level doctors and patients alike. This coordination between two different physicians not only helps ensure that the patient is being evaluated from the beginning for all possible therapies, but also increases access to clinical trials and the depth of coverage for the patient.
Healio: Can you describe the landscape for commercially available CAR-T?
Shah: We have two FDA-approved products in the United States for multiple myeloma. Both are directed against B-cell maturation antigen (BCMA). Approval for idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) — often called ide-cel — was based on results from the phase 2 KarMMa trial. Ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech), often called cilta-cel, was approved in March and evaluated as part of the phase 2 CARTITUDE-1 trial. Patients had overall response rates between 73% and 98% for these products, and had very durable responses depending on which cell dose they received. Both studies included heavily pretreated patients who had a median six prior lines of therapy, and FDA approval for both products requires patients have received at least four prior lines of therapy.
Healio: What impact have these approvals had on clinical care?
Shah: Clinicians generally still approach myeloma the same way, including induction therapy and — for many of our patients — HSCT and maintenance therapy. Now therapies are available beyond the usual relapsed/refractory ones, which means we can keep CAR-T on the back burner as an option for later use. For patients who are newly diagnosed, CAR-T may one day become more available and used earlier after patients proceed to induction and first-line treatment.
Discussion about CAR-T occur more frequently for patients with relapsed or refractory disease. Because patients often are highly educated about their own disease, many of them have heard about CAR-T and bring it up in our conversations. I would recommend discussing with patients all that the CAR-T process requires. It’s also smart to mention that CAR-T may not be available all the time and discuss its limitations. It is best for clinicians to manage their own expectations, as well as those of their patients.
Healio: How do the safety and efficacy profiles of cilta-cel and ide-cel compare?
Shah: Both therapies are very effective for heavily pretreated patients. The overall response rate was slightly higher in the CARTITUDE-1 study of cilta-cel. Results thus far suggest median PFS is higher with cilta-cel, but mature PFS data are not yet available. Nevertheless, I think both therapies are very effective, having worked with both of them in the preclinical and preapproval setting.
Healio: Is one therapy preferable for certain patients?
Shah: I tell patients we will use whatever CAR-T we can get because neither therapy is continually available due to the scarcity of manufacturing slots. Some factors may lead me to choose one therapy over another. If I wanted reliable timing of cytokine release syndrome, I might choose ide-cel over cilta-cel because the median time of CRS in the KarMMa trial was 1 day, whereas cilta-cel is a bit more variable with a CRS onset at a median 7 days after infusion. If a patient has underlying Parkinson’s or neurocognitive symptoms, I might not choose cilta-cel because a small percentage of patients — less than 1% in the entire CARTITUDE-1 trial — had some neurologic side effects, many of which are reversible. If there is a choice between the two therapies, I would advise starting with availability and then considering efficacy. I also would caution against making these judgments because — in terms of efficacy — we lack real-world data that prospectively compares both treatments.
Healio: What is causing the manufacturing delays?
Shah: There is a bottleneck of patients with multiple myeloma who have been waiting up to 2 years to receive CAR-T. Add this to the number of new patients who now qualify as relapsed or refractory and there are many more patients in need of the therapy than can be handled by the number of available manufacturing slots.
Healio: What can clinicians do to expedite the process for their patients?
Shah: Clinicians need to educate patients as much as possible so there are no delays regarding requirements — such as the need for a caregiver — or uncertainty among potential recipients. We must communicate early and effectively with patients, including referring them to patient education sites and advocacy groups, which provide useful information so patients can be prepared for the next step in the CAR-T process.
Healio: Are there any CAR-T in development that target something other than BCMA?
Shah: A couple of investigational CAR-Ts are using novel targets. At the most recent ASH Annual Meeting and Exposition, Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center presented phase 1 results of the MCAR program that targets GPRC5D, which is believed to be another myeloma-specific target. Results from this study showed very nice response rates, especially among patients who received prior BCMA-directed therapy. Cellectis also has an investigational allogeneic CAR-T that targets SLAMF7, which is the same target protein employed in the FDA-approved monoclonal antibody elotuzumab (Empliciti, Bristol Myers Squibb). Both therapies may be used after, in addition to or before BCMA-directed CAR T-cell therapy.
Healio: Do you recommend certain patients seek enrollment into clinical trials evaluating BCMA-directed CAR-T as an earlier line of therapy?
Shah: CAR-T could be beneficial for anybody as second-line therapy and should not necessarily be limited as earlier therapy only to patients with high-risk or early-relapse disease. Anyone with disease burden that CAR T-cell therapy can readily address should consider an available trial. Patients who experience garden-variety relapse on lenalidomide (Revlimid, Celgene) should be eligible to get CAR-T if the data in ongoing trials continue to support this option.
Healio: How is BCMA-directed CAR-T performing thus far in trials for patients with early initial relapse?
Shah: A cohort in the CARTITUDE-2 study, in which patients received cilta-cel after early relapse, showed very good response rates. The bigger question is duration of response. We don’t yet have that data. Current evidence shows that combining CD38-directed therapy with carfilzomib (Kyprolis, Amgen) yields a median duration of response of almost 2.5 years to 3 years, which is the current gold standard for treatment of early-relapse patients. It will be interesting to see if CAR-T can outperform this combination for second- and third-line therapy.
Healio: What should clinicians consider as their next step if a patient has disease progression after BCMA-directed CAR-T?
Shah: These patients are extremely difficult to salvage and should be matched with a clinical trial if possible. If a trial is not available, they should be referred for treatments that have not yet been tried in a particular patient.
Healio: Research has suggested racial and ethnic disparities in CAR-T trial participation, especially for multiple myeloma. What can be done to address this?
Shah: CAR-T must be more patient-friendly to be given more widely. The use of remote medicine/telemedicine is important for getting that initial consult. Once the patient connects with a cell therapy specialist, that relationship and the feeling that they are being taken care of could alleviate some of the fear a patient might have about enrolling in a clinical trial, traveling to a big city for treatment, or being treated at an unfamiliar specialty center.
More consultations with specialty practices and community-level physicians could ensure more patients are aware of available trials. Half of the problem with delivering novel investigational therapies to underserved communities is that patients and other clinicians are not aware of what is being offered. From the standpoint of the myeloma or clinical trials community — which includes the commercial sponsors, as well as the investigators — information has to be widespread and not just on limited channels that may not be accessible to certain patient populations.
Finally, although active treatment will have to be conducted onsite at a specialty center, the rest of the CAR-T process often can be done locally. There is no rocket science involved with monitoring for adverse events and long-term side effects. If we could be a bit more flexible about where and how certain parts of the process are done, more people would have access to CAR T-cell therapy.
Reference:
Mailankody S, et al. Abstract 827. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
For more information:
Nina Shah, MD, can be reached at UCSF, HBC Program, 400 Parnassus Ave., Fourth floor, San Francisco, CA 94143; email: nina.shah@ucsf.edu.
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