CAR T-Cell Therapy for the Management of Multiple Myeloma - Episode 5

CAR T-Cell Therapy in Relapsed/Refractory MM

Parameswaran Hari, MD, MRCP, of the Medical College of Wisconsin, comments on the rationale for studying CAR T-cell therapy as a treatment option for relapsed/refractory multiple myeloma and the discusses the role of more recent data in supporting cost and coverage decisions by payers.

Parameswaran Hari, MD, MRCP: In a managed care setting, when we think about CAR T [chimeric antigen receptor T-cell therapy], we think about the length of remission that a patient can expect to get from CAR T. Diffuse large B-cell lymphoma [DLBCL], which is the most common use of an approved CAR T agent in the United States, is a curable disease. It can be cured by chemotherapy in a proportion of patients. Another proportion of patients who fail chemotherapy cure, can be cured by autologous stem cell transplantation. Additionally, for patients who are either ineligible or unable to get cured by autologous transplantation, a further proportion of patients can be cured by CAR T-cell therapy. That is how we approach CAR T for lymphoma, especially for DLBCL.

Regarding multiple myeloma [MM], it’s generally considered an incurable disease. However, MM is associated with a very long survival now compared to 10 or 20 years ago. Patients with MM can expect to live decades with good care and ongoing therapies.

CAR T in the setting of MM is now shown to be associated with a long progression-free survival [PFS], which means in the one-and-done approach, you get CAR T cells in relapsed/refractory myeloma [RRMM], and even in triple class-refractory myeloma, where the patient can then expect to have about a year of remission where they don’t feel the [adverse] effects of treatment or the [adverse] effects of having the disease. In the recently concluded ASH [American Society of Hematology] 2020 meeting, we found that even when that PFS is only about a year, the overall survival [OS] of those patients can be 3 years or so.

Presumably, this is because the patient gets a break from treatment, from repeated cytotoxic marrow-damaging treatments, and receives a clean break for about a year or sometimes longer. That break restores them to fair health, which means that they can have a second attempt at the agents that they may have failed previously.

Within the managed care setting, we need to approach the cost and the real utility of this therapy in the benefits to the patient in terms of economic activity, restoration of health for a defined long period, and the opportunity to live a longer life than they would have otherwise, even though the actual duration of benefits from the CAR T itself may not be as much as that in lymphoma.

My experience with CAR T in DLBCL has been in the clinical trial setting and the post-approval FDA-approved commercial setting. In both of these settings, we find that patients who have pretty much run out of options have now been able to get cured, and the proportion of patients getting cured are getting a little better, as CAR T has moved more into the earlier line of treatment compared to when it was in clinical trials.

In clinical trials, we saw at least 50%, sometimes more or less, based on the exact type of CAR T therapy that was used, achieve a deep, complete response at day 28. Most of these responses, up to 60% to 70%, were longstanding, which meant that about 30% to 35% of patients who were basically incurable and likely to die from the lymphoma, imminently were cured. That is a big success.

As CAR T became commercial outside of clinical trials, we found that the number of patients undergoing autologous transplantation for lymphoma, which is also a curative treatment for relapsed diffuse large B-cell lymphoma, were now coming to CAR T even prior to [transplant]. Also, the safety profile of CAR T is slightly better than that of autologous transplantation, and patients, even in advanced years of life who we would not have considered for autotransplant, are now able to receive CAR T and then are effectively cure. Getting CAR T earlier in the disease course and making the CAR T available to people who necessarily would not be clinical trial candidates or autotransplant candidates, has changed the success ratio for CAR T in DLBCL.

In real-world studies, especially done by the CIBMTR [Center for International Blood and Marrow Transplant Research] and the immuno-oncology trial registry, have shown that the success of CAR T post-approval has mirrored that of the success of CAR T in the limited setting of clinical trials.

I expect that for RRMM, when CAR T eventually gets approved, it will be a very similar experience to that of DLBCL, ie, there will be initial barriers to uptake based on the limited number of centers that can offer this. There will also be some barriers to uptake in the real-world setting based on finances of the patient, financial situation from the insurance company, approvals, preapprovals, etc. This may be a barrier that I would consider artificial, as it can be overcome by education, communication, and insurance contracts. However, once those have been resolved, I would expect CAR T to move further ahead of the game than in the clinical trials.

In clinical trials, what we find is that most patients who get referred to CAR T clinical trials are, unfortunately, in a very advanced state of myeloma, and many of them cannot wait. Many people have died on CAR T waiting lists. There is limited access because it’s a clinical trial, and each center gets a slot, and the slots are hard to come by. When you get a slot, there are many people, and you must make a very painful decision sometimes to allocate it to the patient whose disease is the slowest growing. If a person’s disease is fast growing, for example, they may fail, get admitted, get infected, or have low blood counts, which then prevent them from going on the CAR T trial.

Those barriers, which are because of the entry criteria of the clinical trial and the pace of the disease, may prove to be less of a barrier when the CAR T is commercially available and we don’t need approval from the trial, or allotment of slots from the trial to go forward. On the other hand, there will be off-the-shelf agents that could compete with CAR T that are also getting approved. We already have BCMA-targeted medication that’s approved called belantamab mafodotin, which is off the shelf. Patients might receive belantamab mafodotin while waiting for CAR T, or instead of CAR T, and we don’t know the benefit of CAR T cells after using this agent. Some of these other elements will depend on what the available competing therapies are. However, I expect to see a substantial uptake of CAR T among patients after approval, while patients who are relapsing relatively early will derive substantial benefit early on, right after the approval.