Questions Remain as CAR T-Cell Therapy Prepares to Transform Relapsed/Refractory Myeloma Treatment

Luciano J. Costa, MD

Investigational CAR T-cell therapy products have demonstrated unprecedented responses rates with seemingly durable remissions in patients with relapsed/refractory multiple myeloma, explained Luciano J. Costa, MD.

However, questions surrounding accessibility, management strategies with supportive care, and time to treatment still need to be fully answered.

“Ultimately, [CAR T-cell therapy] is a terrific therapeutic advance to be further polished,” said Costa, an associate professor of medicine in the Blood and Marrow Transplantation and Cell Therapy Program at the University of Alabama's Birmingham School of Medicine. “Despite this very difficult[-to-treat patient population], the response rates are incredibly high, over 80% across platforms. Evidently, that is very attractive.”

In July 2020, a biologics license application was submitted to the FDA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of patients with relapsed/refractory multiple myeloma. The submission is based on findings from the phase 2 KarMMA trial, in which ide-cel induced a 73% overall response rate, a 33% complete response (CR) rate, a 20% very good partial response rate, and a 21% partial response rate. Additionally, the median duration of response was 10.7 months.

The new submission includes further information on the Chemistry, Manufacturing, and Controls module to address outstanding regulatory requests issued by the FDA in May 2020 following the original BLA submission in March 2020.

In an interview with OncLive^® during the Institutional Perspectives on Cancer webinar on Multiple Myeloma, Costa, discussed the emerging role of CAR T-cell therapy in relapsed/refractory multiple myeloma, investigational products such as ide-cel, orvacabtagene autoleucel (orva-cel; JCARH125), and JNJ-4528, and early intervention strategies to manage the toxicities associated with these products.

OncLive^®: What do we currently know about the state of CAR T-cell therapy in multiple myeloma? What makes this modality a potentially good fit in this disease?

Costa: CAR T-cell therapy has been very promising in multiple myeloma, very much like in other hematologic malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. What we know so far across different platforms with different products is that this is a very potent therapy. Most of the experience that we have is in patients who are heavily pretreated. Nearly all patients are refractory to proteasome inhibitors and immunomodulatory (IMiD) agents. The vast majority were disease refractory to CD38-directed monoclonal antibodies.

[Although] those responses tend to be quick and last several months, the question remains as to the duration of those responses in other malignancies. Many of those responses were permanent; we talk about CAR T-cell therapy curing some patients with lymphoma and leukemia. It is unclear at this point, but it doesn't seem likely that this will be the case in multiple myeloma, at least with the first group of CAR T-cell therapies being developed.

Nevertheless, those patients endure responses for months, and most of that time, the patients do very well [during these responses] and require relatively minimal monitoring.

We still have some problems to overcome, particularly cytokine release syndrome (CRS) that most patients encounter. Although, [the majority of cases] are grade 1 or 2. Fortunately, more severe, life-threatening CRS seems to be quite uncommon with current CAR T-cell therapy in multiple myeloma.

Some other problems that are manageable, but nevertheless burdensome to patients and to practitioners, include cytopenias that can persist for a couple of months, and hypogammaglobulinemia with presupposition for infections.

Could you discuss the CAR T-cell therapy manufacturing process and what challenges remain with it?

Many of the challenges associated with CAR T-cell therapy have nothing to do with posttreatment or toxicity. They are due to getting the patient to the therapy and the logistics that it represents.

First, patients have to be particularly fit. Those therapies that are only now available in clinical trials have specific and somewhat strict inclusion criteria. The patient undergoes 1 session of apheresis where mononuclear cells are collected. Then they are sent to a manufacturing facility that will work on purifying and enriching the cell product for a specific subset of T cells to transect those cells with the chimeric antigen receptor, usually employing a viral vector.

The whole process takes about 2 to 3 weeks, if not longer. When we have anticipation of when the product will become available, then we can treat the patient with lymphodepleting chemotherapy, which essentially prepares the immunologic environment of that patient to welcome the CAR T cells to let them thrive. Then they go to the actual infusion.

The challenge is that those patients often have quite aggressive multiple myeloma. It is not uncommon that those patients who are already quite selected at the beginning experience rapid disease evolution, sometimes even with employment of bridging chemotherapy. In those cases, they may no longer meet the eligibility criteria to actually receive the product. That appears to happen in about 10% to 20% of cases across different platforms with the current data we have so far.

Therefore, the greatest challenge is to optimize the process, making the treatment faster and more accessible to more patients.

Could you discuss the findings of the KarMMa trial and how ide-cel may impact treatment for these patients?

Ide-cel is perhaps the product that is furthest along in development. We recently saw the results of the KarMMa trial, which was a large, international, phase 2 trial. Several encouraging things [were found from that study]. Even across a relatively large number of patients treated in different countries by different investigators, the therapy was found to be very safe. Single-digit incidence of neurotoxicity, which has been a problem in the lymphoma and acute lymphoblastic leukemia arenas.

Also, [ide-cel caused] very few cases of grade 3 or higher CRS. It sounds like those issues can be very well mitigated. Additionally, the field has become more comfortable managing [neurotoxicity and CRS] by early deployment of steroids and tocilizumab (Actemra). These are things that were unclear, just a couple of years ago, whether they could be be administered safely without jeopardizing the therapeutic effect.

We also learned a bit more about the nuances of the duration of response [with ide-cel]. Not unlike most other cancer therapies, the patients who have the best response tend to also be the ones who sustain their responses for a longer period of time. CR was seen in a minority of patients, but those patients who had a CR had a progression-free survival (PFS) that exceeded 1 year.

It has become meaningful because we can tell very early on which patients are likely to sustain their response and which patients are better candidates to test employing maintenance therapy to try to invigorate and prolong the effect of CAR T-cell therapy.

What about the EVOLVE study with orva-cel?

Orva-cel is also a BCMA-targeted CAR T-cell therapy that has a similar co-stimulatory sequence to ide-cel. It is different manufacturing and cellular composition with regulated ratio of CD4- to CD8-positive T cells.

During the 2020 ASCO Virtual Scientific Program, the results of the preliminary review of the EVOLVE trial, which was a dose-finding/dose-expansion study, found that 600 million cells seems to be the optimal dose. That is the maximal dose currently being explored. However, responses were seen even at much lower doses.

Again, we saw very low rates of severe CRS, single-digit rates of neurotoxicity, and there were no cases of severe or life-threatening toxicity. We also have the problem of cytopenia. CRS was manageable with very few grade 3/4 incidences. If one is being proactive and using tocilizumab early, patients do very well, and most of them do not spend more than 5 or 6 days in the hospital.

Finally, could you discuss the findings of the CARTITUDE-1 trial with JNJ-4528?

The CARTITUDE-1 trial was the first study done in the United States [of JNJ-4528]. It was previously tested in China in patients who were not as heavily pretreated. Up to now, we have all been very anxious to see if this product would perform similarly in our patients who have seen 1 or more proteasome inhibitors, 1 or more IMiDs, and 1 or more CD38-directed monoclonal antibodies.

This was a dose-finding study that [enrolled] just under 30 patients; it should be kept in mind that it was a very small study. The safety was excellent, and no deaths were associated with therapy. CRS occurred at mostly grade 1/2 levels, and there were limited periods of cytopenias.

The response rate was 100%, which caught a lot of attention. In particular, the majority of those responses were CRs or stringent CRs. It remains to be seen how the response rate pans out when the study is expanded. It had quite a bit of attrition between collection of the cells and treatment. We saw a bit of a dropout because of that patient selection.

Therefore, it will be very interesting to see how [JNJ-4528] performs in a larger cohort of patients, but the responses, so far, are very impressive. We need long follow-up, but at 9 months, we still had over three-fourths of patients who did not have a PFS event. That is very encouraging.

References:

1. Bristol Meyers Squibb and bluebird bio announce submission of biologics license application (BLA) to FDA for idecabtagene vicleucel (ide-cel, bb2121) for adults with relapsed and refractory multiple myeloma. News release. Bristol Meyers Squibb and bluebird bio, Inc. July 29, 2020. Accessed August 20, 2020. https://bwnews.pr/3f85Iup.
2. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503