Usmani Discusses Emergence of CAR T-Cell Therapy in Myeloma

Saad Z. Usmani, MD

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential therapeutic option in the pipeline of multiple myeloma agents, as early studies have shown encouraging activity.

For example, results of a small phase I trial, presented at the 22nd Annual European Hematology Association Congress, showed that patients with multiple myeloma achieved a response following treatment with an active dose of bb2121, an investigational anti—B-cell maturation antigen (BCMA) CAR T-cell construct.¹

The objective response rate was 100% (95% CI, 78.2-100) in 9 evaluable patients who had been infused with bb2121 at a dose of 5.0 x 10⁷ CAR-positive T cells or higher. Additionally, 27% of patients achieved complete response and 75% of patients demonstrated a very good partial response or better.

In a second phase I trial, 33 of 35 patients (94%) with relapsed/refractory disease experienced clinical remission after treatment with CAR T cells targeting BMCA.² Findings of the Chinese study, which were presented at the 2017 ASCO Annual Meeting, showed that patients achieved clinical remission within 2 months of infusion with CAR T-designated LCAR-B38M CAR T cells. Of the 19 patients who have been followed for at least 4 months, 14 reached stringent complete response criteria, 1 patient experienced partial response, and 4 achieved very good partial remission.

OncLive: What topics were discussed at this State of the Science Summit?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Multiple Myeloma, Saad Z. Usmani, MD, director, Plasma Cell Disorder program, director, Clinical Research in Hematologic Malignancies at Levine Cancer Institute and Carolinas HealthCare System shared his insight on the recent multiple myeloma data that emerged at the 2017 ASCO Annual Meeting, the potential role of CAR T-cell therapy, and what therapeutic advancements the community can expect in the remainder of 2017.Usmani: We had a very extensive program tonight. We tried to focus on topics regarding disease, biology diagnosis, management of newly diagnosed patients both in the transplant-eligible and transplant-ineligible setting, as well as with relapsed and relapsed/refractory disease.

What abstracts from the 2017 ASCO Annual Meeting did you find particularly promising in multiple myeloma?

There are data in each of these spheres. There have been changes in the French Innovative Leukemia Organization over the last couple of years. We are just coming back from the 2017 ASCO Annual Meeting, so there are some updates on data from there.The most exciting [results] presented this year were the Bluebird Bio CAR T-cell data and a Chinese CAR T-cell late-breaking abstract that was also presented. Those 2 were the most exciting abstracts that were presented, and it showed us that the CAR T-cell technology, when targeting BCMA, appears to be efficacious. It appears to be tolerable. Yes, there were [cases of] cytokine release syndrome and grade 3 lysis in both of those studies; however, the depth of response we were seeing with this particular target is very encouraging. We obviously need to see larger cohorts with patients and truly see which patients would benefit from this therapy, but that was an exciting [study].

What do you anticipate the role of CAR T-cell therapy could be in multiple myeloma?

You lectured on the management of relapsed/refractory multiple myeloma. Could you provide your top points of the discussion?

As far as checkpoint inhibitors go, what potential is there with this class of agents?

What other data in multiple myeloma are you excited about?

2016 was a pivotal year in the myeloma landscape. Will 2017 end just as promising for the field?

We also have the triplet plus antibody-based combinations for induction treatment. There are early data with KRd (carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone) data and RVd (lenalidomide, bortezomib [Velcade], and dexamethasone), both with elotuzumab (Empliciti) but, again, it remains to be seen how that data pans out in larger randomized phase III studies. Right now, we are evaluating CAR T-cell studies in the relapsed/refractory setting. However, it could be conceived that you can potentially move this therapy to the upfront setting. But, if we can figure out how to safely deliver it, this could potentially even be a competitor against autologous stem cell transplantation in the frontline setting. It is very likely that if CAR T cells do pan out with BCMA-targeting, you might see randomized trials comparing them to autologous stem cell transplant. There is definitely room for CAR T-cell therapy in myeloma in different spaces. We have a plethora of options for the early relapses, but as patients start getting into their third, fourth, and fifth relapses, that is where we need more guidance and a better understanding of disease biology. That is where we have a lot of mechanisms of action being developed. I spoke on some of them, including checkpoint inhibition, BCL-2 inhibitors, and even touched upon the CAR T-cell technology that is coming down the pike. One can potentially utilize checkpoint inhibition in several different ways. For example, [it could work with] older patients, where immunomodulatory (IMiD)—based therapies, such as lenalidomide/dexamethasone, are utilized for upfront treatment. Therefore, combining that with a checkpoint inhibitor may make sense in providing a long-term progression-free survival and potentially overall survival benefit to those patients. The checkpoint inhibition plus IMiD combinations are pretty recent, and they are used in myeloma. We have some relapsed/refractory data with pomalidomide (Pomalyst) and lenalidomide, but there is potential to use that regimen upfront. We can also potentially utilize the checkpoint inhibitors with IMiDs in the maintenance setting. I am looking forward to hearing more data with the checkpoint inhibitors and the data combinations in later line settings. I am hoping that there will be additional data provided on CAR T-cell therapies, as well as BCMA[-targeting] agents and monoclonal antibodies that may be in clinical trials. There are newer small molecule data updates with venetoclax (Venclexta). I’m excited about that, too. In terms of large, phase III trial readouts, this year will be a little lean. We are going to start seeing a rush of those phase III trials reading out next year. The more exciting therapies this year would be updated data on checkpoint inhibition, as well as other immunotherapies in myeloma.

References

1. Lin Y, Berdeja J, Raje N, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma: updated results. Abstract presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S142.
2. Fan X, Zhao W, Liu J, et al. Durable remissions with BCMA specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 35;2017 (suppl; abstr LBA3001).