High Response Rates Heighten Excitement With CAR T-Cell Therapy in Multiple Myeloma

CAR T-cell therapy is poised to transform the treatment paradigm of relapsed/refractory multiple myeloma now that multiple products are exhibiting high and complete response (CR) rates, said Faiz Anwer, MD, who added that further research may improve safety, prolong responses, and provide insight into resistance mechanisms. 

“Due to the combination of specificity and cytotoxicity, we are seeing very high overall response rates [with CAR T-cell therapy],” said Anwer. “These response rates are variable, but in the range of 80% to 100%. The majority of these responses are very deep, [with most] patients achieving minimal residual disease [MRD] negativity. Achieving MRD negativity is the best outcome that we can expect from any therapy.”

On September 22, 2020, the FDA granted a priority review designation to a biologics license application (BLA) for idecabtagene vicleucel (ide-cel; bb2121) in patients with multiple myeloma who have received at least 2 previous therapies, including a proteasome inhibitor (PI), an immunomodulatory (IMiD) agent, and an anti-CD38 antibody.¹ 

Data from the phase 2 KarMMa trial, which led to the BLA submission, showed that ide-cel induced a response in 73% of patients with heavily pretreated, relapsed/refractory disease. Moreover, the CR rate was 33% with the product.² 

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Anwer, an oncologist, physician-scientist, and stem cell transplant staff physician at the Taussig Cancer Center of Cleveland Clinic, a member of the Hematopoietic and Immune Cancer Biology Program at Case Comprehensive Cancer Center, and an associate professor in the Department of Medicine at the School of Medicine at Case Western Reserve University, discussed the growing role of CAR T-cell therapy in multiple myeloma and areas of unmet need. 

OncLive^®: What are some of the advantages of CAR T-cell therapy in multiple myeloma? 

Anwer: CAR T-cell therapy has some unique advantages compared with other treatments. CAR T-cell therapy has the advantage of targeted specificity, which we see with many monoclonal antibodies. At the same time, because [CAR T-cell therapy is] a cell-based, specifically T-cell–based, therapy, we see the cytotoxic advantage of T cells. 

[Patients] receive a single infusion of CAR T cells. Many of these patients respond very quickly and maintain these responses for a long duration of time. Those longer lasting responses can [persist] for more than 1 year, and in many cases, more than a couple of years.

The benefit is that no maintenance therapy is required at this time. However, in the future, we can postulate that combination therapies will emerge, and a maintenance strategy will be introduced to improve the duration of response. 

The CAR T-cell products [that are used in multiple myeloma] are safer compared with some of the other products that were used in the beginning in other diseases. In terms of safety, we are seeing less central nervous system [CNS] toxicity. The intensity of cytokine release syndrome [CRS], which is another major toxicity [associated with] CAR T-cell therapy, is actually less in multiple myeloma [than in other hematologic malignancies].

Beyond BCMA, what other potential targets are under investigation?  

At this point, many targets are emerging aside from BCMA. We see a role for CD38 as a target as it is being explored with naked antibodies, such as daratumumab [Darzalex], in combination with antibody-drug conjugates. 

In addition, GPRC5D is another target. CD19 has also been explored as another target. More excitement will come from dual targeting where either 2 different types of CAR T-cell therapies can be used, or 1 CAR T-cell product can be configured to achieve dual targeting of the myeloma cell.

How have data from the CARTITUDE-1, LEGEND-2, and KarMMa trials solidified a role for CAR T-cell therapy in multiple myeloma? 

We have more data from the phase 1 and 2 setting. That is where initial CAR T-cell therapy data were very exciting because [the studies] showed quicker, deeper responses with longer durations of response. They provided us with the initial insight into what type of adverse effects [AEs] we are going to face while using the CAR T-cell technology in multiple myeloma, as well as how to best manage [those AEs].

We will continue to see new products and new techniques emerge, which will likely [mitigate] some of these challenges. [Moreover], improved products and techniques will likely resolve some of these AEs that can be [severe]. 

In terms of responses for the products that are more advanced, [the data with] JNJ-4528/LCAR-B38M are exciting in terms of overall responses, which were reported in the range of 100%, with CRs approaching almost 70%. The MRD-negativity rate was also 100%.

At the same time, data from the KarMMa trial showed that ide-cel [induced] very high objective responses above 70%. The progression-free survival is measured in months and [CR rates] are also impressive with ide-cel.

What is your approach to managing patients who develop CRS or CNS toxicities after CAR T-cell infusion? 

We have learned through the treatment of other diseases, such as leukemia and lymphoma, that the challenges [that manifest with] CAR T-cell therapy are CRS and CNS toxicity. We’re facing the same challenges in multiple myeloma. 

Patients [treated with CAR T-cell therapy] are typically monitored very closely with daily assessments to [identify] these AEs. If [a patient] starts developing [signs of] CNS toxicity, such as confusion, seizures, fever, and low blood pressure, they are managed according to the defined protocol. Each individual center may have carved out their own unique approach to managing these toxicities, but typically, patients require close monitoring of fluid balance, antibiotics, and judicious use of steroids and tocilizumab [Actemra].

What strategies should be implemented to reduce CRS and CNS toxicities?

We need to have a comprehensive infection prophylaxis strategy—a vaccination strategy—to prevent any long-term issues with infections. The therapy has to be integrated safety with the existing myeloma treatment [before patients receive] CAR T-cell therapy. 

Where should future research efforts focus with regard to the remaining challenges of CAR T-cell therapy?

At this time, we can potentially count more than 50 open trials in the pipeline that will open for enrollment in the near future. The issues that we want to address include how to continue to make CAR T-cell therapy safe and effective, and to [prolong] responses.

Also, we want to look at the efficacy of repeat infusion and [identify] the optimal combination therapy with CAR T-cell therapy and other existing treatment. [Combinations] may be in the space of an IMiD, a PI, or a targeted antibody.

We also need to figure out how to overcome resistance, which ultimately [occurs] after an infusion while the CAR T cells are still in the body. What is the escape mechanism and how do we address it? Do we need to [implement] a dual-targeting approach? We may need to combine a multi-agent chemotherapy approach to improve upon the efficacy of the product and overcome the resistance.

At the same time, we need to continue to look at novel markers to improve responses and identify markers that we can potentially use to predict outcome. Is there a particular product for which a patient is going to respond better compared with another product? These individualized approaches where we can use unique CAR T-cell products for unique patients is where the future should be headed.

Could CAR T-cell therapy have utility in earlier lines of treatment? 

At this point, CAR T-cell therapy is being testing in heavily pretreated patient populations, but as we get more comfortable and see more data, we need to move CAR T up into the first- or second-relapse settings. In certain cases, it is absolutely justified to start testing CAR T-cell therapy in the frontline setting for patients who have high-risk multiple myeloma, patients who have primary resistance to frontline therapy, and patients who have plasma cell leukemias.

Looking to the future, how could the introduction of off-the-shelf, allogeneic CAR T-cell products provide additional benefit to patients?

The major benefit of off-the-shelf CAR T-cell therapy products will be the time-to-treatment once we make a decision that the patient has relapsed/refractory disease [and requires CAR T-cell therapy].

At this time, we also face the challenge of T-cell collection failure in heavily pretreated patients who have cytopenias or have received heavy doses of radiation therapy to their bone marrow. In those cases, it may be difficult to collect T cells. Therefore, off-the-shelf products [would be advantageous in those cases.

One example [of an off-the-shelf product] is ALLO-715, which is in phase 1 testing at this time. We [may be able] to quickly infuse the cells to achieve effective disease control.

Could you speak to the importance of enrolling patients onto clinical trials?

I encourage patients to participate in clinical trials to support new drug development. That is how we can continue to see further advancements in the field. That is how we have arrived to where we are now, and that is how we are going to [make even more advances] in the future. We need to continue to support research and drug development. 

References

1. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed October 27, 2020. https://bit.ly/2G0K3Iq.
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