Despite an avalanche of novel therapies approved by the U.S. Food and Drug Administration (FDA) over the past decade in the treatment of multiple myeloma, including proteasome inhibitors and immunomodulatory drugs, this blood cancer remains largely incurable, and nearly 13,000 people are expected to die from the disease in 2019.1 Now, chimeric antigen receptor (CAR) T-cell therapy, which has been shown to induce durable remissions and even cures in some patients with acute lymphoblastic leukemia (ALL) and certain types of non-Hodgkin lymphoma, may be the next breakthrough in the treatment of multiple myeloma, especially for patients with highly refractory disease.
Adam D. Cohen, MD
A recent phase I study by Adam D. Cohen, MD, Assistant Professor of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and his colleagues explored the use of CAR T-cell therapy targeting the B-cell maturation antigen (CART-BCMA) in patients with relapsed or refractory multiple myeloma.2 The investigators found that patients with less dysregulated immune systems may generate more effective CAR T-cell products, improving their response to the therapy. In their study, which included 25 heavily pretreated patients, 12 patients had a partial response or better to the CART-BCMA cell therapy and 3 patients remained progression-free, with the longest now more than 32 months postinfusion.
The ASCO Post talked with Dr. Cohen about the results from his study and their potential implications for the treatment of patients with highly refractory or relapsed disease.
Tailoring Treatment for Patients With Myeloma
There were three cohorts of patients with multiple myeloma enrolled in your study. The first cohort received CART-BCMA cells alone, the second received cyclophosphamide conditioning plus a reduced dosage of CAR T cells, and the third received cyclophosphamide conditioning and the full dose of CART-BCMA cells. Which treatment was most effective?
The numbers of patients in each cohort were too small to achieve a statistically significant comparison, but we think that the regimen given to the third cohort—cyclophosphamide plus the higher dose of CART-BCMA cells (1–5 108)—is the most likely approach to use going forward. In the first cohort, we saw responses in four of nine patients, including our first patient, who had a stringent complete response that was ongoing at 32 months. In the second cohort, only 1 of 5 patients responded to the reduced dosage of CART-BCMA therapy, and we closed that cohort early. And in the third cohort, 7 of 11 patients responded, including 2 with ongoing responses at 11 and 14 months.
We didn’t see any increase in toxicity with the addition of cyclophosphamide, but we did see what appears to be more consistent expansion of CAR T cells following lymphodepletion. Although it’s not absolutely required for CAR T-cell expansion and response, it appears that intensive lymphodepletion does enhance CAR T-cell expansion and the patient’s response to the therapy.
“Our results suggest there are predictive clues we can look for in determining who might be good candidates for CAR T-cell therapy.”— Adam D. Cohen, MD
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Predicting Response to CART-BCMA Therapy
Your study found that the response to CART-BCMA therapy was not associated with tumor burden or other clinical characteristics, but rather, with certain immunologic features present prior to T-cell collection and engineering. What does this information tell you about which patients are most likely to benefit from this therapy?
The focus of this analysis was to try to understand why some patients in our study responded very well to CART-BCMA therapy and had good T-cell expansion and other patients did not. We looked at several clinical characteristics of multiple myeloma, including the percentage of bone marrow plasma cells, cytogenetics, prior rounds of therapy, and what treatment patients received right before we collected their T cells or before we infused the CAR T cells. None of those characteristics seemed to correlate with response or T-cell expansion.
We also looked at BCMA intensity on the myeloma cells, as measured by flow cytometry assay, or the amount of soluble BCMA circulating in the serum prior to infusion. Again, neither of those factors seemed to be predictive of response.
My colleague on this study, Jan Joseph Melenhorst, PhD, Director of Product Development and Correlative Sciences Laboratory and Adjunct Associate Professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, examined the characteristics of the patients’ T cells collected by leukapheresis and used to manufacture the CART-BCMA cells. Two immunologic features were associated with both CAR T-cell expansion after infusion and patient response.
The first was having a relatively preserved CD4-to-CD8 T-cell ratio at the time of apheresis, which seemed to be predictive of patients who were likely to have good T-cell expansion and response to the therapy. The second was an increased frequency of CD8 T cells with a CD45RO-negative, CD27-positive phenotype, which represents a subset of T cells with the capacity to more continuously divide and have long-term persistence.
In a previous study of patients with chronic lymphocytic leukemia who received CD19-directed CAR T-cell (CTL019) therapy, we found that having a high proportion of CD8 cells in the leukapheresis product with this phenotype predicted for better responses. We found a similar association in our myeloma study.
These data are preliminary and need to be confirmed in larger studies. But our results suggest there are predictive clues we can look for in determining who might be good candidates for CAR T-cell therapy.
“One of our hypotheses is that if having better-quality T cells is important to how well patients respond to CAR T-cell therapy, maybe this treatment should be started after only one or two prior lines of therapy.”— Adam D. Cohen, MD
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Improving the Quality of T Cells
How many lines of treatment had patients received prior to enrollment in your study, and how did it affect their response to the therapy?
The median number of lines of prior treatment was seven, and that’s been one of the challenges of doing CAR T-cell clinical trials in patients with multiple myeloma. Often, these patients have had so many prior chemotherapies, their T cells are too beaten up to expand effectively. They also often have aggressive, rapidly proliferative disease, making it difficult to prevent disease progression while waiting the 3 to 4 weeks it takes to engineer the CAR T cells and infuse them.
One of our hypotheses is that if having better-quality T cells is important to how well patients respond to CAR T-cell therapy, maybe this treatment should be started after only one or two prior lines of therapy. This might allow us to generate a better CAR T-cell product and perhaps achieve greater response durability.
I also think there could be a place for CAR T-cell therapy in the upfront setting, where it might be more effective. We recently opened a pilot study, led by my colleague, Alfred L. Garfall, MD, Assistant Professor of Medicine at the Perelman School of Medicine, for newly diagnosed myeloma patients with myeloma who have high-risk features, such as poor-risk cytogenetics, plasma cell leukemia, or primary refractory disease. After completing induction therapy and autologous stem cell collection and agreeing to defer stem cell transplantation, they then receive either CART-BCMA cell therapy or CART-BCMA plus CD19-directed CAR T-cell therapy. We will be assessing safety, CAR T-cell expansion, clinical responses, and progression-free survival in this setting, as well as exploring how giving two different CAR T-cell products (CART-BCMA and CTL019) together compares to CART-BCMA therapy alone.
Overcoming T-Cell Defects in Myeloma Cells
Might it be possible to engineer patients’ T cells to override their deficiencies and make CAR therapy effective in more patients with multiple myeloma?
A number of studies are already underway investigating that possibility, and we are just starting to see some of the data. One study is using a CART-BCMA product in which CD4 and CD8 cells are manufactured separately, put together in a one-to-one ratio, and then infused into the patient.3 That is one way of trying to overcome these defects, and we will see if it helps.
Another approach is manufacturing CAR T cells in the presence of a PI3 kinase inhibitor,4 which in preclinical studies has been shown to skew T cells to a less exhausted or less differentiated phenotype. That may allow for better T-cell proliferation and memory.
Finally, we are participating in a study that transduces the T cells with a CAR construct using a transposon rather than a viral vector. This approach more efficiently allows the CAR construct to be expressed in the T cells and maintains more of a stem cell memory–like phenotype in the final product.5 The hope is that once the CAR T cells are infused into the patient, they might expand more gradually, perhaps decreasing the incidence of cytokine-release syndrome and other toxicities, and also persist longer, perhaps leading to more durable disease control.
Understanding the Mechanisms of Resistance in Myeloma
CAR T-cell therapy, including FDA-approved tisagenlecleucel and axicabtagene ciloleucel, is proving effective in the treatment of ALL and some types of large B-cell lymphoma, even achieving cures in some patients. What role does this therapy have in the treatment of patients with multiple myeloma?
Multiple clinical trials have demonstrated that CAR therapy—especially BCMA-directed CAR T cells—can produce deep responses, including minimal residual disease–negative complete responses, in patients with highly refractory myeloma. However, compared to patients with ALL or lymphoma, what seems to be different with CAR therapy in patients with myeloma is that even when they achieve a complete remission or become minimal residual disease–negative, the majority ultimately relapse. We are seeing this pattern in trial after trial.
“The therapy is promising, but we need to do better. We need to understand the mechanisms of resistance to this therapy and why the durability of response is not the same in myeloma as it is in ALL and lymphoma.”— Adam D. Cohen, MD
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I think there is something fundamentally different about multiple myeloma compared to other blood cancers, and it is too soon to say whether CAR T-cell therapy will be curative. There are a handful of long-term responders in every CAR trial, and maybe some of those patients will go on to be cured, but this is just the beginning of the CAR T-cell story in myeloma.
The therapy is promising, but we need to do better. We need to understand the mechanisms of resistance to this therapy and why the durability of response is not the same in myeloma as it is in ALL and lymphoma and whether the cause is intrinsic to the CAR T cells, the myeloma cells, or the microenvironment of the myeloma. One of our big focuses is the examination of correlative samples from our prior studies to see if we can discern the reasons.
There are many exciting treatment advances in myeloma, particularly with immunotherapies that target BCMA, and we are still learning how to sort out the various BCMA-targeted modalities and sequence them effectively when patients have disease progression. We are also still figuring out how BCMA is regulated on the myeloma cell surface and whether it can be targeted multiple times, but we are getting closer to finding the answer. When we do, hopefully, we will have more durable responses and be able to start thinking about a potential cure for patients with multiple myeloma. ■
DISCLOSURE: Dr. Cohen has been a consultant/advisor for Array BioPharma, Celgene, GlaxoSmithKline, Bristol-Myers Squibb, Takeda, Kite, Janssen, Oncopeptides, and Seattle Genetics; has received research funding from Bristol-Myers Squibb and Novartis; has had intellectual property licensed from his institution to Novartis; and has been reimbursed for travel, accommodations, and expenses from Celgene, GlaxoSmithKline, Takeda, and Bristol-Myers Squibb.
REFERENCES
1. American Cancer Society: Key statistics about multiple myeloma. Available at www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed May 21, 2019.
2. Cohen AD, Garfall AL, Stadtmauer EA, et al: B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest 130:2210-2221, 2019.
3. Green DJ, Pont M, Sather BD, et al: Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high-risk multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 1011. Presented December 3, 2018.
4. Shah N, Alsina M, Siegel DS, et al: Initial results from a phase I clinical study of bb21217, a next-generation anti-BCMA CAR T therapy. 2018 ASH Annual Meeting & Exposition. Abstract 488. Presented December 2, 2018.
5. Gregory T, Cohen AD, Costello CL, et al: Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 1012. Presented December 3, 2018.
