CAR T-Cell Therapy Results Reported in The New England Journal of Medicine

This week it is exciting to see the results of CAR T-cell therapy reported fully in The New England Journal of Medicine (NEJM). Results using the bb2121 anti-BCMA CAR T-cells were reported previously in abstract form at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. But the NEJM article provides important details about safety (the primary endpoint for this phase I study), as well as the anti-myeloma activity of the CAR T-cells directed against the BCMA (B-cell maturation antigen) on the myeloma cells of the relapsed/refractory-treated patients.

Trial basics

To refresh everyone’s understanding about this important trial, it included 36 consecutive patients with relapsed/refractory myeloma, with 33 proceeding to infusion of the bb2121 CAR T-cell product. The chimeric antigen receptor (CAR) T lymphocytes were manufactured by Celgene from peripheral blood cells harvested from each individual patient. The genetic engineering inserted the anti-BCMA CAR into each patient’s T cells with transduction (a process that enables foreign DNA to be introduced into a cell) using a lentiviral vector. Lentiviruses work by inserting DNA into their host cells, so this is a method by which genes can be inserted, modified, or deleted in organisms using a virus. 

The process of growing enough engineered T cells to give back to each patient took 10 days. Although some anti-myeloma therapy was allowed during the manufacturing period, myeloma progressed in three patients, who came off the study, leaving 33 patients in the treatment phase. As is standard now, all patients received preparation therapy (to reduce body lymphocyte levels) using a chemotherapeutic combination of fludarabine + cyclophosphamide (the generic name for Cytoxan, an alkylating agent similar to melphalan). Increasing doses of the CAR T-cells were given as part of this phase I testing. Patients were treated between January 2016 and April 2018. In this heavily pretreated patient population, 26 out of 33 patients (79 percent) were refractory to both proteasome inhibitors (such as Velcade and Kyprolis) and IMiDs (such as Revlimid and Pomalidomide). All but one had a prior autologous stem cell transplant. 

Anti-myeloma benefit 

Although the primary endpoint in the study was safety, let’s start with the treatment benefit, which  was remarkably good. The response rate—the so-called Objective Response Rate of partial response (50 percent M-protein reduction or better)—was 85 percent, with 15 patients (45 percent) achieving complete responses. 

To put this in perspective, response rates in the relapsed/refractory setting with new agents (such as pomalidomide, daratumumab, and selinexor) are in the 20-to-30-percent range!  CAR T-cell therapy is remarkably better. In addition, the average length of remissions was 11.8 months versus 2 to 4 months in prior trials of other new agents. Again, remarkably better. 

Although MRD negativity was noted at 10 to the minus 4 level—no myeloma cells found among 10,000 cells tested (rather than 10 to the minus 6, or one in a million)--6 of the patients who’d had complete remissions have relapsed. A more detailed evaluation of MRD in the setting of CAR T-cell therapies is required. It is important to know whether the rapid, dramatic responses are confirmed by traditional IMWG Criteria AND are sustained at one year and longer. In addition, in this late relapse setting, PET/CT scanning will be necessary to assess extramedullary disease and rule out soft tissue relapse.

Safety 

This is not a simple treatment: all patients experienced some adverse toxicity. The most serious toxicity, cytokine release syndrome (CRS), occurred in 25 patients (76 percent). Fortunately, CRS was severe in only 2 patients (6 percent). Some degree of neurological toxicity occurred in 14 patients (42 percent), and a majority of patients had substantial reductions in blood-count levels, especially white cells (85 percent). 

Although CAR T-cell therapy can be classified as a “tolerable treatment,” it is certainly challenging for patients and for care teams, who will require special training and guidance. Specialty care units are necessary to ensure best outcomes for patients, which limits access to this procedure to high-level medical centers, and substantially increases costs.

Looking ahead

We need to wait and see if more sustained responses occur when patients are treated earlier in the disease. And we will continue to monitor and compare the benefit achieved with the many other CAR T therapies in the works, such as the Legend product developed in China and now owned by Janssen Pharmaceuticals that was reported at the 2018 American Society of Hematology Annual Meeting, as well as newer, next-generation therapies. 

There are many potential advantages to the new cellular therapies, which include

• Products that can be given safely in multiple repeat doses, if necessary 
• Treatment using T cells harvested earlier in the disease with the best anti-myeloma capability
• Targeting more than a single BCMA target
• Targeting cell surface antigens other than BCMA
• Combining CAR T-cell therapy with other immune therapies, such as IMiDs or daratumumab
• Using CRISPR to edit the T cells, as is being done in an exciting new trial at the University of Pennsylvania
• BiTEs (T cell therapies that are “off-the-shelf” and don’t require weeks for engineering and expansion before they are infused into the patient)

The bottom line

There is excellent benefit with bb2121 in this relapsed and refractory setting, despite the occurrence of serious side effects and further relapses. If the expanded phase II cohort confirms the early results reported here, I predict this therapy will receive accelerated approval from the FDA as a relapse treatment. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to [email protected]. InfoLine hours are 9 am to 4 pm PT. Thank you.

Dr. Brian G.M. Durie founded and now serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.