Multiple Myeloma: Exploring Immune Therapies on the Horizon

Clinical Expert Commentaries published on May 18, 2018
Joshua Richter, MD
Assistant Professor of Medicine
Icahn School of Medicine at Mount Sinai
New York, New York
Joshua Richter, MD

The management of multiple myeloma (MM) is rapidly changing, and immune-based therapies are beginning to take center stage in the treatment landscape. Recent advances in immunotherapy for MM have led to significant improvements in survival rates. The immune system is significantly impaired in MM because the disease suppresses normal plasma cells and has negative effects on immunity.1 Several monoclonal antibodies have emerged as targeted approaches to killing cancer cells. In short, these agents act like antibodies that the immune system naturally makes to fight diseases. They use the host’s immune system to direct toxicity against a malignant cell to promote apoptosis.2

Two monoclonal antibodies are approved by the FDA for the treatment of relapsed/refractory MM (RRMM). The first is elotuzumab, which targets the SLAMF7 receptor, and the second is daratumumab, which targets the CD38 glycoprotein.3 In May 2018, daratumumab was approved by the FDA for use in combination with bortezomib, a proteasome inhibitor, melphalan, and prednisone for newly diagnosed MM in patients who are ineligible for autologous stem cell transplant. Monoclonal antibodies continue to be an area of active research in MM, but it’s important to recognize that these therapies only target a single cancer cell. There continues to be an urgent need for treatments that can further extend disease control. With that in mind, researchers are exploring other immune-based therapies in the fight against MM, including chimeric-antigen receptor (CAR) T-cell therapy and bifunctional antibodies.

CAR T-cell therapy
With CAR T-cell therapy, immune cells are collected from patients and then modified/reprogrammed to “hunt” and destroy cancer cells. After being infused back into the body, these immune cells attack cancer cells that express B-cell maturation antigens (BCMA) as well as other targets, including CD19, KLC, and CD138.4,5 In 2017, two CAR T-cell therapies were approved by the FDA, one for leukemia (tisagenlecleucel) and one for lymphoma (axicabtagene ciloleucel). Some CAR T-cell therapies are getting closer to receiving FDA approval for RRMM (eg, bb2121, per findings from the CRB-401 study).6 However, it’s important to note that the BCMA platform for CAR T-cell therapy in MM is still in its early stages. Some trials conducted outside the setting of MM have yielded very high response rates with CAR T-cell therapy, demonstrating that the treatment is durable. While these data are encouraging, it’s still unknown how CAR T-cell therapy fits into the treatment paradigm for MM. Ongoing clinical trials are continuing to explore this research gap.

Bifunctional antibodies
To further improve the ability of the immune system to fight cancer, bifunctional antibodies are another class of drugs being assessed as potential treatments for MM. Bifunctional antibodies have also been referred to as bispecific antibodies, bispecific T-cell engagers (or BiTEs), and bifunctional engagement by activation of T-cells (or BEATs) in clinical trials. These agents are artificial bispecific monoclonal antibodies that engage two targets, the T-cell and the cancer cell. The antibodies direct the immune system to link T-cells to cancer cells, which then promotes apoptosis. In 2014, blinatumomab was approved by the FDA as a first-in-class bifunctional antibody to treat acute lymphoblastic leukemia. The drug binds concomitantly to CD3 and CD19 to promote apoptosis. Blinatumomab is currently being explored as a possible treatment for MM in clinical trials.

Other bifunctional antibodies are also being evaluated in studies for use in MM, targeting CD3/CD38 and CD3/BCMA.7-10 With mounting information emerging, it’s imperative to stay up-to-date on new data from these trials and others involving MM patients because both bifunctional antibodies and CAR T-cell therapy are getting closer to becoming a treatment option in our armamentarium. Findings from these analyses will increase our understanding of how bifunctional antibodies fit into the overall spectrum of immunotherapy options, which in turn will impact how we treat our patients.

Comparing therapies
There are some important differences between CAR T-cell therapies and bifunctional antibodies that should be taken into consideration when deciding if these treatments are appropriate for MM patients. For example, CAR T-cell therapies are not “off-the-shelf” products, meaning it could take as long as a month or more to get patients on these treatments. This can be problematic, especially if patients have rapidly progressing MM. Conversely, bifunctional antibodies are “off-the-shelf” products, meaning there could theoretically be greater access to these therapies outside of academic institutions.

“Bifunctional antibodies and CAR T-cell therapies may prove to be important additions to the future management of MM.” – Joshua Richter, MD

Given the known toxicity profiles, CAR T-cell therapies may not be appropriate for all MM patients. The risks and benefits of both bifunctional antibodies and CAR T-cell therapy need to be evaluated in the setting of disease burden and disease status as well as host age, performance status, and comorbidities. Currently, these technologies are being evaluated in heavily pre-treated MM patients. As we gain a better understanding of their efficacy and toxicity, they may then be evaluated in earlier relapsing MM. They also may be studied in the newly diagnosed patient population. 

For many reasons, bifunctional antibodies and CAR T-cell therapies may prove to be important additions to the future management of MM. We need to stay abreast of developments in clinical trials assessing the safety and efficacy of both of these therapies in MM so we are prepared to use them appropriately when they gain FDA approval. These emerging immunotherapies are expected to provide us with more options in our toolbox for treating MM. With the continued emergence of new immunotherapies, it’s an exciting time as we accelerate our efforts to improve patient outcomes in MM. Thank you for reviewing this activity.

References

  1. Kumar SK, Anderson KC. Immune therapies in multiple myeloma. Clin Cancer Res. 2016;22:5453-5460. https://www.ncbi.nlm.nih.gov/pubmed/28151713
  2. Lonial S, Durie B, Palumbo A, et al. Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives. Leukemia. 2016;30:526-535. https://www.nature.com/articles/leu2015223
  3. Sherbenou DW, Mark TM, Forsberg P. Monoclonal antibodies in multiple myeloma: a new wave of the future. Clin Lymphoma Myeloma Leuk. 2017;17:545-554. https://www.ncbi.nlm.nih.gov/pubmed/28734795
  4. Hipp S, Tai YT, Blanset D, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31:2278. https://www.nature.com/articles/leu2016388
  5. Sohail A, Mushtaq A, Iftikhar A, et al. Emerging immune targets for the treatment of multiple myeloma. Immunotherapy. 2018;10:265-282. https://www.ncbi.nlm.nih.gov/pubmed/29421983
  6. Berdeja G, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy. Blood. 2017;130:740. http://www.bloodjournal.org/content/130/Suppl_1/740
  7. Chu SY, Miranda Y, Phung S, et al. Immunotherapy with long-lived anti-CD38 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human myeloma cell lines and CD38+ cells in monkeys: a potential therapy for multiple myeloma. Blood. 2014;124:4727. http://www.bloodjournal.org/content/124/21/4727
  8. Pillarisetti K, Eric Baldwin E, Babich A, et al. Development of a new BCMAxCD3 Duobody® antibody for multiple myeloma. Blood. 2016;128:2116. http://www.bloodjournal.org/content/128/22/2116
  9. Girgis S, Shetty S, Jiao T, et al. Exploratory pharmacokinetic/pharmacodynamic and tolerability study of BCMAxCD3 in cynomolgus monkeys. Blood. 2016;128:5668. http://www.bloodjournal.org/content/128/22/5668
  10. Richter JR, Wermke M, Kauh JS, et al. Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma. J Clin Onc. 2017;36(suppl 5). http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.5_suppl.TPS81
Last modified: May 15, 2018