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The Next Wave of Immunotherapy in Myeloma

In the Spring 2020 edition of Myeloma Today, my column focused on the topic of immunotherapy in myeloma. Employing one’s immune system in the fight against cancer has since become standard practice in many diseases and is becoming a critical part of myeloma therapy.  

Two CAR T-cell therapies have been approved for myeloma by the U.S. Food and Drug Administration (FDA), and at least 10 new agents are being developed!  

Bispecific antibodies have two targets. Think of them as a drug that has two arms – one to grab on to the myeloma cell and the other to directly engage a key immune cell, usually a T cell or natural killer (NK) cell, to help destroy the myeloma cell.  

In fact, currently there are trispecifics in development that have three arms, two to hook on to the myeloma cell and one to engage the immune cell. This unique approach is really a combination of two strategies at the same time:  

  1. A monoclonal antibody that targets myeloma cells and induces the immune system to destroy the myeloma cell – sometimes called “humoral” immunity.  
  2. A monoclonal antibody that engages a local immune cell to directly kill the myeloma cell – sometimes called “cellular” immunity.  

Bispecific antibodies, therefore, have many advantages when compared other humoral and cellular approaches:  

  • Dual treatment – By using both the humoral and cellular pathways together, they can leverage different aspects of the immune system. Dual treatment strategies are very important in myeloma.  
  • “Off the shelf” – Cellular approaches like CAR T-cell therapy require that we collect T cells from patients, manufacture the CAR T cells, and then re-infuse them several weeks later. Bispecifics engage the immune cells in the body directly, and therefore can be directly given to patients “off the shelf.”  
  • Different targets – We are constantly discovering more antigens on the surface of myeloma cells, and bispecifics can be engineered to latch on to different antigens while still engaging immune cells. We are most familiar with B-cell maturation antigen (BCMA) but now we can target other antigens, such as GPRC5D and FcRH5.  
  • Broader use – Many myeloma patients may not be fit enough for CAR T-cell therapy but would likely be eligible for bispecifics. Furthermore, we anticipate being able to deliver these therapies in the community and not only in cellular therapy centers – something very important for patients who cannot access one of these centers.  

The key disadvantage to bispecifics is that they must be given on an ongoing basis. They range in dosing, both intravenous (IV) and subcutaneous (SQ), from as frequently as weekly to as infrequently as monthly.  

In contrast, CAR T-cell therapies are given once, then patients are off treatment for an extended period. All drugs come with risks, and we have seen similar side effects in both monoclonal antibodies and cellular therapies:  

  • Cytokine release syndrome (CRS) – This uncontrolled immune reaction occurs with all of the bispecifics in development. It is less severe than what we see with CAR T-cell therapy, but at present still requires hospitalization for at least the first dose for close monitoring.  
  • Neurological toxicities – We have seen neurological effects of these drugs. As we learn more about them, we anticipate this to be less of an issue.  
  • Infections – As the immune system is affected with these drugs, patients are at higher risk of infection, and this must be watched closely.  
  • Other drug-specific side effects – Unique features have been seen with each agent. For example, skin, nail, or hair effects must be considered.  

Bispecific antibodies are not yet approved by the FDA as they are still in development, but there may be approvals in 2022 in the relapsed/refractory setting. It is exciting to see that so many bispecific antibodies which engage T cells are being tested in clinical trials, including teclistamab, talquetamab, cevostamab, elranatamab, AMG 701, REGN 5758, ABBV-338, and CC-93269. And more are on the way!  

I am particularly interested in NK-cell engagers as it appears their risk of CRS is even lower than with bispecifics, which may reduce the need for hospitalization. Some approaches are combining these agents with therapies currently in use for myeloma.  

Bispecifics are coming soon, and many of us in the myeloma community are very excited about being able to help our patients with these treatments.  

(This article was published in the 2022 Spring Edition of the IMF's quarterly publication, Myeloma TodayRead the full publication here.

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