What to Pair with Bispecific Antibodies in Multiple Myeloma

A significant number of bispecific antibodies are being developed for multiple myeloma, going after a variety of targets including BCMA. The bispecific antibodies are given continuously as compared to the CAR T therapies, which are a one and done treatment. Because myeloma is typically treated with combination therapies, these new immunotherapies introduce the question "What should the bispecific antibodies be combined with for maximum effect?"

Dana Farber Researchers are tackling this question for BCMA targeted bispecifics and published a paper in Blood Cancer Discovery showing that combining a bispecific with cyclophosphamide was better than combining it with an immunomodulator like Revlimid or Pomalyst or a proteasome inhibitor like bortezomib (Velcade).  

Initially, there was early mouse model data that suggested the potency of the BCMA bispecific antibody AMG-701 could be enhanced with the addition of an immunomodulator (like Revlimid or Pomalyst), but more investigation was needed.

Because the immunomodulators work through the Cereblon pathway, the researchers created a new mouse model that manually added cereblon (Vk*MYC^hCRBN) to mimic how it would be used in human models. At first, the (Vk*MYC^hCRBN) mice had great responses after only one dose of the BCMA bispecific antibody, but mice with a high tumor burden relapsed after the treatment was stopped.

The researchers found that although pomalidomide boosted activation of some key cells, it overactivated the T cells and T cell exhaustion, suggesting that only short-lived effects were produced, especially for mice with a high tumor burden. Early death was noted in a fraction of the mice, suggesting that there could be potential toxicity in this combination.

Cyclophosphamide, an older traditional "chemotherapy" was then tested. When combined with the BCMA bispecific antibody, it helped temper T cell activation, prevented T cell exhaustion and created durable anti-multiple myeloma immunity. 

The researchers compared the use of cyclophosphamide to bortezomib, a proteasome inhibitor. Using bortezomib failed to enhance the impact of the bispecific antibody. 

In most CAR T treatment and in clinical trials, cyclophosphamide and fludarabine are a common combination given as a lymphodepleting treatment right before CAR T cells are returned to the patient. According to the researchers, the use of cyclophosphamide helped mice survive longer and protected them from tumor challenge 9 months after initial treatment, strongly suggesting durable tumor-specific immunity. The researchers note that they are not exactly sure how cyclophosphamide primes the bispecific antibody therapy. It can change cytokine levels and different immune cell types within the tumor microenvironment. 

The authors concluded that BCMA- targeted bispecific antibodies are promising as a single-agent. They have lower toxicity compared with CAR T cell therapy, are easy to administer, are an "off-the-shelf" treatment and can be given as an outpatient treatment. However, the durability of response is unknown and combination strategies could improve their durability. 

These early findings provide clues for bispecific combinations. Additional lab research and future clinical trials are needed to find the best treatments to add to the bispecific antibodies.