BCMA-specific antibodies connected to a 'warhead' (known as antibody-drug conjugates) target the cancerous plasma cells.Credit: Alpha Tauri 3D Graphics/Shutterstock
Therapeutic options for multiple myeloma are expanding rapidly. More than a dozen new therapies have been approved since 2012, leading to steadily increasing survival rates1. Most patients with this cancer of blood plasma cells will eventually relapse2, but newer agents directed at a target called B-cell maturation antigen (BCMA) are allowing many to achieve deep, long-lasting remission3,4, even after they no longer respond to other therapies. BCMA-directed agents “reflect tremendous progress in the treatment of multiple myeloma”, says Nikhil Munshi, a medical oncologist at the Dana Farber Cancer Institute in Boston. “The message with BCMA targeting is very positive.”
BCMA is preferentially expressed on plasma cells and other mature B cells in blood5. These cells originate with B-lymphocyte progenitors that mature through successive stages. Earlier stage lymphocytes contain much smaller amounts of BCMA6, which is what makes the protein such a promising target, according to Shari Kaiser, senior director of translational research at Bristol-Myers Squibb (BMS). “You can completely deplete any BCMA-expressing cell, cancerous or healthy, and still maintain populations of memory B cells and B cell progenitors that allow for a functioning humoral immune system.”
Taking out B cells in this manner requires targeted weaponry. There are several options in play that companies are pursuing. BMS, says Kaiser, is tripling down on BCMA across different modalities.
Multiple avenues for therapy
Among these novel modalities, chimeric antigen receptor (CAR) T cells have the longest history of clinical development. CAR T cells are manufactured by harvesting a patient’s T cells, which are subsequently engineered to express the chimeric BCMA-binding receptor. When delivered back to the patient’s body, CAR T cells will expand rapidly and attack BCMA-expressing malignancies7. CAR T-cell therapy offers the advantage of one-time dosing. “Patients who achieve deep responses with a single CAR T-cell infusion remain treatment-free until they relapse,” Kaiser says. “The average duration of response for some patients is close to two years4, which is especially meaningful for those who are refractive to other therapies.”
With a second approach, BCMA-expressing cells can be targeted with ‘bi-specific’ antibodies made up of two parts: one that binds to CD3 receptors on T cells, and another that binds to BCMA. Called immune-cell engagers, these engineered molecules “literally drag plasma cells and a patient's endogenous T cells together,” Kaiser explains. Bringing the cells into proximity activates immune responses with the goal of killing plasma cells. Unlike CAR T-cell therapy, immune-cell engagers require repeated dosing to maintain therapeutic pressure. But they do offer a more immediate treatment option than the several weeks needed to manufacture CAR T-cell therapies.
Finally, targeting BCMA with antibody drug conjugates (ADCs) is being explored. With this approach, a BCMA-specific antibody and a cytotoxic payload (often called a warhead) are joined by a chemical linker. The warheads used in multiple myeloma treatment disrupt microtubules during mitosis. BMS is targeting the warhead directly to plasma cells to avoid the non-specific toxicity observed with systemic administration of chemotherapy. Multiple myeloma cells are highly proliferative, and therefore more vulnerable to mitosis-induced killing than normal plasma cells, which divide less often.
Refining the approaches
Each of these BCMA-targeting modalities has its considerations. CAR T therapy has been demonstrated to offer the chance of complete remission8. But as is also the case with immune-cell engagers, CAR T treatments can unleash an inflammatory cytokine release syndrome and neurotoxicity “that fortunately we are getting better at managing”, says Maria-Victoria Mateos, a haematologist who specializes in myeloma, and director of the Clinical Trials Unit at the University Hospital of Salamanca in Spain.
As off-the-shelf treatments, immune-cell engagers and ADCs have the advantage of immediate availability. However, ADC agents can also pose a toxic risk in that if their chemical linkers degrade, then the warhead detaches from the antibody and circulates as a free poison that attacks other cells. Indeed, a troubling and common side effect associated with ADC therapy is keratopathy, or toxicity to the eye's corneal epithelium, which may lead patients to discontinue ADC treatments. To improve ADC safety, BMS has teamed with Sutro Biopharma, a biotechnology company in San Francisco. Sutro is developing highly stable chemical linkers that bind warheads to BCMA-targeting antibodies more effectively. The aim is to broaden therapeutic windows so that potent doses can be given without these types of toxicity.
Because they kill healthy as well cancerous plasma cells, BCMA-directed agents may also increase the risk of infection. “Treatment may affect healthy plasma cells, which are the source of immunoglobin,” Mateos explains. There is preliminary evidence that BCMA treatment, she says, can cause patients to develop hypogammaglobulinaemia9, an inadequate humoral immune response. Munshi adds that clinicians can counter that risk by giving routine infusions of intravenous immunoglobulin.
BMS scientists are pursuing several avenues for improving BCMA-directed treatments. With one approach, they are developing a new class of immune-cell engager that is designed to leave normal plasma cell populations intact. Instead of harnessing endogenous T cells against the cancer, the new therapies are designed to exploit the biology of natural killer cells that are known to preferentially destroy stressed or abnormal cells and spare normal cells. One such NK cell engager, targeting BCMA, is currently in clinical development (NCT04349267).
Meanwhile, an important overarching need is to predict which patients will benefit most from each approach. BMS is gathering baseline and post-treatment data in its clinical trials, in an effort “to back-calculate what an ideal patient looks like for a given treatment”, Kaiser says. In studying what drives optimal responses, the aim is to provide clinicians with data that inform clinical management with BCMA-targeted therapies. Recent evidence8 suggests that the large majority of patients who relapse after CAR T therapy still express BCMA, which could be an opportunity for treatment sequencing, Kaiser says. “For those patients who don’t get a good initial response, or for who respond and then relapse, giving another BCMA-targeting agent may still be an option.”
Mateos says there’s a lot of excitement surrounding BCMA-directed therapy. One of her recent patients, a man in his 80s with advanced multiple myeloma refractive to other therapies, achieved a complete response after treatment (which he received as part of a clinical trial). “He kept improving, and it was great to see him feeling so much better,” Mateos says. “That’s the kind of outcome we hope to see more of.”