Therapeutic Advancements in Multiple Myeloma - Episode 5

Targeted Therapies in Multiple Myeloma

Cancer Network Staff

So the advent of novel therapies in myeloma has transformed disease outcome in our patients and as a consequence, many patients are living a normal lifespan and growing old and dying of something else. Targeted therapies in our disease have been the reason for this success. The proteasome inhibitors target the proteasome and protein degradation, and have had remarkable efficacy. The immunomodulatory drugs cause protein degradation by binding to the ubiquitin ligase. Monoclonal antibodies target various antigens on the cell surface. So far we have daratumumab (Darzalex) and isatuximab-irfc (Sarclisa), targeting CD38. And the novel therapies that are coming along are also targeted.

The BCMA targeted therapies include immunotoxin belantamab mafodotin, as well as the bi-specific T-cell engagers that are targeting BCMA and other novel antigens, as well as the CAR T cells, again, mostly directed and targeted at BCMA. But now, also some other new antigens as well. I do want to mention that when we think about targeted therapies in cancer in general, we're thinking about targeting a particular pathway or a mutation. And in myeloma in that strict sense, there's really only 1 targeted therapy that looks very promising so far. And that would be venetoclax (Venclexta) targeting BCL2. Now, oral venetoclax is FDA approved in leukemia and lymphoma because of its efficacy targeting BCL2 in those contexts. In multiple myeloma, the 1114 translocation subgroup of patients has overexpression of BCL2, and in that group of patients venetoclax, combined with a proteasome inhibitor, has achieved very high response rates and is likely to be FDA approved.

So if you ask what are the true targeted therapies, in that sense that are approved in myeloma, or are promising it's really venetoclax. We're involved as are many around the world in clinical trials now, trying to target some of the pathways that have been found to be apparent in myeloma particularly in relapsed patients. So the RAS, RAF, MAP kinase pathway, for example, has been found to be apparent. And there are clinical trials of BRAF inhibitors. MEK inhibitors, ERG inhibitors alone or in combination in relapsed myeloma testing whether in fact you can target an aberrant, malignant mutated clone in myeloma and enhance efficacy of relapsed disease treatment. So targeted therapies, initially, starting with proteasome targeted treatments, targeting antigens with monoclonal antibodies immunotoxins bispecific T-cell engagers. And CAR T cells have all contributed to the remarkable progress we have today and will in the future in multiple myeloma.