Therapeutic Advancements in Multiple Myeloma - Episode 6

Immunotherapy for Multiple Myeloma

There have been remarkable developments in new immune treatments for multiple myeloma. As you all know, there is marked genetic heterogeneity right from the outset in myeloma and ongoing genetic DNA damage and clonal evolution that ultimately underlies relapse. The excitement with immune therapies, it's that you may be able to deal with this constitutive and ongoing genetic heterogeneity because the immune system has the ability to adapt over time and deal with this genetic evolution that underlines relapse of the disease.

The first immune class of therapies that demonstrated efficacy in myeloma were the monoclonal antibodies starting with daratumumab (Darzalex) targeting CD38 and isatuximab-irfc (Sarclisa), targeting CD38. All have antigenic targets and they all have different mechanisms, antibody dependent cellular cytotoxicity complement directed cytotoxicity. They either inhibit activating signals or they neutralize or abrogate survival signals that can trigger death signals.

Elotuzumab (Empliciti) in particular has a unique ability to activate and trigger NK cell activity. In addition to his ADCC and other activities against myeloma. Belantamab mafodotin is the first immunotoxin FDA approved in myeloma. It's directed at BCMA. And in fact, it has immune activities against myeloma, but it delivers an ARO status immunotoxin to the myeloma which this toxin is then internalized. So we have a double or dual mechanism of a Potosi, this one immunologic mediated one toxin mediated effect.

The excitement in myeloma about immune therapies is really coming from 2 directions. One are the bispecific T-cell engagers. These are off-the-shelf medicines that bind on the one hand to BCMA on myeloma or other antigens. And on the other hand to see D3 and if you will bring the immune system to the myeloma cell, enhancing specificity potency and improving the therapeutic index. At the American Society of Hematology, multiple BCMA-directed bi-specific T-cell engager or bike clinical trials were reported. And even in early phase clinical trials, remarkable activity is being seen 60% to 80% responses and with a favorable therapeutic index.

CAR T cells in myeloma also are very exciting. They're used now in far advanced relapsed/refractory myeloma, mostly directed at BCMA but summit other novel antigens as well. And they have achieved remarkable frequency and extent of response and far advanced disease, including high rates of MRD negative responses. The toxicity is now being managed better with the early intervention, for example, to minimize cytokine release syndrome. And there are multiple strategies to prolong the durability of responses to CAR T cells: enriching for memory, lineage CAR T cells, for example, or using CAR T cells in combination with other treatments, such as lenalidomide (Revlimid) or other immune treatments.

Finally, I want to mention the concept of immunogenic cell death. This was presented at the American Society of Hematology by our own laboratory on agents we use, for example, bortezomib (Velcade) proteasome inhibitor, has its own direct killing effect on myeloma. But those dying myeloma cells can then trigger in a process called immunogenic cell death, a selective immune reaction or response against myeloma. And we have shown the mechanism whereby this occurs, it goes by the sting pathway. These studies suggest that we need to relook at how we inform treatments and myeloma. Because the proteasome inhibitors, for example, by inducing immunogenic cell death would be a very good partner for other immune treatments. You could envision using a proteasome inhibitor with a bi-specific T-cell engager, for example. So the future is even brighter than the past. I think we can use combination therapies alone and together to overcome the genetic heterogeneity right at the outset in myeloma, and, importantly, overcome the marked heterogeneity in genetic abnormalities that exists in relapsed refractory disease.