Therapeutic Advancements in Multiple Myeloma - Episode 3

Relapsed/Refractory Multiple Myeloma

So, there have been many advances in the management of relapsed/refractory multiple myeloma. Starting 20 years ago, we had the immunomodulatory drugs and the proteasome inhibitors and more recently, the monoclonal antibodies. Each of these modalities showed their initial efficacy in relapsed/refractory myeloma, and now they have moved to the earlier management of this disease. I mentioned this before. Because those patients who now are defined as relapsed or refractory myeloma have often been exposed to these novel drugs. So instead of thinking of patients now as having prior lines of therapy – one, two, or three prior lines of therapy, as we've done in the past – we more and more now are thinking of patients who have had lenalidomide (Revlimid) or who have had bortezomib (Velcade) or who have had CD38 monoclonal antibody, those patients whose myeloma relapses after that combination would be called triple refractory.

And then there's penta-refractory myeloma, which is myeloma that's relapsed in spite of therapy with lenalidomide and pomalidomide (Pomalyst), as well as Velcade, or bortezomib and carfilzomib (Kyprolis), as well as CD38 antibody, they're penta-refractory. Fortunately for us, we have so many regimens now that are FDA approved, that we can usually come up with the right treatment for the right patient.

And so when you and I see patients in the clinic with relapsed refractory myeloma, we think about what are the comorbidities? What is the frailty status? Is the patient fit or frail? What are the goals of therapy, but importantly, the genetics of the disease and probably primarily thinking of what is the prior history?

So we have regimens that have lenalidomide dexamethasone, for example, that are combined with a variety of agents, monoclonal antibodies or proteasome inhibitors that are effective in the context of bortezomib-refractory myeloma. We have a bunch of triplet therapies that are bortezomib based, so bortezomib decks plus monoclonal antibodies, for example, which are effective, even in lenalidomide-refractory myeloma. But most importantly, upfront myeloma right now is often managed with lenalidomide, bortezomib, and dexamethasone. So patients even at first relapse have disease that's resistant to both of those agents. So we have daratumumab (Darzalex), that's combined with pomalidomide. And daratumumab, that's combined with carfilzomib. We have isatuximab-irfc (Sarclisa), a new CD 38 antibody that's combined with either pomalidomide or with Kyrpolis, or carfilzomib in patients who are triple refractory or penta-refractory. We have 2 agents that are approved. We have Selinexor, the nuclear transport inhibitor, and we also have the first immunotoxin.

And finally, there's such excitement in myeloma because we still are developing novel agents. An example would be Ventoclax, which is very effective, as you all know, and FDA approved in leukemia and lymphoma, in myeloma in the 1114 translocation subgroup for those patients whose myeloma overexpresses BCL2 gene and protein venetoclax, combined with a proteasome inhibitor achieves 80% to 90% responses. So in that subgroup of BCL2 overexpressing myeloma Venetoclax is a wonderful novel therapy that will be soon is likely to be soon FDA approved, and then the future is even brighter, because we have the immune therapies BCMA-directed but other new targets as well, that are immunotoxins that are bi-specific T-cell engagers.

At the American Society of Hematology, (there were presentations about) many BCMA-directed bi-specific T-cell engagers in early clinical trials. Once the dose for phase 2 testing has been defined, there has been 60% to 80% responses commonly observed. And finally, (there are) CAR T cells mostly directed at BCMA. But some other targets as well, are demonstrating remarkable efficacy including MRD negative responses. And now the effort is to try to prolong the duration of these responses. So I think the summary is that we've been very blessed in myeloma that we have multiple options. Second generations of the immunomodulatory drugs or proteasome inhibitors, new classes of drugs like monoclonal antibodies, nuclear transport inhibitors and BCMA-directed therapies immune to toxins and then the future with bi-specific T-cell engagers. And CAR T cells is brighter even still.