Emerging Immunotherapies and the Future of Multiple Myeloma Treatment

Thomas G. Martin, MD, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California, discusses a few promising immunotherapies in the pipeline for multiple myeloma and how they will affect the future treatment of this disease.

Transcript

We have some very exciting, merging immunotherapies in multiple myeloma. We've seen great success with daratumumab, what we call a naked monoclonal antibody. In daratumumab, we now have promising studies in using daratumumab as frontline, as early relapse, and then the relapsed or refractory setting. Now, we're really testing the next generation molecules.

What I'm really excited about are some of the second generation antibody therapies. We can tailor the antibody, or we can manufacture antibodies that have two binding domains, one that binds or anchors itself to myeloma, and the other domain that can actually bind to a T cell and activate the T cell.

These dual-targeted antibodies are now really showing dramatic potential in antimyeloma responses in early phase trials.

We saw at ASH this past year, a dual-targeted antibody from Amgen, the AMG420, which showed that this dual-targeted antibody could have a very deep responses in patients that have very refractory multiple myeloma. In fact, in seven patients treated, what probably is going to be the maximum tolerated dose, they saw five responses, and of that four patients achieved MRD-negative status.

That's a deep response in a very refractory patient. These are early days in these dual-targeted antibodies. There are about 10 different companies that are now investigating this type of therapeutic in myeloma. It's really going to be fun watching how it evolves over the next 12, 24, 72 months just to see which is going to be the best therapeutic in myeloma.

The other way we can modify an antibody-based therapy is by attaching a poison to it. I call it the smart bombs. We can attach a poison and have an antibody drug conjugate.

There's one in clinical trial right now from GSK. It's a BCMA-targeted ADC. The antibody binds to the surface of the myeloma cell, gets taken up into the cell, and then releases its toxin in the cell.

In an early study called the DREAM-1 study, which is just updated in publication, I showed that in 35 patients, treated at what's presumed to be the best dose of this molecule, the overall response rate in relapsed or refractory myeloma was 60 percent.

This was single agent responses. This response rate, the single agent response rate of 60 percent, is better than all our other myeloma therapeutics. It's quite exciting. There are many studies using this antibody drug conjugate together with all kinds of agents in early relapse, in later relapse together with polmalidomide, etc. It would really be fun to watch how this antibody is developed.

The other thing that's been really exciting is cellular therapies in myeloma, and specifically the chimeric antigen receptor T cells or the CAR T cells.

We saw some data initially in 2016 from the NIH showing that, when you can take out some of these T cells, use gene therapy to modify those T cells, and direct the T cells at BCMA, probably the best target for myeloma cells, and inside these T cells put a secondary signal on the T cell, so that the T cell will get very activated when it binds the myeloma cell, that's what's the gist of this chimeric antigen receptor T cells, that you can see deep responses for just the administration of T cells, pretty amazing.

We've seen reports from several other centers, from UPenn by Adam Cohen. We've seen reports from Nanjing, from this Legend Technologies, and we've actually seen responses or data from Bluebird, the bb2121 CAR T cell therapeutic, showing that responses can be in this relapsed or refractory population of over 80 to 90 percent.

Initially, we thought, potentially, that this might be a curative therapy for myeloma. However, with longer follow-up, what we're seeing is we're seeing initial deep responses, but over time we're actually seeing patients relapse.

At the current time, when a patient gets a CAR T cell therapy for relapsed or refractory myeloma, the progression free survival is about 12 months. Some patients are lucky, and they actually have longer responses, some are not and only have short responses, three to six months.

Really, what we need to do in the next year to two years is figure out why some patients are responding better than others. We also need to modify the CAR to make them more efficacious. Perhaps, we have to add a monoclonal antibody to a CAR therapy as a maintenance afterwards, or add one of these other next generation antibodies.

I think that really the next two to five years in myeloma therapeutics is going to be how do we incorporate the immunotherapies? Do we do them earlier on in therapy? Do we add the immunotherapies together? Do we add them to current existing myeloma medications? It's going to be really fun, but it's a very exciting time for patients and doctors that have or treat myeloma