iwMyeloma 2024 | History and upcoming projects of the MMRF

Hello. We’re here at the iwMyeloma 2024 meeting in Miami, and we just finished the session on the Multiple Myeloma Research Foundation projects and future directions.

My name is Larry Boise. I am from Emory University, the Winship Cancer Institute.

I’m Hearn Jay Cho. I’m the Chief Medical Officer for the Multiple Myeloma Research Foundation and I’m also associate professor of medicine at Mount Sinai School of Medicine in New York City.

Larry, we had a good review of the history of the Multiple Myeloma Research Foundation, in addition to some forward looks. Can you summarize your and Noa’s talks?

Sure. So, we, in the first two talks in the session, I talked about the CoMMpass study. And this was a large genomics and clinical observational study that the Multiple Myeloma Research Foundation had sponsored. It started actually going back to 2011 and it is now finally complete. So, all the 1147 patients are through and the clinical data of eight years follow-up on all of them is complete now.

And so I got to talk about the things that that we confirmed about myeloma genomics using the data set, about the types of mutations that myeloma patients have at diagnosis. About the gene expression that’s associated with different types of myeloma and how that’s changed a little bit by having so many samples with RNA seq expression and that hasn’t changed that much, but it’s really an interesting group, the hyperdiploid group, which I think is a little bit understudied at times. We now learn [it is] expanded from one gene expression subtype to at least four of those subtypes. So that was kind of interesting.

But I think the most important thing about that was that we, by using, multiple data sets that were available in CoMMpass, the investigators were able to assign function as well as just assigning whether a mutation occurred or a gene was expressed/expression occurred. And so we can really now hone in on what are the gain of function and loss of function changes associated with myeloma genesis.

The other really important thing in that study was that the MMRF included whole genome sequencing, which really allowed us to look at structural variations, which has kind of been the backbone of myeloma genesis really from the get go, but it’s far more complex than we had previously described, and we learned lots of new things, new translocations that are not new translocations, but we identified translocations associated with poor outcomes that we had never seen before, and structural variation hotspots as well, and the potential gain and loss of function there. So that was what I talked about.

One of the other things that came out of that, by knowing these mutations, how many of them were actionable, and could we take advantage of therapies that target some of those mutations and include them or incorporate them in clinical trials where patients who had a specific mutation would receive a backbone therapy in addition to the one that targeted their mutation?

And this is the MyDRUG study. And what we heard about in this study was about one arm of this. And these are patients who had mutations in the RAS-MAP kinase pathway, received cobimetinib as the drug, and we heard a little bit about the responses and some of the molecular outcomes for those patients.

Right. So Noa Biran from Hackensack University Medical Center gave us an overview of MyDRUG and the structure, how we used information that was gained from CoMMpass about the frequency of actionable mutations and some of which have FDA-approved drugs in other types of cancers, and applying those treatments to patients with multiple myeloma who have those specific mutations. And as you noted, she focused in on the RAS pathway mutation arm, which featured the MEK inhibitor cobimetinib. So, as you pointed out, the sample acquisition and the clinical data gathering has been completed as of August last year. The CoMMpass study is closed, but that doesn’t mean it’s over. Right? And I think Manoj Bhasin from Emory University gave us an overview of immune atlas, which is the next wave of data that’s going to be generated from CoMMpass samples. So, in addition to the tumor samples from all the patients in CoMMpass, the MMRF banked the non-tumor bone marrow microenvironment cells as well. And what was your impression of what’s being done in the immune atlas project which is associated with CoMMpass.

Yeah, I think first I want to take a step back and say that this is really one of the true strengths of the design of the CoMMpass study, was that a lot of these samples were banked, so it allowed the addition of other types of analyzes that weren’t planned in that very first study of just doing the genomics of the myeloma. And it actually opens up a lot of opportunities even moving forward, even before this session, we heard about using CoMMpass studies to look at DNA methylation in the patient samples from Ben Barwick. But back to, Manoj’s discussion of the immune atlas. So, this is using single-cell approaches to look at what other cells are in the microenvironment and how they may be associated. And so what are the cells, what are the immune cells that are there? And are they associated with outcomes? So high-risk patients versus standard-risk patients and poor outcomes. And really just showing what, you know, what I think Manoj’s really identified in this, is that there were certain subsets of cells that were clearly associated with, in many cases, dysfunctional T-cells that were associated with these outcomes.

And so, we can’t think of myeloma as just the plasma cell tumor, but everything surrounding it, especially in light of the fact that we’re using so many immune therapies now with two CAR T-cell products that are FDA-approved, with two T-cell engaging…

Three now!

…three, that’s right. You’re right. I’m sorry. It’s hard to keep up in myeloma with FDA approvals, but three, also FDA-approved, that we have to really think about what those immune cells are like in those patients for this approach to work.

Yeah. That’s really an excellent point. And as George Mulligan, my colleague, the Chief Scientific Officer for the foundation, summarized in the wrap up talk, looking forward the MMRF is gathering all of the learnings from CoMMpass, from immune atlas, from MyDRUG, and other platform trials, to formulate our forward-looking strategy. So, George focused on three aspects of our forward-looking strategy. One is the Horizon clinical trials program. So, we see that there’s outstanding drug development in the space, as you pointed out, there’s a bunch of new approvals for immune-based therapies that are very encouraging, but we still don’t have curative therapy. We don’t understand what are the best combinations, what are the best sequences of immune agents, for targeted agents, and for other types of chemotherapy. So, we felt that the best place to address this was in areas of high unmet needs: in patients with relapsed/refractory myeloma, and in patients with high-risk, newly diagnosed multiple myeloma. So, the platform trial program- Horizon one is in relapsed/refractory, this is the most developed and we expect that we’re going to be able to open this in the third quarter. And then, Horizon high-risk newly diagnosed, which hopefully will be open by the end of the year.

And so, we are working with our academic colleagues and with our pharma partners to collaborate around innovative, investigational protocols that will be benchmarked against a standard of care control. So, it’s a real randomized controlled trial, which is geared towards evidence generation to support innovative treatment. So, we’re not looking to duplicate any companies, registrational path, or anything like that.

And that’s paired with what’s happening in George’s shop on the translational side, which is doing prospective sample collection, data generation, and analysis that will help us understand how these contemporary therapies work. So, it’s a really very tightly integrated clinical and translational research program.

And then the third aspect of this, which is really intrinsic to the nature of the disease, is to address health equity and disparities in the multiple myeloma space. So, we are conducting our health equity summits to generate best practices for clinical trials in multiple myeloma, so that we can make them available and equitable to the entire multiple myeloma patient population. And that we’re building workforce diversity through programs like the MMRF scholars, which are bringing, young black clinicians and scientists and supporting them in their career development so that they can get to that first faculty job and become the future leaders in this field. So, I thought it was a real great opportunity to take a look back at the 25 year history of the foundation, and then look ahead at where we’re going with the guiding principle is that we’re seeking to cure multiple myeloma for every myeloma patient.

Yeah, I think that’s a great summary of what George presented and what the foundation is going to do moving forward. And I’m excited to participate and to watch how these projects move forward.

Well, thanks. You’ve been a terrific collaborator and partner, and I look forward to more.

Great. Thank you.