Moon Shot concentrates on treating, preventing high-risk multiple myeloma

Multiple myeloma is the second most common hematological malignancy in the United States, and it’s increasing in incidence. An estimated 32,110 new cases will be diagnosed in 2019, with nearly 13,000 deaths caused by the disease. Certain patients have what is known as high-risk multiple myeloma (HRMM), meaning they have distinct molecular features that lead to more rapid progression and poorer outcomes.

The High-Risk Multiple Myeloma Moon Shot® team is committed to improving the lives of patients with HRMM by learning to better understand and treat patients with asymptomatic disease, before it progresses, and developing novel therapeutic options for patients with advanced, symptomatic disease.

The effort is part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Robert Orlowski, M.D., Ph.D., professor and chair ad interim of Lymphoma/Myeloma, is one of the co-leaders of the Moon Shot® team and he spoke with Cancer Frontline about the scope and goals of their work to improve multiple myeloma treatment.

Q: What are the primary focus areas for the work of the Moon Shot?

A: We’re focused on two primary areas within the Moon Shot – advancing new treatments for patients with high-risk symptomatic disease and developing approaches to delay or prevent progression in patients with high-risk asymptomatic, or precursor, myeloma.

In patients already diagnosed with symptomatic myeloma, we can identify “high-risk” patients based on molecular features such as deletion of chromosome 17p or amplification of 1q21. These are patients who, based on available data, will survive only about 3-4 years, compared to survival of 10-15 years for those with “standard-risk” myeloma. Those high-risk patients respond well to our current therapies, but the duration of their response is very short, which is why we need new options.

The other high-risk area we’re targeting are those with precursor disease, such as smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS). If you have high-risk smoldering myeloma, you have an estimated 50-70% chance of progressing to symptomatic myeloma within 2 to 3 years of diagnosis. Our patients don’t want to just wait for that to happen, and as doctors, we want to be able to help our patients. So we’re working to understand why patients progress and develop treatments that will allow us to delay or prevent their progression to myeloma.

Q: What sort of projects is the Moon Shot team working on for patients with high-risk asymptomatic disease?

A: We’re engaged in several clinical trials to investigate the use of immunotherapy to delay or prevent disease progression for these patients. This work is led by Elisabet Manasanch, M.D., Sattva Neelapu, M.D., and Eric Davis, M.D.

We have one trial wrapping up investigating the use of pembrolizumab in intermediate- to high-risk smoldering myeloma patients, because expression of PD-L1 (part of the drug’s targeted pathway) was correlated with disease progression. In our pilot study, this treatment was well-tolerated and even led to a complete response in one of 13 patients, suggesting that it is possible to prevent disease progression with immunotherapy.

We also have a trial with an anti-CD38 antibody, isatuximab, to see if treatment can prevent or delay progression. That concept is likely going to move forward to a Phase III trial based on our results.

Finally, our current study is with a personalized vaccine approach. We’re sequencing DNA and RNA from myeloma cells to identify mutations most likely to be antigenic, and creating a vaccine of 10 peptides based on those findings. We’re going to be looking at whether the vaccine induces anti-myeloma immunity and hopefully also some clinical response.

Q: For patients with more advanced disease, how is the Moon Shot working to provide new and better therapeutic options?

A: Our team is developing a variety of cell therapy approaches for these patients, leveraging the expertise found at MD Anderson and within the adoptive cell therapy platform. This work is led by Katy Rezvani, M.D., Ph.D., Elizabeth Shpall, M.D., and Rohtesh Mehta, M.D.

We’ve shown in a Phase I study that we can expand natural killer (NK) cells derived from umbilical cord blood to safely treat patients with symptomatic disease. The preliminary data shows that this approach is safe, and there is evidence that they benefit patients with high-risk disease and keep them in remission longer. Moving forward, we’re planning to use engineered chimeric antigen receptor (CAR)-NK cells that will be targeted to the cancer cells.

We’re developing the best approach for targeting multiple myeloma cells with a new generation of CAR-NK cells and plan to launch the first-in-human Phase 1 study in patients. We hope these CAR-NK approaches will have minimal toxicity and lots of clinical activity.

Q: Is there a project you’re particularly excited about at the moment?

A: One of the more exciting projects is the vaccine study I mentioned. I’m excited for several reasons. First, it’s personalized to the patient. Each patient will be receiving a vaccine with a different set of peptides, specific to their cancer. Secondly, the vaccine is cancer-specific, meaning that none of these mutations are present in normal cells. You can’t get much more personalized than that, and hopefully we’ll see some good benefit for our patients.

The hope is if we catch people when they’re in the asymptomatic phase, when the disease is less progressed and their immune system is healthier, we might be able to find a sweet spot where we can cure patients and prevent symptomatic myeloma from appearing.

Q: How has your work been enabled by the Moon Shots Program and its infrastructure?

A:  The Moon Shots Program has provided tremendous support for research that wouldn’t initially have been funded by other sources, such as the NIH. Generally, those sources prefer that you have preliminary data and good hypotheses in place.

So what the Moon Shot allowed us to do is some of the important exploratory work, utilizing the infrastructure of the platforms to look at important questions and gather this preliminary data. For example, we were able to do RNA and DNA sequencing, bioinformatics analysis and immune profiling to find some exciting things.

To start, some of our work was exploratory. The best example is trying to understand why some patients progress to multiple myeloma from precursor diseases and others don’t. That’s a long-term project because it represents a small percentage of patients, so the work spans many years. But, with the support of the Moon Shot we’ve discovered some compelling things and we’ve been able to obtain extramural funding. For example, we were awarded a Specialized Center for Research (SCOR) award from the Leukemia & Lymphoma Society based on our work, and three of the four projects there started off in the Moon Shot. It’s been a great way to do important work that we can leverage for further outside funding.