Transforming Treatment for Multiple Myeloma: Q+A with Dr. Suzanne Lentzsch

New research in multiple myeloma by Suzanne Lentzsch, MD, PhD, points to a novel connection between bone-depleting cells and our immune system. 

Multiple myeloma (MM) is a relatively rare cancer originating from plasma cells, white blood cells found in the bone marrow. Plasma cells normally produce antibodies that help fight infection, but when they become cancerous, they can damage various organs of the body. Eighty percent of patients with MM experience bone disease, resulting in fractures, osteoporosis or the need for radiation to treat pain. To date, there are no preventive strategies for MM.

In a project funded by a new three-year, $775,000 Translational Research Program (TRP) grant by The Leukemia & Lymphoma Society, Dr. Lentzsch and collaborators unveil a promising new approach to treat MM. The research simultaneously addresses the problem of immunosuppression and bone disease experienced by the majority of MM patients, leaving them with debilitating bone disease or vulnerable to life-threatening infections.

Dr. Lentzsch, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, directs the Multiple Myeloma and Amyloidosis Program at Columbia University Irving Medical Center and is a member of the Herbert Irving Comprehensive Cancer Center’s Tumor Biology and Microenvironment research program. 

Tell us about the new discovery.

We are focused on studying osteoclast activity—the bone-degrading cells—that are associated with myeloma bone disease. We know that multiple myeloma cells produce a lot of proteins activating those osteoclasts. We’ve identified one protein, called MMP-13, that’s secreted by the multiple myeloma cells as an effector protein that activates osteoclasts. Since multiple myeloma cells and osteoclasts are very close in proximity; multiple myeloma cells secreting MMP-13 induce the development and activation of osteoclasts subsequently destroying the bone.

We also found that this same protein, MMP-13, binds to a receptor called PD-1H, mainly known as a checkpoint inhibitor. What we know in cancer is that proteins bind to checkpoint inhibitors like PD-1H on T cells (immune cells) and subsequently inhibit their activity. This means that PD-1H plays a key role in blocking our immune system, our T cells, from doing their job to fight cancer. 

Why is that second half of the discovery important?

There has been a lot of excitement around checkpoint inhibitors and cancer immunotherapy—medications that bind to PD-1 and PD-1H to block their ability to suppress T cells from fighting against disease.

For the first time, we’ve identified a protein, MMP-13, secreted by multiple myeloma cells that activates osteoclasts, resulting in bone disease and that also binds to T cells, resulting in T cell inhibition. Our research has developed a connection between bone destruction and immunosuppression in multiple myeloma. Patients come to us with extensive bone disease—fractures of the spine and pelvis—and we have MM patients who are extremely immunocompromised, suffering from pneumonia, and severe bacterial or viral infections. Furthermore, the majority of multiple myeloma patients die of infection. Since MMP-13 contributes to bone disease and to immune suppression in multiple myeloma, we are really excited about targeting that signaling axis.

What are the next steps for this research?

Our focus is to move this research into the clinic. One challenge that we identified with our research was that MMP-13 is an enzyme. Usually, enzymes can be blocked by enzymatic inhibitors. But what we’ve learned is that MMP-13 is activating osteoclasts and inhibiting T cells independent of its enzymatic activity. That means we can’t just block the enzyme with a targeted drug. We need to produce a neutralizing antibody to disarm MMP-13. Our next steps involve investigating whether we can produce an antibody that can inhibit MMP-13, or develop an immunotherapy checkpoint inhibitor to block PD-1H.

How does this new finding contribute to the advancement of multiple myeloma treatment?

Right now, we are able to treat multiple myeloma better and better with  novel drugs, and with new cell therapies, like CAR T-cell therapy. Treatments, to date, control symptoms and pain but multiple myeloma remains incurable. Most of our research is focused on anti-myeloma strategies, with the consequence that we lost focus on bone disease. Even when multiple myeloma patients are in complete remission, they are still dealing with bone disease and lytic bone lesions, which never heal. We think that our research will help to improve the outcome of patients by better treatments of MM-associated bone disease and immunosuppression.