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Multiple Myeloma: Promising New Therapies, But Challenges Remain

This week, our series on multiple myeloma continues as we talk about immunotherapies and other promising new treatments with Shaji Kumar, MD. Dr. Kumar is a professor of medicine in the division of hematology at Mayo Clinic, where he chairs the myeloma group across all three Mayo sites. Dr. Kumar conducts National Institutes of Health-funded research on resistance mechanisms to common myeloma drugs and epidemiology of disease progression. He also receives funding from the Multiple Myeloma Research Foundation to study the relationship between molecular profiles, treatment regimens for patients with multiple myeloma and outcomes.

Inspirations

Real World Health Care: How did you become interested in the field of multiple myeloma?

Shaji Kumar, MD, Mayo Clinic

Shaji Kumar: I did my fellowship training at Mayo Clinic. Mayo is one of the most renowned institutions in the field of plasma cell disorders. Training at Mayo, and having the fortune of working with people like Professor Robert Kyle, was very inspiring and led to my interest in this group of disorders. The patients I see keep me inspired. While we have made some progress in this area, much work needs to be done and we need to develop a cure for this disease. The progress so far convinces me that we can reach this goal if we keep at it.

High-Risk Multiple Myeloma Patients

RWHC: What is the significance of your research work to the multiple myeloma patient community?

SK: I am involved in several aspects of myeloma research. In the laboratory, we try to understand how the myeloma cell survives, especially how the other cells in the body help them grow, and try to develop new drug combinations that can lead to better treatments. I try to translate these findings to the clinic in the form of early clinical trials, which if successful, can lead to larger phase 3 trials. I am the principal investigator of several phase 1, 2 and 3 clinical trials. Another area of great interest to me is risk stratification and identification of high risk myeloma. What we have seen is that patients with high risk myeloma continue to do badly despite all the new therapies. Moreover, there are still significant issues with the current systems for identifying high risk patients. We are trying to develop new approaches for risk stratification in myeloma and develop new treatment approaches for these patients.

Monoclonal Antibodies and Immunotherapy

RWHC: What promise do monoclonal antibodies and chimeric antigen receptor (CAR T-cell) therapies hold for the treatment of multiple myeloma? Could a cure be around the corner?

SK: Immunotherapy is the next frontier for myeloma. The results so far have been spectacular. The monoclonal antibodies have opened up a new class of drugs, and daratumumab especially has led to high response rates and deep responses in patients with myeloma. The next step is to combine the current classes of drugs to develop the most effective regimens. Other immunotherapy approaches, especially CAR T-cells, while early in the testing phase, has shown significant benefit among patients with very few options left. Other approaches to enhancing the T-cell immunity such as BiTE platforms as well as vaccination approaches are in clinical trials. All in all, this is an exciting time for myeloma and I am convinced that a cure is around the corner. What needs to be determined is if this will come from treating myeloma with these approaches or whether we need to intervene at the smoldering phase.

What Triggers Multiple Myeloma?

RWHC: What are some of the biggest challenges facing researchers studying multiple myeloma?

SJ: There are many challenges facing researchers. These include the lack of understanding the triggers for development of the disease, and the ability to identify patients who progress to myeloma in a specific fashion. Lack of good models for testing the myeloma cells outside of the patient, both for its behavior and responses to treatment, remains a problem. In the clinical trial arena, the ability to do clinical trials fast and also have faster readouts using surrogate endpoints remain a challenge.

The Multiple Myeloma Landscape

Editor’s Note: This article originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

Emily Burke, BiotechPrimer.com

Multiple myeloma is a cancer formed by a type of white blood cell called a plasma cell. These cells are the antibody-producing cells of our immune system and play a critical role in our defense against infections. If they begin to grow and divide in an uncontrolled manner, however, they form a plasmacytoma – a mass of cells within the bone marrow that no longer function in our defense but instead simply take up space and interfere with the functions of healthy cells. Instead of producing normal disease-fighting antibodies, plasmacytoma cells produce abnormal antibodies called M proteins, which don’t provide any benefit to the body and crowd out normally functioning antibodies.

Easily Confused: Plasma Cells vs Blood Plasma

Plasma cells are specialized white blood cells that produce infection-fighting antibody proteins. Most plasma cells are found in the bone marrow. Blood plasma is the straw-colored liquid component of blood that holds blood cells in suspension, made up of water (95%), proteins, glucose, clotting factors, electrolytes, hormones, carbon dioxide, and oxygen.

Picking Apart Plasmacytoma

Plasmacytoma formation can lead to a host of problems with recognizable clinical symptoms. Because all blood cells are formed in the bone marrow, over-production of plasma cells can essentially “crowd out” normal blood-forming cells. This can lead to anemia, caused by a shortage of oxygen-carrying red blood cells; increased bruising and bleeding due to a reduction in clot-promoting platelets; and an increased risk of infections due to lower levels of healthy infection-fighting white blood cells.

Although multiple myeloma is classified as a blood cancer, it has a significant impact on bone health. As the plasmacytoma grows, bone-forming cells called osteoblasts are suppressed. At the same time, production of a substance that activates bone-reabsorbing cells, osteoclasts, is increased. The resultant damage to the bone structure results in soft spots or lesions which may extend from the inner bone marrow to the outside surface of the bone. Bone lesions result in significant pain and increase the risk of fracture. Bone destruction also releases excessive calcium into the bloodstream, which leads to a range of symptoms including changes in urination, restlessness, confusion, increased thirst, nausea, and loss of appetite. Excess blood calcium, combined with high levels of M protein, also contributes to the impaired kidney function seen in multiple myeloma patients.

Unmasking Multiple Myeloma

There is no one diagnostic test for multiple myeloma. Blood and urine tests to detect some of the symptoms listed above such as low blood cell counts, elevated blood calcium levels, and impaired kidney function may suggest multiple myeloma. These tests can be followed by a bone marrow biopsy for confirmation.

Most cases of multiple myeloma have no known cause, although some research suggests that regular exposure to herbicides, insecticides, petroleum products, heavy metals, and asbestos increases the risk of developing the disease. And although there is not a specific gene yet associated with multiple myeloma, abnormalities in chromosome structure or number are associated with the disease.

Multiple Myeloma Treatments

Once considered incurable, there are now a number of effective treatments for multiple myeloma, and several more are in the pipeline.

Currently, there are two FDA-approved monoclonal antibody therapeutics approved to treat multiple myeloma.  They work by recognizing and binding to proteins on the surface of multiple myeloma cells, activating the patient’s immune system to destroy those cells.

Another type of approved therapy for multiple myeloma is a small molecule proteasome inhibitor therapy. A proteasome is a specialized compartment within the cell that gets rid of damaged proteins by digesting them. If the proteasome is inhibited, damaged proteins build up within the cell. This triggers a process called apoptosis – essentially, cell suicide. In other words, the cancer cell kills itself.

Small molecule histone deacetylase (HDAC) inhibitors have also been shown to be safe and effective in treating multiple myeloma. HDACs are enzymes that modify chromosomes (strands of DNA that contain our genes) and influence how often specific genes are activated. Some cases of multiple myeloma are associated with changes in gene activation. By inhibiting HDACs, this faulty gene expression can be corrected.

In the Pipeline

Two novel drugs in the multiple myeloma pipeline are Mivebresib and Selinexor.

Mivebresib influences the activation of specific genes by inhibiting a group of proteins called Bromodomain and Extra Terminal motif (BET) proteins. In some types of cancer, genes are activated or deactivated inappropriately due to BET activity. By inhibiting BET, normal gene activity may be restored to these cells.

Selinexor helps to increase the number of tumor suppressor proteins present in the nucleus of cancer cells. These proteins help to protect against cancer by detecting DNA damage and promoting apoptosis in those cells that have high levels of DNA damage. In many types of cancer cells, tumor suppressor proteins are transported out of the nucleus, where they can no longer do their job of detecting DNA damage. Selinexor blocks this transport and enables tumor suppressor proteins to do their job of triggering apoptosis in cancer cells.

A number of CAR-T therapies are also in development for multiple myeloma, with several early stage clinical trials ongoing. 

Multiple myeloma is a complex type of cancer. In recent years, a better understanding of the disease has led to the approval of several new therapeutics. In the coming years, we can look forward to additional approvals as novel therapeutics move through the pipeline.