Key Advances and the Future of Multiple Myeloma Research and Care: Q+A with Dr. Rajshekhar Chakraborty

Multiple myeloma, or oftentimes referred to as myeloma, is the second most common blood cancer that originates from plasma cells within 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 such as kidneys and bones. To date, there are no preventive strategies for myeloma. Symptoms that are commonly experienced by patients before diagnosis include fatigue and bone pain.

Rajshekhar Chakraborty, MD, is focused on finding new ways to treat multiple myeloma, a disease that requires lifelong treatment. Dr. Chakraborty’s research is focused on designing and conducting clinical trials on novel agents in myeloma and amyloidosis at the Herbert Irving Comprehensive Cancer Center (HICCC). He is also working with Columbia University’s Department of Radiology to implement whole body diffusion weighted MRI for imaging-based disease assessment in myeloma. A member of the multiple myeloma team at NewYork-Presbyterian/Columbia since July 2020, Dr. Chakraborty is an assistant professor of medicine at the Vagelos College of Physician and Surgeons.

How is multiple myeloma diagnosed? Are there common symptoms?

To diagnose multiple myeloma, we traditionally identify four features. This criteria is referred to as CRAB, an acronym that stands for high calcium (we look for high calcium levels in the blood);  renal insufficiency or kidney disease; anemia or low hemoglobin levels; and destructive bone lesions. These criteria still forms the backbone of myeloma diagnostics.

However, recently, we’ve added three new criteria with the intent to  diagnose and begin treatment earlier, before patients develop organ damage such as fractures or kidney failure. One of these criteria is the presence of more than 60% cancerous plasma cells in the bone marrow. The other two criteria are ratio of involved to uninvolved serum free light chain of greater than 100 and more than one focal lesion on MRI. Testing for M-protein and serum free light chain (proteins produced by plasma cells) help us better detect and monitor the disease. In addition to blood tests, a bone marrow biopsy is conducted in all patients to confirm the diagnosis and to also identify how much of the cancerous plasma cells are present. Additionally, patients also have either a low-dose, whole-body CT or PET-CT to identify destructive bone lesions.

What are the risk factors?

Not a lot is known about specific risk factors for myeloma. Some potential risk factors for myeloma and its precursor states are exposure to Agent Orange, which is common in Vietnam War veterans, and exposure to the 9/11 World Trade Center disaster. Unfortunately, there hasn’t been any evidence-based preventative strategies at this time to help prevent myeloma. Some experts have advocated for screening for myeloma in populations with a higher prevalence, such as Black patients and immediate relatives of people with myeloma.

How is multiple myeloma treated?

When we see a patient newly diagnosed with multiple myeloma, we first determine whether they are “transplant-eligible” or “transplant-ineligible.” That basically means whether or not they will be fit enough to receive an autologous stem cell transplant. However, this designation can change for patients. For instance, a patient who is  classified as transplant-ineligible can become transplant-eligible after a few courses of initial therapy. After determining transplant eligibility, we start a three-drug or four-drug combination chemotherapy, which is also known as induction therapy. Patients who are transplant-eligible either proceed to an autologous transplant after four to six courses of induction therapy or delay transplant until first relapse after weighing the pros and cons with their physician. Patients who remain transplant-ineligible continue the same treatment for additional three to four courses. Subsequently, all patients receive maintenance therapy as long as they are able to tolerate it and myeloma remains in remission.

What are some of the existing treatment challenges?

Unfortunately, myeloma is still an incurable disease for most patients, and the paradigm of treatment is still continuous therapy from the point of diagnosis. Since patients are usually on continuous therapy, that causes substantial physical as well as financial toxicities. As a community, we are still working on how to better individualize treatments to patients, disease biology, as well as response to therapy.

Additionally, in ongoing clinical trials in multiple myeloma, patient reported outcomes and quality of life has been a key focus, more so now than it was say 20 years ago. That’s very encouraging because as we improve on the current treatments in myeloma, it's also important to make sure that our treatments are tolerable, and patients are able to continue their life normally. So it's really exciting that most clinical trials are now measuring  patient reported outcomes when testing new drugs.

Tell us about recent advancements in multiple myeloma.

A major advance that we have seen in the past decade is the sheer number of safe and effective drugs that are available currently for treating multiple myeloma. Among the currently approved drugs, the three most important are proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Recently at the American Society of Hematology 2020 meeting, results from long-term follow-up of a clinical trial was released in which patients got treated with modern chemotherapy drugs— proteasome inhibitor and immunomodulatory drug—followed by autologous stem cell transplant. Investigators found that 60% of patients were alive at eight years This tells us how much progress we have made in myeloma. In the 1990s, the average survival of myeloma patients was just approximately three years.

We’ve also been able to provide more sensitive methods for disease assessment and assess what we call “MRD,” or minimal residual disease, which is a new buzzword in myeloma management these days. MRD is basically an assessment of the last myeloma cell present in the bone marrow, and there are various techniques to assess MRD. We can now do this with higher sensitivity using flow cytometry or next-generation sequencing. MRD is more sensitive compared to the traditional blood-based protein tests that are commonly used for response assessment. Additionally, with the availability of sensitive MRD assays, we are able to detect very small amounts of myeloma present in the bone marrow and will be able to tailor our treatments accordingly in the near future. Finally, another big progress that we have made is the advent of immunotherapies, mainly CAR T-cell therapies (using genetically engineered T-cells to fight cancer) and BiTEs or bispecific T-cell engagers, which have also improved outcomes in patients with multiple myeloma.

What does the future hold for multiple myeloma? What are you most excited about?

We are gaining more and more insights into the disease biology of myeloma, based on a lot of research currently ongoing in myeloma genomics. And as we gain more insight into the disease biology one of the things that is possible in the future is bringing targeted therapy for our patients. Also, as we get more familiar with the use of minimal residual disease, or MRD, testing as a tool for treatment modification, I can see in the future that we’ll be able to change the paradigm from continuous therapy to fixed-duration therapy with ongoing MRD surveillance. Another thing I would say is using immunotherapy earlier in the course of disease, especially in patients with high-risk myeloma, is very promising. For example, CAR T-cell therapy and BiTEs (infusion therapy that activates a patient's own T cells to help kill cancer cells) have the potential to really make a dent in the natural history of high-risk patients—these novel therapies all have promise to change the treatment landscape in multiple myeloma.