A Conversation About Multiple Myeloma with Dr. Edward Faber, The Nebraska Medical Center
The Nebraska Medical Center is serving as a Community Resource Center (CRC) for ACCC’s Improving Quality Care in Small-Population Cancers: Multiple Myeloma education program. Dr. Faber is a member of the Advisory Board for this initiative. ACCCBuzz asked Dr. Faber to provide an overview of this small-population cancer and some perspective on advances that have been made in treating this disease.
Q: Can you provide a snapshot of the progress that has been made in treating multiple myeloma?
Dr. Faber: Arguably, very few other cancers have enjoyed the success of new therapies that have been derived from great translational research. These successes include new therapies and numerous combinations of therapies, which may or may not be combined with stem cell transplant strategies.
Two classes of chemotherapeutic agents, proteasome inhibitors and IMiDs, have solidified the era of “novel agents” by increasing progression-free survival and overall survival. Median five-year survivals for multiple myeloma are over 60 percent. I would anticipate this number to be better once the newest SEER data is reported.
From a certain view point, treatments for another small-population cancer, chronic myeloid leukemia (CML), might best represent our greatest advancement in the last 25 years. In the case of CML, we’ve taken a disease that was almost universally lethal without allogeneic transplantation and turned it into a chronic disease requiring a pill. For this simple reason, the strategy of targeted therapy developed for CML has ushered the era of “targeted” or “individualized” therapy. Many very intelligent people believe that’s where we’re headed with multiple myeloma.
Q: How has a better understanding of the disease biology and pathophysiology led to improvement in care for multiple myeloma?
Dr. Faber: Key pathways such as proteasome inhibition are vitally important for multiple myeloma and, to a lesser degree, mantle cell lymphoma. For reasons that are not clear, proteasome inhibition does not seem to be an important target for other cancers. Understanding the relationship between proteasome inhibition and multiple myeloma has led to drugs like bortezomib and carfilozomib.
The second class of medications is immunomodulatory agents, called IMiDs. Agents such as thalidomide, lenalidomide, and pomalidomide are the direct results of understanding the pathophysiology. Furthermore, many new therapies now available have been first proven in the lab. Direct science correlatives are now quite common, and have led to new drugs and new combinations of drugs both with and without the use of the novel agents.
Q: What is the progression of multiple myeloma?
Dr. Faber: We have made significant strides to improve up-front response rates for both transplant-eligible and non-transplant-eligible patients. Even though we are achieving deeper and more durable responses which lead to better quality of life, ultimately myeloma will relapse. We have made some progress to increase progression-free survival (PFS) and responses, but generally speaking, each successive treatment will have a shorter and shorter PFS, until finally the disease becomes refractory. A few researchers have demonstrated the heterogeneity of the disease. If I may elaborate, when we look at the myeloma genetically at relapse, it can present as different clones, which may or may not have been present at initial diagnosis. So maybe we can consider myeloma to be a series of clones. Each successive treatment addresses one or a combination of the clones, but ultimately there is one clone that becomes resistant to whatever we have and eventually claims the patient’s life.
Q: In your presentation at the ACCC 29th National Oncology Conference, you commented that multiple myeloma is not a “what you see is what you get” disease. Can you elaborate?
Dr. Faber: We know that all multiple myeloma patients relapse at some point. The question is why do patients who have achieved a complete response then relapse? Where did the disease go? Where does it hide?
With the advent of more sensitive testing, the term “minimal residual disease” is now often used. In my presentation I recalled an iceberg analogy, which I remembered hearing in a presentation by Sagar Lonial, MD, from Emory University. What we used to see with multiple myeloma in the bones, bone marrow, and the blood work was above the water—like the tip of an iceberg. Just as with the hidden underwater area of an iceberg, there was a significant disease burden that was unable to be seen or tested. And I think many of us, as we work with the more sensitive tests, realize that the newer agents eradicate not only what we see (the tip of the iceberg) but also what we had previously been unable to see. But, ultimately, there is disease deep down that you still can’t see. That’s where much of the research is currently focused. Finding a way to detect minimal residual disease is a great way to begin to discover how we can eradicate it.
Q: Ultimately multiple myeloma outsmarts the available treatments?
Dr. Faber: Correct. There are so many pathways that cells can use to signal growth in cancer cells. The pathways can ebb and flow to avoid the toxic effects of our available therapies. The current targeted agents are very good at shutting down certain pathways, but the cell then learns how to see other pathways to continue its growth advantage. That is exactly what I mean by the cell starting to outsmart the therapies. This is coupled with the fact that patients can develop side effects to treatments, which is disheartening, especially when the drug is still working but the patient can no longer have the drug because of the side effects.
Q: Today what do you see as major challenges for providers treating this disease?
Dr. Faber: Drugs that we can use for long periods of time without side effects. Finding the laboratory tests that can help us assess minimal residual disease and are easy enough to be translated into the community. We can do a lot of good things at the big centers, but sometimes it’s not feasible to translate them to the community setting because they are complicated and are not cost effective.
In terms of newer agents which have targets that may work when the available drugs stop working, it would also be nice to have specific laboratory tests to assess for when we should use certain drugs. Maybe this is where we are headed with genomics and gene expression profiling, which would lead to individualized therapy. I want to believe that multiple myeloma can be a disease that you get diagnosed and treated; then, when it relapses, a test would help characterize it so that the “right” drug(s) can be given. In other words, try to give a drug to patients when they need it, while sparing them drugs that may not be as useful at the time.
Q: What interests you most in working with multiple myeloma?
Dr. Faber: The complexity of the disease draws me—its effects on the bones, the kidneys, the heart, and the bone marrow. It truly requires a multidisciplinary approach today in order to try to coordinate the efforts of radiation oncologists, spine surgeons, orthopedic surgeons, kidney specialists, and so forth. And I think the success of the newer therapies allows us to treat patients longer while maintaining a good quality of life. The newer treatments and the newer combinations really do help quality of life.
Multiple myeloma is a very heterogeneous disease. Not all the patients are alike and few are similar. It is that variety that makes multiple myeloma challenging to treat. When you have patients that are failing the new therapies or relapsing harshly, finding the right therapy for these patients is similar to “righting the ship.” This success, of course, is very rewarding.
Q: How can physicians who may see just a few patients with multiple myeloma a year keep up with rapidly changing treatment options?
Dr. Faber: As with most cancers today, the literature can be behind. The advances happen at American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) meetings, as well as during discussions in the conference rooms. ASH and ASCO can be overwhelming, which is why I think it is important to prepare by “attending the conference” before you actually attend the conference.
Establishing a relationship with a referral center with someone specializing in myeloma is also important. Establishing a network that you can call when you have questions or problems is also important. I don’t know very many people at referral centers who would be unwilling to help. The Community Resource Centers established through ACCC’s Improving Quality Care in Small-Population Cancers program are one way for ACCC members to access providers with expertise in treating multiple myeloma, chronic myeloid leukemia, and acute promyelocytic leukemia.