Developing early-phase clinical trials that incorporate combinations of novel agents targeting different pathways in the hematologic cancer multiple myeloma is a leading focus of the work of Sagar Lonial, MD, Professor of Hematology and Vice Chair of Clinical Affairs in the Department of Hematology and Medical Oncology; and Director of the Translational B-cell Malignancy Program at Winship Cancer Institute at Emory University School of Medicine. Dr. Lonial’s laboratory is also investigating combinations of drugs that may inhibit the PI3 kinase/Akt pathway—a central gatekeeper for important cellular functions in myeloma cells, including the development of drug resistance—and facilitate myeloma cell death.
While more effective therapies for myeloma as well as advances in the genomic sequencing of myeloma cells have succeeded in extending overall survival from 3 years to 7 years, the cancer remains incurable, resulting in the deaths of nearly 11,000 people each year, according to the American Cancer Society. To combat these statistics, Dr. Lonial is also investigating strategies to identify newly diagnosed myeloma patients at high risk for relapse and establishing a treatment plan to keep them in long-term remissions.
The ASCO Post talked with Dr. Lonial about how innovative clinical trial designs and a better understanding of the genetic abnormalities in myeloma cells are leading to longer remissions and potential cures.
Evolving Concepts
How has our understanding of multiple myeloma at the molecular level improved?
Many of the cancers we treat, not just in hematology but in all of oncology, are not simple diseases. That is, there is not one key that unlocks the door. Other than diseases like chronic myelogenous leukemia or gastrointestinal stromal tumor, where you use one drug that shuts down the tumor pretty significantly, most cancers (and certainly most hematologic malignancies) have a complicated genome with multiple areas that have gone awry. So the idea of sequencing single agents doesn’t make a lot of sense. And because these cancers are so complex, it’s going to take more than one drug to make them go away.
As we have started to understand more about the basic biology of myeloma cells, we’ve also tried to understand what different pathways are involved. For instance, we know that plasma cells, which become myeloma cells, are particularly good at making lots of protein, and in order for those cells to survive, they need pathways that enable them to deal with the production and maintenance of large protein loads. Chiefly, that is the proteasome pathway, so we use proteasome inhibitors like bortezomib (Velcade) and now carfilozomib (Kyprolis) in attempts to gum up a system that even a normal plasma cell depends on for survival.
Once you’ve identified that one pathway, you start thinking about what else becomes active to help the cells stay alive, and that’s where a lot of the preclinical and clinical combination strategies come from. For example, we’ve looked at ways to block the heat shock protein response or DNA-repair response, both of which can be mediated through the proteasome inhibitors, and that accounts for why a drug like cyclophosphamide has a synergistic effect when combined with drugs like bortezomib and carfilzomib.
The two most active classes of drugs we have in myeloma are proteasome inhibitors and immunomodulatory drugs, including thalidomide (Thalomid), lenalidomide (Revlimid), and now pomalidomide. Those three potent drugs can be made even more powerful by combining them with a proteasome inhibitor, or they can make an antibody more effective because they can enhance immune function. That discovery came from laboratory work and is now being borne out in phase I and II clinical trials.
Obstacles in Trial Design
What are some of the obstacles in designing clinical trials that combine several agents?
One of the challenges we struggle with in oncology generally is that multiple pathways are involved with drug resistance, so we want to begin to put together combinations of drugs that are not all FDA approved. That’s challenging from a regulatory and operational perspective; it can be very complicated to put together two nonapproved drugs in a clinical trial.
What can be done to overcome those obstacles?
In myeloma research, we are fortunate that the industry partners we work with understand the importance of testing combinations of agents in trials. They are more willing now than they were 10 years ago to talk about doing those challenging but groundbreaking clinical trials, even when the drugs are not FDA approved.
The FDA is certainly willing to allow these trials of what we call novel-novel drug combinations—meaning neither drug is FDA approved—because it doesn’t want to hold up this kind of progress.
Patient Selection
Is participation in novel-novel clinical trials determined by a matchup between the patient’s specific myeloma characteristics and the agents’ ability to target the tumor’s pathways?
Yes, but there are two answers to that question. First, we want to hone down and get to the genetic nuts and bolts of the different subsets of this disease, rather than treating it as a single entity. But you cannot put each patient in his own bucket. The lumping and splitting has got to occur somewhere in the middle, where you get a reasonable number of patients who may not be genomically identical but are genomically similar enough that a given treatment approach will work.
Second, we often think we know how a drug works, but many drugs may go after one target and also have off-target effects. One of the potential dangers of being too focused on drugs for individual patients is that we may miss an active drug because we do not really understand the true mechanism at work.
PI3 Kinase Pathway
What role does the PI3 kinase pathway play in the development of myeloma?
One of the pathways that is highly overexpressed or highly active in almost all malignant plasma cells is the PI3 kinase pathway. PI3 kinase is a very important activator, and many of the external growth factors stimulate the plasma cell growth signal through PI3 kinase.
A while ago, we noticed that multiple myeloma patients may have highly active PI3 kinase, but it is not for genetic reasons, like in renal cell carcinoma, where the cells have mutations in PTEN. It is because they are receiving growth factor stimuli from outside the cell.
Early on, we found that while we did get an inhibition of growth with some PI3 kinase inhibitors, that didn’t really kill the cell by itself. What we are looking at now are ways to enhance the cell death associated with inhibiting PI3K and whether subsets like the specific isoform inhibitors, such as the gamma and delta inhibitors, can be more effective in inducing myeloma cell death.
High-risk Patients
While many newly diagnosed patients successfully achieve remission with standard therapies, most eventually relapse. What treatments are you investigating for the high-risk myeloma patient who relapses repeatedly?
The high-risk subset of myeloma patients is particularly challenging. The key, at least with the medicines available, is to create a focused treatment algorithm for them from the very beginning. For example, in our center we give patients very effective induction therapy, typically with RVD (lenalidomide, bortezomib, and dexamethasone); then we give them a single transplant, and afterwards, put them on RVD maintenance, with the idea that these are our three best drugs.
We want to maintain high-risk patients in remission because we know that if we stop—if we pull our foot off the brakes for even a few months—the disease has a chance to ramp itself back up, and then it becomes resistant to therapy. The idea of long-term maintenance has been around for a long time, but we now finally have more drugs that are effective and can be given in doses and schedules that are more tolerable, to try to keep those high-risk patients under better control. Still, it’s not a perfect strategy by any stretch of the imagination.
How do you determine which newly diagnosed patients fall into the high-risk category?
There are a number of ways to define high risk in newly diagnosed patients. Fluorescence in situ hypridization (FISH) analysis can give you some clue about a certain subset of high-risk patients, and gene-expression profiling can give you another prediction of high-risk patients. You can use genomic sequencing to identify patients who may or may not be at high risk as well.
I won’t say that we are perfect in identifying these patients, but in general, at diagnosis, we can identify patients with P53 deletion, 14;16 translocation, and even 4;14 translocation, which with modern therapy may not be as bad as we thought it was 10 years ago.
But this is an important point: You have to look for these genetic abnormalities at the time of diagnosis. If you don’t get the studies done when patients are diagnosed, you may not know their risk stratification until they’ve relapsed. By that point, you may have missed an opportunity to maintain that patient with high-risk disease.
Closing Thoughts
What else would you like ASCO members to know about myeloma and advances in the field?
Access to enrollment in clinical trials is key, because that has really contributed to extending patient survival. I do not want patients to die waiting for certain drugs that may put their disease in remission, and the only way to get a lot of these drugs is on trial. Whether you are a community oncologist or an academic oncologist, it is important to be connected to a myeloma center that has access to these drugs, so you can get them for your patient. ■
Disclosure: Dr. Lonial has served in a consultant or advisory role with Millennium, Celgene, Novartis, Merck, Onyx, and Bristol-Myers Squibb.
