Investigators are currently determining how to best redefine multiple myeloma (MM) and smoldering multiple myeloma (SMM), a process that could have an impact on a percen-tage although small, of patients with early disease. Based on these new definitions, some patients with SMM who were once managed only by observation for progression may now be eligible for treatment. However, because MM therapies are associated with a number of side effects, the vast majority of SMM patients will still need to receive treatment in a clinical trial.
“We need to define the goals of treatment and what we are trying to achieve,” said Ashraf Z. Badros MD, Professor of Medicine at the University of Maryland School of Medicine and Director of the Multiple Myeloma Service at the Greenebaum Cancer Center.
Clinical criteria are used to determine whether someone has multiple myeloma, including abnormal plasma cells infiltrating the bone marrow with and without abnormal immunoglobulins in the blood, and end-organ damage—meaning hypocalcemia, renal failure, anemia, and bone lesions (CRAB), said Ola Landgren, MD, PhD, Senior Investigator and Chief of the Multiple Myeloma Section of the National Cancer Institute. The current definition of MM is a “clinical syndrome with complications causing symptoms.”
Unfortunately, the distinction between early myeloma and actual MM is not very well defined, Badros said. “There's a lot of overlap.”
A “gray zone” exists where patients don't fit the classic definition of active myeloma and don't have smoldering disease, noted Joshua Richter, MD, a multiple myeloma specialist at John Theurer Cancer Center.
Two models, one developed by Mayo Clinic and the other by the Spanish “PETHEMA” working group, have been developed to identify high-risk smoldering MM. The Mayo Clinic uses serum monoclonal protein levels and clonal bone marrow plasma cell percentage, while the PETHEMA model uses decreased levels of normal immunoglobulins and the proportion of abnormal plasma cells in the bone marrow to assess risk.
Risk is ranked as high, intermediate, and low in both models, Landgren explained. “However, we recently found that among SMM patients, 75 percent of the patients did not overlap these categories if one uses both scales in parallel on the same patient [Leuk Lymphoma 2013;54:2215-2218]. Most patients are concurrently high-risk with one scale and low-risk with the other scale, he said. “We clearly need better risk models to counsel our patients.”
Some SMM Cases May Be Redefined as MM
“We are redefining what we call myeloma,” agreed S. Vincent Rajkumar, MD, Professor of Medicine in the Department of Hematology at the Mayo Clinic Minnesota. He said he anticipates that the International Myeloma Working Group (IMWG), which he co-chairs, will make revised MM definitions available within the next year or so, likely moving a small number of patients with SMM into the MM category.
Ultimately, classic definitions will change because oncologists will better understand the early disease process and have insight into who will progress to symptomatic MM based on imaging data, molecular data, and gene-expression data, Richter said. Myeloma is likely hundreds of different diseases, much like lymphoma, he said, adding that each type of myeloma probably needs to be treated differently.
“Already, several myeloma investigators have decided to treat certain subsets of patients with smoldering myeloma who have a high risk of progression as multiple myeloma,” Rajkumar said. Approximately 10 percent of SMM patients progress to MM per year, he said, citing NEJM2007;356:2582-2590, of which he was senior author (Robert Kyle was first author).
However, researchers have found several biomarkers enabling them to identify a cohort of patients with smoldering multiple myeloma who have a risk of progression of about 40 percent over the course of a year (JCO 2010;28:1606-1610). “In these patients, there's no point in waiting for treatment,” he said.
These biomarkers include 60 percent or more clonal plasma cells in bone marrow, serum free light chain ratio of 100 or more, and more than one focal lesion on MRI, and the IMWG is finalizing the remaining criteria, he said.
This SMM subset has an 80 percent or greater risk of progression over two years, he said, citing Nat Rev Clin Oncol2013;10:554-555, which he co-wrote with Robert Kyle. However, that group represent only about 20 percent of all SMM patients. The remaining 80 percent should be receiving care on a clinical trial evaluating observation versus treatment, Rajkumar said.
Agents of interest for treating smoldering multiple myeloma include lenalidomide with dexamethasone. The two-drug regimen was associated with delayed active disease progression and increased overall survival in a study of 119 patients with high-risk SMM randomized to treatment or observation (NEJM2013;369:438-447).
While those results are intriguing, Badros said, “they're not enough to make us change our practice,” and the data need to be confirmed in further studies.
Landgren's research group is now evaluating use of lenalidomide and dexamethasone with the second-generation proteasome inhibitor carfilzomib—data that will be presented in December at the American Society of Hematology Annual Meeting. He told OT that although he can't share specific data, the treatment “looks promising.”
“Personally, I think if you start treating earlier, you should use the best drug upfront as long as it is not unacceptably toxic, and I think we are getting there for sure,” Landgren continued. “However, I'm cautious to recommend treatment for SMM patients in 2013 not occurring outside of a clinical trial. We actually don't know for sure if treating early is the way to go. Clinical trials will give us the answer.”
As definitions of the disease evolve and a better understanding of SMM develops, oncologists will eventually know who should and should not receive full myeloma treatment—for example, with full induction therapy and stem cell transplant, Richter said. “My belief is that we need to use all of our tools and knowledge, both now and in the future, to be better about drawing the line in the sand.”
Drug Side Effects
Doctors have to be straightforward in their discussions about drugs having risks such as blood clots and infections, especially with patients who have early disease, Landgren said. “Some side effects are quite dangerous and could be devastating in a small number patients, while many adverse events are manageable.” Treating asymptomatic patients with potent drugs without data indicating they prolong life makes the issue quite complicated, he added.
Richter noted that although overall, the drugs used to treat MM today are more effective and tolerable than in years past, agents such as bortezomib, carfilzomib, and lenalidomide can have long-term side effects such as neurotoxicity and second primary malignancies.
Rajkumar added that pulmonary embolism is another risk factor of these drugs, and the agents may also contribute to fatigue, diarrhea, and rash, thereby affecting quality of life. Generally, these drugs are not recommended except in high-risk patients where the benefits outweigh the risks, he said.
The measurement of response in myeloma patients is also likely to evolve, Richter said. “As good as our measurements are, in many patients, they represent just the tip of the iceberg.” For example while blood and urine measurements may be negative, a PET scan or bone marrow plasma cell assessment may still indicate a substantial disease burden.
With the newer drugs, oncologists see the vast majority of MM patients obtaining a complete response as indicated by paraproteins in the blood and urine, Landgren said. “But we need to develop more sensitive technology to really measure the response beyond those markers. As therapies get better and better, tests that tell us whether the disease is active over time would be valuable. In my opinion, the development of minimal residual disease [MRD] should be a priority for the MM field.”
Cellular and molecular assays for MRD are all the rage right now, but there's no standardization for these tests, Richter said. “Nobody really knows what the results mean.”
Further research should identify biomarkers distinguishing between patients with SMM who have an actual malignancy and will present with end organ damage and those with clonal but premalignant disease who should just be observed, Rajkumar said. Clinical trials should also investigate how to both cure and control disease, he said.
Oncologists also need research evaluating what happens to SMM after treatment, Badros said. While data on SMM progression are emerging, data on outcome when therapy is initiated are limited, and it remains unclear whether SMM behaves in the same way as MM after the initiation of therapy.
Research also needs to evaluate what happens to the bone marrow microenvironment in SMM patients who undergo treatment, Badros said. Even if these patients experience a tumor reduction, physicians need to know what the overall impact is on changing the host factors that may enhance or prevent future disease progression.
Finally, oncologists need to verify whether the survival advantage is worth the side effects of early therapy and its impact on quality of life.
“If we're going to advocate therapy, we need proof it works,” Rajkumar said. “We need one or two large randomized, controlled trials showing a clear benefit.”
Richter said he is especially looking forward to the results of the Multiple Myeloma Research Foundation's CoMMpass study (themmrf.org/research-programs/commpass-study), which is evaluating the molecular segments and variations in MM. The hope, he said, is that oncologists will eventually be able to map out a full plan of care based on these data.