Before we can recommend the routine use of therapy for high-risk patients with smoldering myeloma, we need solid data that will enable routine identification of risk.
—Sagar Lonial, MD
Over the centuries it has become clear that, as physicians, what we say and how we say it can have a major impact on those who seek our help. Our pronouncement that a patient is in remission or harbors a serious illness carries with it a large number of spoken and unspoken implications. So when we say a patient has “myeloma,” what does it mean? When we use certain language, it becomes a common bond by which we as physicians communicate a given set of information, but is that information interpreted similarly among all of us?
This question concerning the meaning of myeloma is even more important—and confusing—when viewed in the context of the recent paper by Mateos et al in The New England Journal of Medicine, where early treatment of “smoldering myeloma” demonstrated an improvement in overall survival.1 Does this mean that “smoldering myeloma” and “symptomatic myeloma” are now the same entity? Have we changed what it means to say “myeloma”?
Need for Treatment
Unlike many other diseases, the diagnosis of a plasma cell disorder or myeloma is only in part dependent on the pathologic identification of a malignant clone. The current or potential future impact of that clone is a clinical determination, and one that allots patients into either solitary plasmacytoma, monoclonal gammopathy of unknown significance (MGUS), asymptomatic (smoldering) myeloma, or symptomatic myeloma. The assignment of a patient into the symptomatic category requires the presence of the CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, or Bone disease), and the detection of even one of these symptoms indicates the need for treatment.
Does this mean that patients in the other categories do not have a malignancy and therefore do not warrant treatment? No, but currently there is not sufficient evidence demonstrating that early treatment improves outcomes. Until symptoms are present, the natural history of MGUS or smoldering multiple myeloma is heterogeneous, and the challenge remains in identifying—among an older population—which patients will develop symptoms related to the plasma cell clone vs which will never be bothered by the presence of this indolent clonal disorder.
The basic issue at hand is this: Can we predict whose clone has or will have clinical impact in a relatively short time and intervene early to prevent this, while avoiding overtreatment of patients who may not harbor the risk of progression required to justify the risk of early treatment?
Identifying High-Risk Patients
The key to success is to identify which patients have a high chance (70%–80%) of developing end organ damage with 2 years. For these patients, early treatment will likely prevent complications, while for others, the risk-benefit ratio likely does not favor early treatment.
In the Spanish trial, using highly specialized flow cytometry, Mateos and colleagues clearly identify a group of patients who not only have a high risk of progression to myeloma in a short time, but whose mortality, when observed without intervention, is very high. By the “letter of the law,” none of the patients enrolled in the trial had any evidence of CRAB criteria. But is there a difference between the clear, symptomatic presence of CRAB vs nearly CRAB, vs smoldering? I think the answer is yes.
This illustrates the real clinical decision-making at work every time we see a patient with a plasma cell disorder. However, there is no easy and prospectively validated tool we can employ to define these patients. The ongoing E3A06 trial is seeking to prospectively test criteria developed by the Eastern Cooperative Oncology Group and Mayo Clinic. Utilizing flow cytometry, criteria from the PETHEMA Working Group seemed to identify a group of high-risk patients, but even in their control group, > 50% had not converted to myeloma within 2 years. Thus, in a small PETHEMA study, there were patients with rapid disease progression, yet using the group’s definition of high risk, a significant fraction of patients did not show rapid progression.1 Can such an approach be used to categorize high risk?
Work in Progress
How can we piece all this together as practicing clinicians with the goals of alleviating potential symptoms without increasing the risk of unnecessarily doing harm? First, we need to take care of those we know need treatment—those with evidence of end organ damage. This has not changed. Second, if a patient has what appears to be smoldering myeloma, we should either enroll him on a clinical trial, or closely watch him.
The most important point from a clinician’s perspective, and one that is not addressed by current risk models, is that a single data point is not the answer. We need longitudinal follow-up to see the tempo of disease progression, and with follow-up, many of those whom we may consider to be at high risk will declare themselves rapidly. Close monitoring will likely reveal any major changes before the development of end organ damage.
The book is not yet closed on whether we can treat smoldering myeloma patients sooner. But before we as a community embark on treating all patients with the diagnosis of smoldering myeloma, we first need to identify which patients are at risk, and determine if these risk factors can be prospectively validated.
The upsides of identifying and treating early are clear, as demonstrated by the Spanish study, but we must remain mindful of the downsides. Early treatment results in exposure to risks and side effects of treatment for a group of patients who may not need treatment at all, or for a long time.
Before we can recommend the routine use of therapy for high-risk patients with smoldering myeloma, we need solid data that will enable routine identification of risk. In this way, we can exclude patients who won’t benefit from early treatment (or may be harmed)—patients in whom intervening early changes the natural history of their disease. The Spanish trial is an important first step, but it is not yet the final answer. ■
Dr. Lonial is Professor of Hematology and Medical Oncology at the Winship Cancer Center at Emory University, Atlanta.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.
Disclosure: Dr. Lonial reported no potential conflicts of interest.
1. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.