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Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are asymptomatic plasma cell disorders that are associated with a risk of progression to multiple myeloma, light chain amyloidosis (AL), Waldenström macroglobulinemia, or related malignancy [1–3]. Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder prevalent in over 4% of the general population over the age of 50, and carries a risk of progression of approximately 1% per year [4,5]. There are three distinct categories of MGUS each with a different mode of progression: IgM MGUS, non IgM MGUS, and light-chain MGUS (Table 1) [6–8]. Smoldering multiple myeloma (SMM) is a heterogeneous entity created primarily for clinical purposes to identify a group of patients with asymptomatic plasma cell dyscrasia that have a much higher risk of progression than MGUS (10% per year), and therefore need to be managed differently [9,10]. From a biologic standpoint, SMM includes patients with premalignancy (biological MGUS) and patients with early asymptomatic malignancy (MM). At present, there are no reliable plasma cell markers that can be used to accurately distinguish the two biological groups contained in the SMM category. Patients with MGUS and SMM are currently observed without therapy until evidence of symptomatic progression. The main reasons for this conservative approach are that until recently options for MM treatment have been limited (alkylators and steroids), toxic, and unable to demonstrate an overall survival benefit for early therapy in randomized trials. However, the paradigm of delaying therapy until evidence of MM related end-organ damage needs to change [11]. We now know that MM is almost always preceded by an asymptomatic premalignant stage [12,13]. Further, MM is a serious malignancy with significant morbidity, and one of the reasons for the lack of cure may be related to the fact that we are embarking on therapy when the disease is cytogenetically and clinically more advanced. There are two ways of overcoming the barrier to early therapy. One option is to identify biomarkers that can predict patients who will inevitably progress to symptomatic MM within 2 years with high (90% or greater) accuracy. Many groups are actively working towards this goal, and several promising biomarkers have already been identified as candidates for further study (Table 2) [14,15] In fact, we have shown that one of the simplest is the bone marrow plasma cell percentage. Patients with SMM who have bone marrow involvement of 60% or greater almost invariably progress to MM within 2 years, and we now recommend that such patients be considered as MM regardless of the presence or absence of end-organ damage and be initiated on therapy [16]. The second option is the more traditional route, but also the most difficult one: conduct randomized trials that demonstrate clinical benefit of early therapy in MGUS and SMM. In this issue of the American Journal of Hematology, Golombick et al., report on a randomized trial of curcumin versus placebo given as preventive therapy in patients with MGUS and SMM [17]. Although the trial is a placebo-controlled, randomized trial, from a clinical standpoint it can best be described as a pilot study in terms of preventing progression of MGUS. Both in terms of sample size and the study endpoints, this is far from the type of trial that is needed to change practice. Nevertheless, this is an important hypothesis generating trial that has biologic value. The trial also highlights some of the issues and caveats to consider in our approach to clinical trials in this patient population. Further there is a lot of interest in the study drug, curcumin (the most active component of the commonly used Indian spice, turmeric), among the myeloma patient population. Therefore, results from a randomized trial are always welcome since they put the agent in the right perspective. The trial is a follow up to a previous phase II study conducted by the same group in which curcumin showed some evidence of activity in terms of reduction in monoclonal protein levels [18]. The current trial results show that curcumin has a hint of biologic activity with lowering of free light chains (FLC) levels and a marker of bone resorption in treated patients compared with the placebo group. But overall in clinical terms, its effects on MGUS and SMM are minimal, at best. There were no statistically or clinically significant reductions in paraprotein concentrations with treatment. The main positive finding is a modest decrease in FLC levels by 25-50% in one quarter of the patients, but the mechanism of this effect is unclear, since FLC levels are also affected by factors other than the bone marrow plasma cell burden. The absolute level of the involved FLC showed a median decrease of only about 10%. Using standard metrics by which myeloma therapies are assessed, the overall partial response rate was 0% as reported in Table 4A in the supplementary appendix of the trial publication [17]. Even minor responses defined as 25-50% reduction in paraprotein levels were not seen. Patients with MGUS and SMM are interested in exploring preventive options on well-designed clinical trials, and many phase II studies have been conducted [19]. In the case of curcumin, we clearly need more randomized data. Until such data emerge, I would not recommend curcumin as a preventive or therapeutic strategy in MGUS, SMM, or myeloma. Unfortunately, this trial was inadequately powered to determine if curcumin has any role in MGUS or SMM. Further, I am not convinced that the data so far are