Chemoprevention for smoldering multiple myeloma: not ready for prime time.

In the preceding correspondence, Irene Ghobrial of the Dana Farber Cancer Institute makes a compelling and articulate defense of initiating treatment in patients with high-risk smoldering multiple myeloma in the hope that the benefi ts outweigh any risks. In my response, I argue that any consideration outside of a randomized clinical trial would be unwise. Smoldering multiple myeloma is defi ned by the presence of a monoclonal protein in the serum of 30 g/L or a bone marrow that shows 10% plasma cells. Using this defi nition, 50% of patients will not develop the CRAB (creatinine, anemia, bone lesions) criteria of overt myeloma by 5 years, and one-third of patients will remain asymptomatic at 10 years [1]. Clearly, the treatment of patients with smoldering myeloma to prevent development of the CRAB criteria would be unwarranted, as it would expose a substantial population to treatment when they are not destined to develop active disease [1]. However, if a defi nition existed that would identify patients destined to develop active myeloma within 24 months, rational interventions could be designed. Unfortunately, there are no established criteria for highrisk smoldering multiple myeloma that would allow such a population to be targeted for early intervention. Attempts to identify a truly high-risk smoldering population, destined to develop overt myeloma in a relatively short period of time, have been inconsistent. Criteria proposed for highrisk features of smoldering myeloma include the fi nding of 60% bone marrow plasma cells at diagnosis in an asymptomatic patient [2]. High levels of circulating plasma cells in the blood identifi ed by a slide-based immunofl uorescent assay performed on fi xed peripheral blood mononuclear cells [3] has been proposed. Th e fi nding of high-circulating plasma cells predicted a 2-year progression rate of 71% [3]. Th is technique is not widely available. Th e ratio of κ to λ immunoglobulin free light chains has also been proposed as a measure of risk of evolution to symptomatic disease [4]. Recently, measurements of the ratio of isotype specifi c heavy and light chains, which refl ects the suppression of uninvolved immunoglobulins, also appear to predict progression in patients [5]. Th e Spanish PETHEMA group (Programa para el Estudio de la Terap e utica en Hemopat i a Maligna) have also developed high-risk smoldering criteria. Unfortunately, they are completely diff erent from the criteria reported above. In their modeling, high risk includes patients who have both 10% plasma cells in the bone marrow and an M-spike 30 g/L. Th ese criteria, when applied to the Mayo Clinic dataset as published, demonstrate that 30% of Mayo Clinic patients remain disease-free after 5 years using PETHEMA criteria. Th e other PETHEMA criteria include the fi nding of aberrant immunophenotype plasma cells by fl ow ( 95% aberrant plasma cells), a technique that is not widely utilized. Unfortunately, these two defi nitions result in radically diff erent predictions of high risk smoldering disease. Seventy-seven patients were reported as fulfi lling criteria for smoldering multiple myeloma from the National Cancer Institute; and of these 77, the Mayo Clinic model classifi ed four (5%) as high risk, whereas the Spanish model classifi ed 38 out of 77 (49%) as high risk. Clearly, an agreement does not exist on what actually constitutes high-risk disease. Th is