Response: Multiple myeloma is universally preceded by a prolonged premalignant stage: novel clinical insights and future directions

Go and Doyle address important clinical questions based on our recent study showing that multiple myeloma (MM) is universally preceded by a prolonged premalignant stage.¹  Although the questions raised are not directly related to our paper, which focused primarily on a key biologic question, they are commonly encountered in clinical practice and worth discussing.

Routine screening for MGUS is not indicated. Therefore, almost all individuals diagnosed with MGUS represent incidental cases diagnosed when physicians order a serum protein electrophoresis and/or immunofixation as part of the workup of several common symptoms and laboratory abnormalities. Once diagnosed, patients must be appropriately counseled that MGUS is a premalignant entity with a relatively low risk of progression to MM or related malignancies. In fact, MGUS cases with small (< 1.5 g/dL) IgG monoclonal (M)–proteins and with a normal serum free light chain ratio, represent approximately 40% of all cases, and have only a 2% lifetime probability of developing MM or related malignancies. We have previously recommended that such MGUS cases may not need annual follow-up, but can rather be followed if symptoms suggestive of MM or related disorders occur.²  In contrast, we feel that MGUS cases with higher risk may benefit from annual follow-up of the M-protein in addition to their usual medical care. Although the value of this is not proven, the test is simple, and, in our opinion, worth doing considering that MM can present with devastating bone complications that may be preventable in some patients if a significant rise in the M-protein is detected in time.

Although, for the individual patient, it is currently not possible to predict whether the underlying MGUS will remain benign or transform to MM, from a population standpoint the significance of MGUS has been well characterized. Several studies have determined the risk of transformation of MGUS patients over time,^3,4  and identified risk factors for such transformation.^2,5  In addition to malignant transformation, MGUS patients also have a higher risk of several pathologic conditions, including fractures⁶  and deep vein thrombosis.⁷  Furthermore, recent data suggest that MGUS cases (compared with the general population) have a significantly reduced life expectancy and an excess risk of dying from bacterial infections and heart, liver, and renal diseases,⁸  although this may be related to the various underlying medical conditions that led to the detection of the MGUS. Additional clinical and epidemiologic studies of MGUS are needed.

Our recent observation that MM is universally preceded by a prolonged premalignant stage, with up to 75% of MM patients having detectable M-protein 8 or more years before diagnosis of the malignancy, fills a key gap in the present literature on myelomagenesis.¹  Simultaneously, we found that stable M-protein or free light chain levels do not exclude the development of MM development.¹  Weiss et al reported similar findings in their study based on samples from a US military serum repository.⁹  Thus, as pointed out in our prospective study,¹  important tasks for the future are to develop individualized follow-up and intervention approaches for MGUS patients. We are undertaking further clinical and laboratory studies to provide insights on the pathogenesis of MGUS, racial disparities in the incidence of MGUS and MM, and to understand the cellular and microenvironmental events that are result in the transformation of MGUS to MM or related malignancies. Clinical trials investigating preventive therapy for high-risk patients with MGUS are also under way.