Shall we treat smoldering multiple myeloma in the near future?

Abstract

In recent years, several new drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are highly efficacious and less toxic than older chemotherapy drugs. In 2014, the diagnostic criteria for multiple myeloma were revised. The intent with the new criteria was to identify patients who require therapy at an earlier stage than at manifestation of organ complications. A subset of patients who were previously defined as having high-risk smoldering multiple myeloma was redefined as having multiple myeloma. In this context, it is logical to raise questions regarding the optimal clinical management of patients who are diagnosed with smoldering multiple myeloma in the current era. When is the optimal time to start therapy? Do the clinical trajectories for patients suggest there are distinct sub-entities hidden in the current category of smoldering multiple myeloma? How can we move the field forward from here? This paper reviews and dissects data and models on the topics of clinical features, underlying biology, and early treatment trials in smoldering multiple myeloma. The text highlights assumptions, facts, and gaps in the literature. As indicated in the title of the paper, the recurrent theme of the text is this: shall we treat smoldering multiple myeloma in the near future?

Figure 1.

Risk stratification schemes for smoldering multiple myeloma. Two major models for risk stratification are the Mayo Clinic and the PETHEMA models. The Mayo Clinic model focuses largely on serum protein abnormalities. For smoldering myeloma patients, the following features are considered to be adverse risk factors: >3 g/dL M protein, an FLC ratio outside the reference range of 0.125 to 8, and >10% BMPCs. The PETHEMA model uses multiparametric flow cytometry of bone marrow aspirates to differentiate aberrant from normal plasma cells (aPC versus BMPC). Plasma cells characteristically express CD138 and intense (bright) CD38. The features of aPCs included decreased CD38 expression, expression of CD56, and the absence of CD19 and/or CD45. In their study, smoldering multiple myeloma patients with >95% phenotypically aPC of total BMPC (ie, >95% aPC/BMPC) at diagnosis had a significantly higher risk of multiple myeloma progression. In addition, they characterized uninvolved immunoglobulins in peripheral blood in relation to risk of progression to multiple myeloma. For smoldering multiple myeloma patients, the risk factors in their model are >95% aPCs/BMPC and immunoparesis. Adapted from Landgren et al.

Figure 2.

Dissecting Mayo Clinic retrospective data from smoldering multiple myeloma to multiple myeloma: 3 patterns of clinical trajectory. When the patterns of progression from smoldering multiple myeloma to multiple myeloma in the retrospective Mayo Clinic study are looked at (A), as discussed in detail in the text, in my opinion, this definition is highly clinically heterogeneous, and it could be dissected into 3 main clinical patterns: multiple myeloma with early detection (B), indolent multiple myeloma (C), and monoclonal gammopathy (D). That patients with early detection multiple myeloma, typically, develop multiple myeloma within 1 to 2 years indicates that they have the same disease as patients with multiple myeloma, just at an earlier stage.^, As discussed in the text, to me, it seems logical to propose that the clinical implication of these arguments is that patients with high-risk smoldering multiple myeloma should be moved into the definition of multiple myeloma so they can be offered access to active therapy. Regarding the role of early treatment in the group of patients with indolent multiple myeloma, it is less obvious to form strategies. Reviewing the literature on indolent lymphomas, for example, early intervention vs delayed intervention (eg, at rising biomarkers) are both options that may be proposed. We need properly designed clinical trials to obtain answers on optimal management of indolent multiple myeloma. Also as discussed in detail in the text, with new data that link the precursor and multiple myeloma together, the “uncertain significance” (ie, MGUS) terminology seems no longer relevant. To me, it seems reasonable to propose the terminology “monoclonal gammopathy” for current patients with MGUS and patients with low-risk smoldering multiple myeloma. To caution the reader and to avoid confusion in the clinical field, before going forward, these ideas and concepts will have to be agreed on and endorsed in a consensus document. The intent is to share expert opinions based on clinical experience and original data, beyond the regular text book. The hope is to stimulate the reader to approach the current paradigm in a critical manner and to facilitate avenues for new translational research. Panel A is adapted from Kyle et al.