This paper is a first attempt at creating an international consensus classification of multiple myeloma (MM). Undoubtedly this paper will present a working classification for MM, and will be updated as additional information becomes available regarding the underlying biological and genetic composition of the disease. The goals of this paper are: (i) to provide a biological classification of MM based on known genetic subtypes with associated clinicopathological associations; (ii) to establish the prognostic value of known and new genetic factors for MM outcome, including the information generated through genomic tools; (iii) and lastly, to provide a framework for evaluation of new markers capable of serving as predictive for efficacy of novel therapeutics.
Multiple myeloma is a clonal late B-cell disorder in which malignant plasma cells (PCs) expand and accumulate in the bone marrow, leading to cytopenias, bone resorption and the production (in most cases) of the characteristic monoclonal protein.1
MM is a heterogeneous disease with some patients dying within a few weeks of diagnosis, whereas others live for longer than 10 years. The reason for this heterogeneity is compound and involves interaction between host factors and features intrinsic to disease biology. It is increasingly evident that the underlying genetic features of the tumor cells largely dictate the clinical heterogeneity of MM. The advent of interphase molecular cytogenetics and genomics has unraveled a complexity hereto underappreciated for MM oncogenomics.
Throughout this paper we will review current knowledge regarding the effect those factors have in determining the likelihood of a better or worse outcome for patients with new diagnosis MM (prognosis). However, the validity of most prognostic factors has been tested predominantly in the new diagnosis setting, and little validation exists for the same factors in the case of relapsed and refractory disease. Moreover, the value of different prognostic factors possibly changes with advancing stages of the disease (that is, first relapse versus second and subsequent relapses). Biological factors that can predict outcome at diagnosis possibly will have much lessened effect when tested in patients receiving third-line chemotherapy. For instance, although it is generally accepted that patients entered into clinical trials for relapsed/refractory disease carry the worst outcome, this is generally not true if one estimates survival since the time of diagnosis. Patients with the most dire host factors, or the most aggressive biological variants of MM, will not live for long enough to be enrolled in these types of clinical trials. Lastly, it is important to stress that different stages of clonal evolution can be categorized as all being ‘new diagnosis MM.’ Some patients with new diagnosis MM may be a slow progressive evolution from monoclonal gammopathy of undetermined significance (MGUS) (for example, evolving anemia over several months), whereas others may be associated with features of high clonal aggressiveness (for example, PC leukemia or extramedullary plasmacytomas) (). Although both can be clinically categorized as ‘new diagnosis MM’ they clearly present two different biological states of evolution of the monoclonal PCs.
Figure 1 Relationship between clonal evolution of plasma cells and time of diagnosis. The picture depicts the biology and genetic heterogeneity of patients with a clinical diagnosis of ‘new diagnosis myeloma.’ In some cases (a) the situation involves (more ...)
The purpose of this proposed classification is not merely to provide prognostic estimates; the ability to accurately prognosticate is one of the several features to be discussed here. There may be subgroups of the disease that have no known or demonstrable prognostic associations, but are perceived at the biological level to be unique. These associations, though supporting unique biology, should not be considered prerequisite for creation of a biological subtype of the disease. Conversely, there may be biological factors or gene expression signatures capable of discerning prognosis, which may not yet be explained by unified biological concepts, but have the ability to discern patients with clearly dissimilar outcomes. In this paper, we will not attempt to discuss all available prognostic models for MM, but rather focus on the prognostic implications of the genetic derangements of MM and discuss the power of genomics to unravel the prognostic subcategories of the disease.
There are many reasons why an accurate prognostic determination is paramount for clinical practice and research (). It allows the physician to engage in a more direct discussion with the patient regarding disease threat and likelihood of survival. This risk stratification also allows for a more rational selection and sequencing of therapy approaches. This prognostic classification is essential for better understanding the composition of patients entered into clinical trials, and also allows, albeit with the usual statistical limitations, cross comparison of different clinical trial populations. Indirectly, this prognostic classification can also provide relevance to new biological factors proposed as significant in disease pathogenesis (but, as will be shown below, biological factors that are considered crucial in the pathogenesis do not need to necessarily have prognostic associations).
FISH markers and association with outcome for patients with MM
Although undoubtedly a large fraction of disease heterogeneity can be determined by the genetic subtypes of MM,2,3
an important component in determining outcome is related to host features. The contribution of these factors will not be discussed here further, but some general considerations apply. For instance, genetics alone cannot fully explain outcome heterogeneity and it is likely that host factors, such as performance status, comorbidities (for example, renal function) and age, have a predominant role in the prognosis determination in the immediate period after diagnosis.2,3
It has been recently shown that, despite being enriched for higher-risk genetic subtypes, younger patients live longer, presumptively as a consequence of their ability to better tolerate treatment.4
With passage of time it is also likely that progression (also called secondary events) have important roles in determining the fate of patients.