Implications of heterogeneity in multiple myeloma

Abstract

Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.

Figure 1

Implications of heterogeneity on MRD detection. MM involvement may be patchy and involve extramedullary sites. All these lesions may be detected by whole body imaging modality such as PET-CT scan. Within the individual lesions, 2 dimensions of heterogeneity may exist in the population of tumor cells. On one hand, there may be clonal heterogeneity where related clones with different genetic composition may coexist. On the other hand, clonally related progenitor populations at earlier stage of differentiation may exist. Flow cytometry can detect the plasma cell component but not the precursor population while ASO-PCR can detect all the clonal cells including the precursor population but its applicability is limited. The development of NGS methods may allow utility in larger population of patients.