Faculty Bibliography

Since the mid-1990s, the multiple myeloma treatment landscape has evolved considerably, which has led to improved patient outcomes and prolonged survival. In addition to discovering new, targeted agents or treatment regimens, the identification and validation of biomarkers has the potential to further improve patient outcomes. The International Staging System relies on a number of biochemical parameters to stratify patients into risk categories. Other biologically relevant markers that are indicative of inherited genetic variation (e.g., single-nucleotide polymorphisms) or tumor-acquired genetic events (e.g., chromosomal translocations or mutations) have been studied for their prognostic potential. In patients with high-risk cytogenetics, plasma cells (PC) undergo genetic shifts over time, which may partially explain why high-risk patients relapse and are so difficult to treat. Although novel agents have improved treatment outcomes, identification of markers that will enable clinicians to determine which treatment is most appropriate for high-risk patients following initial diagnosis represents an exciting frontier in the clinical management of multiple myeloma. Biomarkers based on quantitating PCs or factors that are secreted from them (e.g., serum free light chain) may also help to risk-stratify patients with asymptomatic multiple myeloma. Eventually, identification of novel biomarkers may lead to the creation of personalized treatment regimens that are optimized to target clonal PCs that express a specific oncogenomic profile. Although the future is exciting, validation will be necessary before these biologic and molecular beacons can inform decision-making processes in a routine clinical setting.

In recent years significant progress has been made in the understanding of multiple myeloma (MM) biology and its treatment. Current strategies for the treatment of MM involve the concept of sequential blocks of therapy given as an induction followed by consolidation and maintenance. In an age characterized by emerging and more powerful laboratory techniques, it is of primary importance to understand the biology of MM and how this biology can guide the development of new treatment strategies. This review focuses on the genetic basis of myeloma, including the most common genetic abnormalities and pathways affected and the effects that these have on MM treatment strategies. MM biology is discussed also in the light of more recent theory of intraclonal heterogeneity.

The chromosomal translocation t(4;14) deregulates MMSET (WHSC1/NSD2) expression and is a poor prognostic factor in multiple myeloma (MM). MMSET encodes two major protein isoforms. We have characterized the role of the shorter isoform (REIIBP) in myeloma cells and identified a clear and novel interaction of REIIBP with members of the SMN (survival of motor neuron) complex that directly affects the assembly of the spliceosomal ribonucleic particles. Using RNA-seq we show that REIIBP influences the RNA splicing pattern of the cell. This new discovery provides novel insights into the understanding of MM pathology, and potential new leads for therapeutic targeting.

Despite recent advances in therapy, subgroups of multiple myeloma continue to have a poor prognosis. Numerous epigenetic changes have been described and occur as both etiologic and secondary events, making myeloma a good disease in which to understand the role of epigenetic therapies. Here, we describe a number of current and potential epigenetic targets in myeloma.

Intraclonal heterogeneity was recently described in multiple myeloma (MM), but its full impact on disease progression and relapse has not been entirely explored. The immunoglobulin type produced by myeloma cells provides an excellent marker to follow changes in clonal substructure over time. We have prospectively evaluated serial paraprotein and serum free light chain (FLC) measurements and found that 258 of 520 and 54 of 520 patients who presented with a whole paraprotein relapsed with paraprotein only (PO) and "FLC escape," respectively. The median overall survival of PO patients was longer, when compared with patients whose relapse manifested as an increase in FLC both alone and with a whole paraprotein, as a result of a significantly shorter survival from relapse of the latter groups. These observations fit a model in which 1 clone is able to produce a complete antibody, whereas the other secretes only FLC; the type of relapse represents the outgrowth of different clones, some of which are more resistant to therapy. To our knowledge, this is the largest series describing patients who have relapsed with FLC escape and highlights the importance of monitoring FLC when there is a suspicion of clinical relapse. This study was registered at www.isrctn.org as ISRCTN68454111.

It is clear that cancers comprise a mixture of clones, a feature termed intra-clonal heterogeneity, that compete for spatial and nutritional resources in a fashion that leads to disease progression and therapy resistance. This process of competition resembles the schema proposed by Darwin to explain the origin of the species, and applying these evolutionary biology concepts to cancer has the potential to improve our treatment strategies. Multiple myeloma (MM) has a unique set of characteristics that makes it a perfect model in which to study the presence of intra-clonal heterogeneity and its impact on therapy. Novel therapies have improved the outcome of MM patients, increasing both progression-free and overall survival. Current therapy comprises an induction, consolidation and maintenance phases and it is important to consider how these components of MM therapy are affected by the presence of intra-clonal heterogeneity. In this evolutionary context therapy can be considered as a selective pressure differentially acting on the myeloma clones and impacting on their chances of survival. In this review current knowledge of intra-clonal heterogeneity, as well as its impact on the different components of MM treatment is discussed.