Treatment options for patients with MM have improved considerably over the past decade, resulting in survival rates that surpass 10 years for some patients. These advances have also led to improved outcomes for those with high-risk cytogenetic abnormalities, such as t(4;14), when compared with conventional therapeutic approaches, although these improvements are less substantial for high-risk than for lower-risk patients. Clinical data suggest that bortezomib and, to a lesser extent, lenalidomide may partially overcome the poor prognosis conferred by the t(4;14) translocation, although there are discrepancies among the various studies, and prospective analyses are clearly needed to determine the true impact of these agents on patients with this abnormality.21, 24, 56, 57
MM is a heterogeneous disease; however, treatment options outside of clinical trials are currently limited to combinations of bortezomib, thalidomide and its analogs (IMiDs, thalidomide and lenalidomide), chemotherapy and steroids (dexamethasone, prednisone) with stem cell transplantation in eligible patients. Although these agents are effective in the treatment of a majority of patients with MM, a clear unmet need remains for high-risk patients. The Mayo Stratification for Myeloma and Risk-Adapted Therapy guidelines have provided an example of a personalized therapeutic approach for the treatment of MM; however, among the different risk groups, there remains a considerable degree of heterogeneity.60
Molecular-based targeted therapeutic approaches, analogous to those used in the treatment of other diseases, such as breast cancer, may help to identify patient subsets that derive benefit from novel investigational agents and lead to the development of personalized therapeutic approaches.
The use of FGFR3 inhibitors for patients with t(4;14) MM represents a potential targeted and personalized approach. Based on the preclinical data, these therapies may benefit a subset of patients with the t(4;14) translocation, particularly those with increased expression of FGFR3 and absence of NRAS mutations.63, 64, 65, 67
Further research is needed to determine the ideal therapeutic combination partners (for example, bortezomib, IMiDs, chemotherapy and steroids), but early evidence suggests that this class of agents synergizes with bortezomib and dexamethasone.68
Based on the available data, FGFR3 inhibitors should be investigated in clinical trials for patients with t(4;14) translocations, both as monotherapy and in combination with standard-of-care agents used in the treatment of MM. Carefully designed clinical trials that incorporate biomarker analyses will be needed to ultimately determine the ideal patient population that will derive benefit from this novel approach.