For me, the top story for multiple myeloma in 2018, is venetoclax. Venetoclax represents the culmination of efforts to develop a therapeutic agent tailored to work in certain genetic subtypes of the disease. How did we get here? How can this development be the most important one for 2018, when everyone is talking about CAR T-cell therapies and bispecific antibodies? How can this development be so important given that we have the results of phase III trials showing improvement in disease control with daratumumab-based combinations? How could this be the story of the year when we have the possible addition of new drugs such as selinexor? The answer is simple. This is the first time that a truly targeted therapeutic has been developed for multiple myeloma. Let me explain.
Myeloma has been, for several years, one of the best understood tumors when it comes down to disease biology and genetic changes. Description of the major subtypes of the disease and secondary genetic changes dates back now close to 15 years. Although we have had important refinements to this knowledge framework, the basic genetic groups are the same. The addition of novel tools, such as gene-expression profiling and mutation analysis with next-generation sequencing, has increased the depth of our understanding of the genetic nature of the disease. Myeloma is divided into two broad subgroups, the hyperdiploid and the non-hyperdiploid variants.
One of the hallmarks of myeloma is that the non-hyperdiploid variant is enriched for chromosome translocations involving the immunoglobulin heavy-chain locus. Although the translocation t(11;14) could be detected through cytogenetic analysis, it was not until molecular genetic studies performed by Bergsagel, Kuehl, and Chesi identified the presence of the translocations t(4;14) and t(14;16). Despite having this detailed knowledge of the disease, genetics had been predominantly used to stratify patients into risk categories and to propose different treatment pathways. However, none of these treatments has directly targeted the consequence of genetic aberrations. Previous efforts to target the FGFR3 gene, associated with t(4;14), have failed. Genetic understanding did not provide to myeloma the opportunity that was fully realized in chronic myelogenous leukemia.
Nevertheless, genetics in myeloma did help with a better understanding of the prognostic categories of disease. This has allowed for a more tailored conversation with patients regarding the likelihood of better outcomes. Furthermore, the knowledge about high-risk genetic features changed the paradigm upon which we recommend maintenance therapy in the post–stem cell transplant setting. Knowing that patients with high-risk genetic features derive greater benefit from the use of proteasome inhibitors became important practical knowledge. Arguably, the natural history of patients with t(4;14) was changed because of the addition of bortezomib to treatment. At the same time, great strides were made in the fight against multiple myeloma by the incorporation of medications that target “normal plasma cell differentiation” and protein metabolism. The introduction of proteasome inhibitors and IMIDs, followed by the introduction of monoclonal antibodies, greatly improved the survival for myeloma patients. Nevertheless, genetics have not augmented our treatment armamentarium. However, that will change with venetoclax!
Although there is still significant room for a better understanding of the mechanism of action of venetoclax in multiple myeloma, it is now very clear that this drug seems particularly effective for patients with the translocation t(11;14). Even if better biomarkers are developed for the selection of the right patients, venetoclax provides options for patients with this translocation and for whom no treatments have been available. We are all hoping that venetoclax will be approved by the FDA soon. Patients have been treated with venetoclax, often in combination with steroids or with proteasome inhibitors, off-label when no further treatment options were available to them. Several clinical trials have now demonstrated a very high rate of response to combination strategies that use venetoclax, particularly in patients with t(11;14). We have seen patients who have been heavily pretreated and who have achieved a complete response with venetoclax and dexamethasone alone.
The obvious corollary questions are as follows. Should venetoclax be used as maintenance therapy in patients who have the translocation t(11;14)? What is the role of venetoclax in patients who have light-chain amyloidosis (50% have this translocation) and in patients with primary plasma cell leukemia (50% also have this translocation)? Should venetoclax be used earlier in the course of the disease in patients with this genetic abnormality as a part of combination strategies? If venetoclax can treat effectively the 15% of patients with this genetic abnormality, what about MCL-1 inhibitors?
Recent data from the Mayo Clinic has shown that, although survival for most myeloma patients has improved over the past 15 years, these improvements have lagged among patients with the translocation t(11;14). Perhaps this has been because t(11;14) plasma tends to be more lymphoid and their cytoplasm contains fewer proteins. Accordingly, the protein stress associated with the use of proteasome inhibitors and IMIDs is lessened in patients with t(11;14).