This article is a review of Novel Therapeutic Avenues in Myeloma: Changing the Treatment Paradigm
The article by Ghobrial and colleagues highlights the wealth of good news in the recent past and on the horizon for patients with myeloma. With the US Food and Drug Administration (FDA) approval of three drugs in as many years, and the potential for several more down the road, clearly the myeloma cup "runneth over." But with this wealth of new agents and an improved biologic understanding of plasma cell development come many new challenges. These include choosing optimal combinations of novel agents, correctly identifying subsets of patients who may gain more or less benefit from classes of agents, and finally, challenges with respect to patient access and disease status in the evaluation of new agents or combinations.
It is clear that the recent development and approval of three new agents for the treatment of patients with myeloma has improved outcomes. However, the single greatest limitation for all these agents is that they are not universally effective, and even those who initially respond ultimately relapse. Median overall survival from the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial, comparing bortezomib (Velcade) vs high-dose dexamethasone, and the MM-009 trial, comparing lenalidomide (Revlimid) plus high-dose dexamethasone vs high-dose dexamethasone, was 29 months for the treatment arms of both trials. Based on these two trials, the use of high-dose dexamethasone in the relapsed disease setting has now been replaced by the use of two superior agents, yet the benefit from either of these agents given alone is not sufficient, as there is no plateau on the survival curve.
In aggregate, however, do combinations of novel agents—with or without conventional agents—represent the potential for being greater than the sum of their individual parts? Preclinical data suggest that the combination of bortezomib and lenalidomide are at least additive, and recent clinical experience suggests that refractory patients can be salvaged when these two agents are combined, even if patients were resistant to either or both agents individually. The combination of bortezomib with heat shock protein inhibition is predicted to be synergistic, and early clinical data suggest that this is, in fact, correct. The addition of the novel agents thalidomide (Thalomid), lenalidomide, or bortezomib to melphalan (Alkeran) and prednisone seem in most published data to be superior to historical data using melphalan and prednisone alone.
These observations, bolstered by a solid preclinical rationale, set up the first major challenge facing clinicians today: What is our standard "cocktail" of greatest efficacy? The solid tumor paradigm of sequential single-agent administration does not take into account synergistic interactions between agents that are unrealized when agents are given individually. The impact of this preclinical science is likely magnified in an era of targeted agents, as most will have only modest activity when delivered as single agents, but have the potential to overcome resistance or to sensitize with conventional agents in combination.
Do we have to slog through multiple trials of combination vs sequential single-agent therapy to answer those questions, or can we forge ahead trying to develop the best three or four drug cocktails based on preclinical and clinical experience? Given that we cannot cure myeloma with single agents, doesn't it make sense to try combinations of our best novel agents or novel agents in combination with conventional agents? These are as yet unresolved questions, and the answers will be critical to maintaining our current momentum.
Myeloma does not encompass a homogeneous group of disorders. Several different categories of patients can be identified using markers ranging from a test as simple as beta-2-microglobulin measurement, to fluorescence in situ hybridization (FISH) analysis, and ultimately via patterns of gene expression. The relative importance of any given target in this mixed-biology setting clearly changes between patients and accounts for the observed differential responses among commonly used agents. Is there a method by which we can clinically identify sets of patients more or less likely to respond to a given agent? The use of cytogenetics and FISH potentially may serve this effect, yet all risk-stratification schemes using FISH or cytogenetics have done so in the context of historical data using conventional agents, not novel agents.
Both lenalidomide and bortezomib have demonstrated activity despite elevated beta-2-microglobulin, and there are hints that in patients with the t(4;14) translocation, bortezomib may indeed produce a higher response rate than among those without t(4;14) (L. Bergsagel, personal communication). Additionally, Bergsagel and colleagues recently reported that patients harboring mutations in tumor-suppressor genes regulating the noncanonical NF-kappaB pathway may have an increased chance of responding to bortezomib. These kinds of in-depth analysis are clearly needed to identify which patients may or may not benefit from individual novel agents and represent a more insightful approach to risk and response stratification than the current International Staging System, which focuses solely on surrogate markers of prognosis from a previous era.
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