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Our better understanding of the complex interaction of multiple myeloma (MM) cells with their bone marrow microenvironment and the signaling pathways that are dysregulated in this process has resulted in a dramatic increase in the therapeutic agents available for this disease. A number of these new agents have demonstrated significant activity in patients with MM. Over the past 5 years, three drugs have received approval from the US Food and Drug Administration for therapy in MM—bortezomib, thalidomide, and lenalidomide. To date, the choice of therapy for MM is not individualized according to the biologic characteristics of the disease, but future studies should enable us to identify patients who may benefit most from certain therapeutic interventions, and thus develop individualized therapy for MM. In this review, we will present some of the treatment algorithms currently developed for patients with MM and focus on established advances in therapy, specifically with thalidomide, bortezomib, and lenalidomide. We will also discuss some of the emerging novel therapeutic agents showing promise in phase I/II clinical trials in MM.
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.
But does risk stratification really matter if we move forward with combination therapy? A major benefit of combination therapy, aside from synergistic interactions between agents, is the ability to overcome negative prognostic features associated with any given single agent. Either way-single agent or combination-it is clear that new methods for identifying risk strata, as well as for defining how to optimally choose patients who will benefit from the use of current and future novel agents, are clearly needed.
Clinical Trial Enrollment
The recent wealth of new agents in myeloma did not materialize without a great deal of preclinical and clinical work. Trials subsequently leading to the approval of bortezomib, thalidomide, and lenalidomide enrolled between 400 and 700 patients each, and did so quite rapidly. In order to achieve these lofty goals quickly, a concerted effort among patients, advocacy groups, the pharmaceutical industry, and myeloma centers all over the world was required. Clearly this collaborative effort has benefited all parties involved, but now another clinical challenge has arisen: Given the availability of bortezomib, thalidomide, and lenalidomide, which patient population should be used to test the efficacy of new agents? Should we wait until patients have refractory disease before introducing a new agent? Given that efficacy, performance status, and bone marrow function are usually worse in the setting of advanced disease, is this really the best situation in which to test new agents? Is there a method by which we can test new agents earlier than in the refractory disease setting, and how can that be balanced with ethical consideration of withholding or delaying the use of approved agents?
Since we cannot accurately predict which patients will respond to a given agent, waiting until all "approved" agents have failed seems counterproductive, but no clear standard exists. One approach would be a short run-in period for the new "experimental" agent, followed by the addition of a second more active agent at the time of progression. This method would be a useful way to introduce new agents earlier in the disease process, and has the potential to also provide data on combination therapy, but requires that the combinations are supported by solid preclinical data. Alternative approaches are certainly welcome and needed if we are to make further advances in disease therapy, and do so in a more rapid and efficient manner.
There is much to be excited about in the myeloma community. First-rate science is rapidly being translated into clinical practice, and through this process, our patients are reaping the ultimate benefit. However, real challenges lie before us now. We must take these new trials and create a biologically based model that exploits the synergistic effects of combinations, test the best combinations, and create new standards of care for myeloma. Only then will we have succeeded in realizing the potential of our newly gained knowledge.
-Sagar Lonial, MD
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