Maximizing the Clinical Benefit of Novel Therapies in Multiple Myeloma

In this issue of ONCOLOGY, Dingli and Rajkumar provide an expert review of novel therapies in multiple myeloma. As their work underscores, the rapid clinical development of the immunomodulatory drugs-specifically thalidomide (Thalomid) and lenalidomide (Revlimid), and the proteasome inhibitor bor­tezomib (Velcade)-has changed the therapeutic landscape of this disease, resulting in significant improvements in patient outcomes.[1]

The efficacy of these agents has been rigorously confirmed in a series of phase III trials. In the upfront setting, for example, thalidomide-based therapy is superior to conventional approaches in both transplant-eligible and transplant-ineligible patients.[2-6] Lenalidomide plus dexamethasone has outperformed dexamethasone alone in patients with relapsed disease,[7,8] and phase III trials comparing lenalidomide-based and conventional therapies in the upfront setting are ongoing. In addition, bortezomib-based treatment has proven superior to conventional therapy in both newly diagnosed and relapsed multiple myeloma,[9-11] as well as in the relapsed/refractory setting, establishing its approval for both frontline therapy and treatment of advanced disease. In aggregate, the introduction of the novel agents has thus improved the survival of individuals with multiple myeloma overall.[1]

Choice of Initial Therapy
As the review by Dingli and Rajkumar makes clear, however, important questions have surfaced in the face of these advances. One such question pertains to the choice of initial therapy for individuals with newly diagnosed disease. Many factors are considered when determining initial therapy, including the clinical/biologic features of a patient’s disease, comorbid conditions, and mode of drug administration. Risk stratification on the basis of the International Staging System, conventional and fluorescence in situ hybridization (FISH)-based cytogenetic analysis, and other measures of biologic activity such as plasma cell labeling index influences the choice of initial therapy, and it is likely that more sophisticated genomic and proteomic approaches will soon strengthen such prognostic models. We prefer bortezomib-based therapy for individuals with high risk disease based on cytogenetic analysis, as there is substantial evidence that bortezomib overcomes the poor prognosis conferred by factors such as del(13q) and t(4;14)[12,13]

In addition, we utilize bortezomib in newly diagnosed multiple myeloma patients with renal insufficiency at the time of diagnosis, as it can be safely administered in this context and improves renal function in a significant number of patients.[14] Individuals with extensive bone disease are also treated initially with bortezomib-based therapy in our practice, for while both lenalidomide and bortezomib inhibit osteoclastogenesis,[15,16] bortezomib also promotes osteoblast differentiation and proliferation,[17] and thus may have a more pronounced overall effect on new bone formation.

Lenalidomide is preferred in our practice for patients with preexisting peripheral neuropathy and those who cannot make frequent clinic visits for bortezomib infusion. On the basis of data regarding its efficacy and tolerability, the combination of bortezomib and lenalidomide is especially popular in our group. Whenever possible, patients are of course encouraged to participate in clinical trials investigating novel agents in newly diagnosed disease.

Combination Regimens
The impact of combination regimens incorporating multiple novel agents or novel drugs in conjunction with conventional chemotherapeutic agents is an area of ongoing investigation. By targeting multiple pathways involved in the pathogenesis of multiple myeloma, combination regimens lead to greater tumor kill and higher rates of clinical response. Indeed, as Dingli and Rajkumar point out, regimens such as bortezomib, thalidomide, and dexamethasone (VTD); bortezomib, doxorubicin, and dexamethasone (PAD); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and lenalidomide, bortezomib, and dexamethasone (RVD) produce excellent overall and complete response (CR) rates with manageable toxicity. Recognizing these favorable outcomes, the National Comprehensive Cancer Network includes VTD, PAD, and RVD among its recommendations for initial treatment of transplant-eligible multiple myeloma patients.[18] Will higher rates of response associated with combination regimens translate into long-term improvements in survival? Extended follow-up of randomized studies will ultimately address this question, but there is reason to believe they may. Although not a substitute for survival, response rate-and particularly CR rate-has historically correlated with improved outcomes for multiple myeloma patients who undergo high-dose therapy and autologous stem cell transplantation (ASCT)[19-22] as well as for those who do not.[2326] In our practice, therefore, we encourage patients to participate in clinical trials assessing combination regimens, and in the nonprotocol setting, to weigh the relative merits of a two-agent induction vs a combination regimen accordingly.

Novel Induction Therapies
The use of novel therapies in conjunction with ASCT is also showing great promise. For over 10 years, ASCT following induction therapy has been a standard of care for younger multiple myeloma patients considered eligible for the procedure, based on the high response rates and clinical benefit associated with this approach. Indeed, a meta-analysis of nine randomized studies comparing conventional therapy to the same plus ASCT demonstrated superior progression-free survival, although not overall survival, with ASCT.[27] However, the studies included in this analysis utilized traditional induction regimens such as vincristine, doxorubicin, and dexamethasone (VAD) rather than novel therapies.

Whether the novel therapies, which are associated with higher levels of response and excellent 1- and 2-year survival rates, improve the relative benefit of ASCT in multiple myeloma is a question that should be addressed through a randomized comparison of novel therapy-based induction with or without ASCT consolidation. In the absence of results from such a comparative study, insight on this issue is ascertained from existing data suggesting that synergy may well exist between the novel agents and high-dose therapy.

In the Intergroupe Francophone du Myelome (IFM) 2005/01 study, compared with VAD induction, bortezomib/dexamethasone (VD) produced significantly higher rates of CR/near CR (nCR) and very good partial response (VGPR) or better.[11] Importantly, higher rates of VGPR or better were observed posttransplant in patients who received VD induction. Similarly positive results were seen in the Italian randomized study comparing bortezomib, thalidomide, and dexamethasone (VTD) to thalidomide and dexamethasone (TD) prior to and after ASCT, in favor of the VTD arm.[28] Most recently, in the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)-65/German Myeloma Multicenter Group (GMMG)-HD4 study, rates of both partial response (PR) or better and VGPR or better were significantly higher in patients who received PAD than in those who received VAD.[29] The benefit of PAD persisted after transplant, where higher rates of CR and PR or better were observed in patients who received PAD, and the impact of bortezomib-based maintenance also appeared favorable.

In addition, high rates of response have been observed with the incorporation of novel agents in the Total Therapy program advocated by the group in Arkansas; 83% of patients who underwent Total Therapy 3 achieved at least an nCR after 24 months of intensive therapy, although it is clear that such an approach is only feasible in selected patients.[30] On the basis of encouraging results such as those described, we continue in our practice to use ASCT in the management of appropriate patients who have received successful induction with novel agents.

Novel Drugs for Maintenance
Finally, the role of novel drugs as maintenance therapy is an area of continued investigation. Among the novel agents, thalidomide has been the most extensively studied as maintenance therapy following ASCT. While several randomized studies have demonstrated benefit using this approach,[31-33] the practice must be undertaken with a degree of caution, as there is suggestion that thalidomide maintenance is associated with shorter survival times following relapse.[31,34] Lenalidomide maintenance following ASCT is currently undergoing evaluation in phase III clinical trials conducted in both Europe and the United States. The efficacy of bortezomib maintenance has been evaluated as part of the previously referenced HOVON-65/GMMG study, in which patients who receive VAD induction receive thalidomide maintenance for 2 years following transplant, while those who receive PAD induction receive 2 years of posttransplant bortezomib maintenance, 1.3 mg/m2 every other week. Final results of this study are awaited with keen interest.

While we do not believe available data support a uniform practice with respect to maintenance therapy, we use a 6-month or less course of low-dose (50–100 mg/d) thalidomide for selected patients, particularly in those who fail to achieve a VGPR or better and have no significant neuropathy. Alternatives include lenalidomide, especially if neuropathy is an issue. In this setting as in others, clinical trial participation is encouraged when feasible.

Conclusions
As the review by Dingli and Rajkumar clearly illustrates, advances in multiple myeloma have occurred rapidly in the past decade, with improved understanding of disease biology and the introduction of novel therapies. The challenge before us now is to address important questions related to the use of these agents in terms of sequence and appropriate combinations so as to maximize clinical benefit for our patients.

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