Union of forces advances myeloma care

Together, this team conceived of a winning combination chemotherapy regimen using lenalidomide, bortezomib, and dexamethasone (RVD) in newly diagnosed myeloma patients. An unprecedented 100% of patients treated at the defined phase 2 dose level responded to treatment: 74% of patients experienced a 90% reduction in tumor burden and 57% entered a complete remission (CR) within a few months of starting treatment. Comparable results have previously been reported only after comparatively toxic regimens involving intensive rounds of combination chemotherapy and repeated doses of high-dose melphalan supported by autologous stem cell transplantation.^2,3  It is noteworthy that the RVD regimen often took more than 4 cycles of therapy to achieve maximal response, with an upgrade in response occurring in 75% of patients who continued therapy up to 8 cycles and in half of the patients treated for more than 8 cycles.

There is little doubt that this regimen represents a leap forward in myeloma care and serves as an important platform on which to build. Nevertheless, there were still significant issues. The combination is complicated by painful sensory neuropathy in 32% of patients; 40% of patients required dose reductions, missed doses, or had to discontinue therapy due to toxicity. Furthermore, despite such high initial response rates, 25% of patients relapsed within 18 months of beginning therapy, particularly those with advanced stage II/III disease (using the international staging system)⁴  at baseline. These drawbacks highlight the need for further refinements of dosing schedules, consideration of longer treatment periods, addition of active agents targeting new pathways, and adoption of genetic risk stratification to “tease out” very high-risk patients requiring a bolder treatment plan.⁵ 

Building on the spirit of collaboration and excitement over the encouraging results fostered by the RVD trial, studies addressing these issues are already under way, for example, through the Multiple Myeloma Research Consortium (addition of doxorubicin to RVD),⁶  in company-sponsored trials (adding cyclophosphamide to RVD),⁷  or by examining longer-term use of the RVD cocktail (P. G. Richardson, personal communication, June 2010). As these and larger phase 3 trials expand and build on the RVD regimen, the impact of this drug combination on stem cell collection success, need for thrombosis prophylaxis, effects on cardiac function, and its use and safety in the face of renal failure will all need ongoing monitoring.

For some, the glass will still be half empty, highlighting the need to also prove survival advantages given the potential economic impact of the use of 2 very expensive drugs in combination. Funding agencies and insurance providers will no doubt ask for a higher burden of proof before paying for this expensive regimen. Phase 3 trials which will address survival benefit are under way through US cooperative groups examining the use of RVD versus lenalidomide and dexamethasone alone in newly diagnosed patients (http://clinicaltrials.gov/ct2/show/NCT00644228). Until the results of such trials are mature, one can point to an increasing volume of studies in myeloma that highlight the value of obtaining a CR in this disease^8,–10 ; thus, as a surrogate for survival, the high CR rate reported with RVD treatment bodes well. Economic considerations aside, this pilot study, and other small combination studies recently reported with similar high CR rates,^{6,7,11,,–14}  should be especially encouraging for patients worldwide.

Further advances in myeloma should be expected as second-generation proteasome inhibitors (eg, carfilzomib, NPI-052, MLN9074, CEP-18770) and immunomodulatory drugs (pomalidomide) with varying delivery routes and toxicity profiles are now in early clinical testing along with a large series of drugs targeting novel pathways in this disease.¹⁵  A critical next step building on RVD will be reducing toxicity (one model might be use of weekly bortezomib)¹⁶  and prolonging and maintaining remission through consolidation and maintenance therapy.^17,18  Such advances will require an ongoing team effort, with industry, academia, foundations, and government working together. In this era in which increasing oversight, regulation, and negative media attention threaten to suffocate the interaction of the pharmaceutical industry, academic researchers, and hematologist-oncologists¹⁹  it is refreshing to point to the example of RVD where the significant benefits to patients that result from such positive interactions are apparent. In this light and with respect to the future of myeloma trials and to the prerequisite for close industry–physician interaction, I will quote President Andrew Jackson who, in a different context, famously opined, “Our Union: it must be preserved.”