Multiple myeloma: so much progress, but so many unsolved questions

High-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) for multiple myeloma (MM) was developed in the 1980s and has been considered the standard front-line treatment for younger patients with normal renal function since the mid-1990s.1 The recent introduction of the novel agents, thalidomide, bortezomib, and lenalidomide is now changing the transplantation scenario in several ways. These agents are being incorporated into the pre-transplantation setting as part of induction regimens with the objective of increasing the response rate prior to ASCT, as well as following the transplantation procedure as consolidation or maintenance treatments.1,2 Consolidation is aimed at increasing the quantity and depth of responses achieved with high-dose melphalan, while the goal of maintenance therapy is to prolong the duration of the first response and to delay relapse. The overarching goal of applying treatments in the post-ASCT setting is undoubtedly the extension of progression-free survival (PFS) and, importantly, overall survival (OS). Some authors are even considering that MM has become a potentially curable disease.3 These major improvements have been widely adopted in the medical community. Nevertheless, important issues and challenges remain, and we would like to address some of these here.

Notably, the high efficacy of the novel agents has led some groups to investigate these agents upfront without the application of ASCT, and interesting results have been reported. Lenalidomide plus low-dose dexamethasone (Len/dex) as part of front-line therapy without ASCT yielded similar survival rates at two years as compared with Len/dex followed by ASCT in a non-randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG).4 Furthermore, in a non-randomized phase II trial of lenalidomide-bortezomib-dexamethasone in the upfront setting, in which the choice of proceeding to HDT or not was left to the physician or patient, no difference in outcome was seen for the two approaches.5 Based on these results, many colleagues have begun to consider the use of such novel agent-based therapies without the upfront application of ASCT as an alternative to early transplantation and the role of ASCT itself has become a matter of debate: should it be used upfront or as a salvage treatment at the time of progression for patients initially treated with novel agents? In 2013, we only have the preliminary data of a single prospective study addressing this issue to try to solve this burning question. The Italian Myeloma Network, GIMEMA, has reported in abstract form the results of the first randomized study comparing conventional chemotherapy plus novel agents to tandem high-dose melphalan and ASCT in 402 newly diagnosed MM patients.6 At the time of the report, with a short follow up, there was no significant difference in OS between the two groups, but PFS was significantly improved in the early HDT arm. Two other ongoing trials, one conducted by the European Myeloma Network (NCT01208766) and one by the Institute Francophone du Myelome (IFM) together with a US consortium (NCT01208662), are investigating the same issue and will enrol 1500 and 1000 patients, respectively.

The debate surrounding HDT comes at the very time when important advances in the understanding of the biology of the disease, including the complexity and dynamics of the MM genomic landscape,7 are leading some physicians to believe that a risk-adapted strategy should be routinely used, with serial biological examinations guiding treatment decisions in daily practice.

Up to now, the concept of a risk-adapted strategy relies on prognostic factors identified at the time of diagnosis, such as stage according to the International Staging System (ISS), chromosomal and genetic abnormalities detected through conventional cytogenetics, fluorescence in situ hybridization (FISH) or gene expression profiling, the combination of ISS and FISH, or other biological parameters. Currently, there are two groups who are routinely applying a risk-adapted strategy. In Little Rock, Arkansas, systematic gene expression profiling, performed at the time of diagnosis in all patients eligible for high-dose therapy, is used to segregate patients with high-risk versus standard-risk disease.8 A specific total therapy 4 program is proposed to patients with standard-risk disease, while those with high-risk disease receive a more intensive approach (total therapy 5), which is aimed at sustaining the duration of complete remission (CR). The group at the Mayo Clinic is routinely using the mSMART algorithm to define patients with standard, intermediate, or high-risk disease, and recommended treatment options vary according to risk-group category.9 These two different US options are interesting, and the development of a risk-adapted strategy is undoubtedly one of the most important goals in the 2010s. Nevertheless, we have to keep in mind that the choice of therapy proposed in the Little-Rock program is not based on the results of phase III trials. Similarly, the mSMART algorithm is not evidence-based.

Moreover, these strategies do not take into account two major points: 1) the disease response to therapy and its evaluation; 2) the clonal evolution of the disease and the intrinsic genomic instability of the myeloma clone. Let us take each of these one at a time.

In the attempt to define the best therapeutic strategy, future trials should not only be designed to investigate prognostic parameters at diagnosis, but also to evaluate disease response in and outside of the bone marrow, and to assess the dynamics of clonal expansion of the disease. An enormous challenge awaits us!

Footnotes

• Philippe Moreau, MD, is Head of the Hematology Department at the University Hospital of Nantes, France. He specializes in clinical hematology, with a particular focus on multiple myeloma and its treatment with high-dose therapy and novel agents.
• Dr Stéphane Minvielle is a research group leader at the INSERM CNRS Cancer Center of the University of Nantes, France. He is mainly interested in the genomics of multiple myeloma.
• Financial and other disclosures provided by the author using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are available with the full text of this paper at www.haematologica.org.