Toward deeper response in MM

In this issue of Blood, Gay and colleagues report that in 1175 elderly myeloma patients treated with melphalan/prednisone plus novel agents, the achievement of complete remission was an independent predictor of outcome.¹ 

Multiple myeloma (MM) is a proliferation of clonal bone marrow plasma cells (BMPCs) characterized by a high degree of resistance to chemotherapy. In fact, complete remission (CR) was rarely observed with the use of conventional chemotherapy. For many years stabilization of tumor load was considered a more powerful prognostic factor than degree of tumor reduction.²  More recently, it was shown that high-dose therapy followed by autologous stem-cell transplantation (ASCT) results in a higher tumor reduction, and a significant correlation between the degree of tumor decrease and survival was observed. This lead to the definition of CR by the European Blood and Marrow Transplantation (EBMT) group as negative immunofixation electrophoresis (IFE) in serum and urine, in the absence of increased BMPCs. More recently, the International Myeloma Working Group (IMWG) expanded the CR EBMT criteria by adding the category of stringent CR (sCR), defined by negative IFE in serum and urine with a normal serum free light chain (FLC) ratio plus the absence of clonal BMPCs by immunohistochemistry or immunofluoresce.³  The IMWG also introduced the concept of very good partial response (VGPR; ≥ 90% M-protein decrease) as a separate category of partial response (PR; ≥ 50% M-protein decrease). In addition to the EBMT and IMWG response criteria, the achievement of negative minimal residual disease (MRD) by multiparameter flow cytometry (MFC)⁴  or by molecular studies⁵  are essential for long-term remission duration and prolonged survival. Finally, between 10% and 40% of patients with MM in CR after ASCT develop oligoclonal bands, a fact likely resulting from a robust humoral response and associated with a favorable outcome.⁶ 

For many years the gold standard for patients with MM not eligible for ASCT has been the combination of melphalan and prednisone (MP) or dexamethasone-based regimens. The overall response rate was < 50% with a CR rate of < 5%, a median duration of response of 1.5 years, and a median overall survival (OS) of ∼ 3 years. Interestingly, for this population of patients, new combination regimens incorporating novel drugs such as MP-thalidomide (MPT), MP-bortezomib (MPV), MP-lenalidomide (MPR), or lenalidomide plus dexamethasone have resulted in an unprecedented CR rate of up to 15%, 30%, 24%, and 24%, respectively.⁷  However, the impact of these CRs on event-free survival (EFS) and OS in the nontransplantation setting has not yet established.

In this issue of Blood, Gay et al report on the impact of response to therapy on progression-free survival (PFS) and OS in 1175 newly diagnosed patients with MM, not eligible for ASCT and enrolled in 3 multicenter trials, treated with either MP alone (332), MPT (332), MPV (235), or MPV followed by VT maintenance (254).¹  Concerning response, CR was achieved in 17%, VGPR in 19%, and PR in 35%. According to the treatment group, CR was attained in 49%, 31%, 15%, and 5% of patients treated with MPV-VT, MPV, MPT, and MP, respectively. After a median follow-up of 29 months, PFS and OS were significantly longer in patients who achieved CR versus those who attained VGPR or PR. Of interest, the PFS and OS were virtually identical in patients who achieved VGPR and PR. Finally, the achievement of CR was an independent predictor of longer PFS and OS irrespective of age, International Staging System stage, and treatment arm.

There is no doubt that, in the transplantation setting, the achievement of IFE-negative CR is a crucial step forward for long-lasting response and survival in MM.⁸  Gay et al clearly demonstrate that the achievement of IFE-negative CR in elderly patients treated with MP plus novel antimyeloma agents has also a significant impact on PFS and OS.¹  Interestingly enough, in a recent transplantation series, the achievement of VGPR did not result in a better outcome than the achievement of PR.⁹  It has been shown that approximately one-third of CRs achieved after ASCT in younger myeloma patients last for > 10 years, representing the so-called “cure fraction” or “operational cure.”⁸  Although the achievement of a PFS of 67% at 3 years in elderly patients with MM in the study of Gay et al is encouraging,¹  it must be considered that the follow-up is still too short with few patients at risk beyond 4 years from initiation of therapy, to know whether or not operational cures can be expected with primary therapy incorporating novel agents in elderly patients. Furthermore, with the availability of novel technologies, the achievement of IFE-negative CR should no longer be the ultimate goal in the treatment of MM. In this regard, the impact of sCR should be investigated. It has been recently reported that the achievement of CR with primary therapy including novel agents results in the emergence of oligoclonal bands in up to 60% of the patients.¹⁰  Whether this phenomenon is because of a higher tumor reduction or a more robust immune reconstitution as well as its potential prognostic influence are unknown. Finally, sequential MRD measurements with MFC or molecular studies could be helpful in determining from what level of MRD further treatment is or not needed. Ideally, the treatment approach in elderly patients with MM should include a triple-agent induction regimen such as MPT or MPV followed by maintenance incorporating novel agents along with sequential MRD studies to establish for how long treatment is still of benefit.