Incorporating Monoclonal Antibodies Into the Therapy of Multiple Myeloma

Abstract

The outcome of patients with multiple myeloma (MM) treated with cytotoxic therapy has not been satisfactory, with a median survival of about 3 years for elderly patients and of about 6 years for younger patients receiving up-front autologous stem-cell transplantation (ASCT). The incorporation of novel drugs, particularly thalidomide, bortezomib, and lenalidomide, has resulted in a significant survival prolongation. However, MM is still an incurable disease with an important shortening in the expected survival. A number of novel drugs with many different mechanisms of action have been developed and are currently investigated in clinical trials with the hope of further improving the survival of patients with MM. In this regard, the use of the anti-CS1 humanized monoclonal antibody in combination with bortezomib is described in an article accompanying this editorial. In order to place the findings of this study into clinical context, it will be helpful to briefly review recent progress made in the therapy of this disease. ASCT is the gold standard as part of the initial therapy in younger patients with MM. With the use of induction regimens based on conventional chemotherapy, the post-transplantation complete remission (CR) rate is between 30% and 35%, the median survival of about 6 years, and the proportion of patients surviving in continued CR beyond 10 years after ASCT is less than 10%. The incorporation of novel drugs into induction therapy has improved the posttransplant CR rate and the progression-free survival (PFS), when compared with the above mentioned results. Thus, triple induction regimens PAD (bortezomib/doxorubicin/dexamethasone) and, particularly, VTD (bortezomib/thalidomide/dexamethasone) result in a post-transplantation CR rate from 43% to 52% with a significant PFS prolongation. Furthermore, post-transplantation consolidation and maintenance with novel agents appears to be an important step forward. Despite the apparent benefit of these treatment approaches incorporating novel drugs, long-term results are required to demonstrate that the improvement is real in comparison with the results achieved in the previous era. Concerning elderly patients, for many years the standard of care has been melphalan and prednisone (MP) or dexamethasone-based regimens, leading to an overall response and CR rates of 50% and 5%, respectively and to a median survival of about 3 years. The novel agents thalidomide, bortezomib and lenalidomide have been associated with MP (MPT, MPV or MPR) or dexamethasone, particularly low-dose lenalidomide/dexamethasone resulting in a higher response rate and PFS in almost all studies and in a significant overall survival prolongation in some of them. The best results have been obtained with MPV which results in approximately 30% immunofixation negative CR and a significant PFS and OS survival prolongation when compared with MP. However, the incidence of grade 3 and 4 peripheral neuropathy is approximately 13%. A large international trial including over 1,600 patients by the Intergroup Franchophone du Myelome comparing MPT versus lenalidomide and dexamethasone with or without lenalidomide maintenance is ongoing (NIH Clinical Trials identifier NCT00689936). Finally, although the improvement with the incorporation of novel agents is clinically relevant, it is still far from satisfactory. In this regard, the median duration of complete remissions achieved with the above-mentioned combinations is only of 2 years and it unknown if any prolonged remissions (ie, continued CR beyond 10 years from therapy) can be achieved. Therefore, there is also a need for further improvement in the elderly. The treatment of patients with relapsed or refractory myeloma is a real challenge. Bortezomib, bortezomib plus pegylated liposomal doxorubicin, or lenalidomide plus dexamethasone are effective regimens and were first approved for patients with relapsed and/or refractory myeloma (Table 1). However, the duration of response is limited and, unfortunately, all patients will ultimately develop progressive disease. Therefore, there is a need for the development of newer drugs or drug combinations in order to increase not only the response rate but also the durability of responses. In this sense, a new generation of novel drugs is currently being investigated in clinical trials (Table 2). Among them, the most promising are the immunomodulatory drug pomalidomide, the irreversible proteasome inhibitor carfilzomib, which can be active even in refractory patients to bortezomib and that shows an acceptable toxicity profile, and the histone deacethylase inhibitors, particularly SAHA (vorinostat) and LBH 589 (panobinostat). Unfortunately, most of these new drugs have shown limited efficacy when used as single agents. An interesting approach consists of the addition of a new agent as a second or third drug to a wellestablished agent or regimen such as bortezomib or lenalidomide/dexamethasone in order to obtain an additive or, hopefully, a synergistic effect. Despite the availability of an impressive number of new drugs, there is still an unmet need for treatment possibilities in patients with MM. In thisregard,anovelanticancerstrategy is theuseofmonoclonalantibodies (MoAb) that act though completely different mechanisms of action. The JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 16 JUNE 1 2012