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Salvage Therapy of Multiple Myeloma: the New Generation Drugs

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Salvage Therapy of Multiple Myeloma: the New Generation Drugs Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 456037, 14 pages http://dx.doi.org/10.1155/2014/456037 Review Article Salvage Therapy of Multiple Myeloma: The New Generation Drugs Alessandra Romano,1,2,3 Concetta Conticello,3 Maide Cavalli,3 Calogero Vetro,1,3 Cosimo Di Raimondo,3 Valentina Di Martina,1,3 Elena Schinocca,1,3 Alessia La Fauci,1,3 Nunziatina Laura Parrinello,1,3 Annalisa Chiarenza,3 and Francesco Di Raimondo1,3 1 Hematology Section, Department of Clinical and Molecular Biomedicine, University of Catania, Via Citelli 6, 95124 Catania, Italy 2 Fondazione Veronesi, Via Lancellotti 18, 00186 Roma, Italy 3 UOC di Ematologia con Trapianto di Midollo Osseo, Ospedale Ferrarotto, Via Citelli 6, 95124 Catania, Italy Correspondence should be addressed to Francesco Di Raimondo; [email protected] Received 20 February 2014; Accepted 2 May 2014; Published 19 May 2014 Academic Editor: Dong Soon Lee Copyright © 2014 Alessandra Romano et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways. 1. Introduction after an off-therapy period, or refractory disease if nonre- sponsive while on salvage therapy, or progressing within 60 During the past decade, overall results of treatment of multi- daysoflasttherapy(seethefollowingpart,[4]). ple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained Definition of Progressive Disease in accord with MM Uniform with historical treatment. These improvements are linked Reporting of Clinical Trials, Report of the 2008 International to a deeper knowledge of the biology of disease and to Myeloma Workshop Consensus: the introduction in clinical practice of drugs with different Definitions of Relapsed/Refractory MM mechanismofactionsuchasproteasomeinhibitors(borte- zomib, carfilzomib) and immunomodulatory drugs (IMiDs; Refractory myeloma. It is a disease that is nonrespon- thalidomide, lenalidomide, and pomalidomide) [1]. sive while being on salvage therapy or progresses However, MM remains in most cases an incurable disease, within 60 days of last therapy. and new drugs and therapeutic strategies are required for continued disease control. In this perspective, several new Primary refractory myeloma.Itisadiseasethatis drugs are currently undergoing evaluation, and many appear nonresponsive in patients who have never achieved a very promising on the basis of reported initial results [2, 3]. minor response with any therapy. The natural history of MM includes recurrence of active Relapsed myeloma. After a period of being off therapy, disease defined as relapse when salvage treatment is needed it requires the initiation of salvage therapy. 2 BioMed Research International Relapsed-and-refractory myeloma. It is nonresponsive eventually patients develop resistance against them and the while being on salvage therapy (achieved minor search for new alkylating agents is fully justified. In this response (MR) or better at some point in their disease scenario, MM researcher has shown an increased interest for course). bendamustine, an older alkylating drug developed behind the Iron Curtain but only recently used in Western countries. Most of the studies reporting results of the new drugs are difficult to interpreter because they are small single arm Bendamustine is a nitrogen mustard with both purine studies, they deal with very heterogeneous groups of patients, analogue and alkylating cytotoxic effects for its unique and quite often relapsed and refractory patients are lumped chemical structure: a 2-chloroethylamine alkylating group together. In addition, there is a lack of information about the (like melphalan and cyclophosphamide), a benzimidazole natural history of MM in the relapsed setting, after exposure ring, and a butyric acid side chain (like in chlorambucil) [25]. to novel agents. Therefore, bendamustine can activate apoptosis and inhibit A recent study described the poor outcome of patients mitotic checkpoints instead of inducing necrosis alone, as all who are refractory to current treatments and provided con- other alkylators do. text for interpreting trials of new drugs [5]. This study Bendamustine is effective as a single agent and in several included 286 patients with relapsed MM, who were refractory combinations with novel agents (bortezomib, thalidomide, tobortezomibandwererelapsedfollowinganIMiD.Median and lenalidomide) for the treatment of relapsed/refractory age at diagnosis was 58 years, and time from diagnosis MM (Table 1). to salvage treatment (T0) was 3.3 years. The first regimen In a phase I study involving 31 patients with progressive disease after autologous stem cell transplantation (ASCT), contained bortezomib in 26% patients and an IMiD in 33% 2 of patients. A minor or better response was achieved after at bendamustine was tested starting from 60 mg/m on days 1 least one therapy after T0 in 44% of patients, including partial and 2 of each 28-day cycle. Dose-limiting toxicity of febrile neutropenia developed in one patient after bendamustine response (PR) in 32%. The median overall survival (OS) and 2 event-free survival (EFS) from T0 were 9 and 5 months, 100 mg/m with an overall response rate (ORR) of 55%. respectively. Median duration of response was 8 months and median Thanks to new information on the biology of MM plasma progression-free survival (PFS) for the whole study popu- cells and deeper knowledge of the metabolic pathways that lation was 26 weeks and for the patients receiving 90 or 2 the neoplastic cells use for their growth, new drugs have 100 mg/m it was 36 weeks [26]. been developed. However, the new therapeutic strategies for A phase I-II study including 40 MM patients previously relapsed and refractory patients arise not only from drugs exposed to bortezomib or alkylators tested the association of 2 with a new mechanism of action, targeting the deregulated escalating doses of bendamustine 50, 70, or 90 mg/m (days 2 pathwaysinMM,butalsofromanalogsofagentsalready 1 and 4) plus bortezomib 1.0 mg/m (days1,4,8,and11)for approved for treatment of MM such as new chemotherapy up to eight 28-day cycles [7]. The bendamustine MTD was 2 drugs, second and third generation of proteasome inhibitors, 90 mg/m . The most common grade 3/4 adverse events were and new IMiDs. leucopenia (58%), neutropenia (50%), lymphopenia (45%), Inaddition,itisnotclearifthenoveldrugsshouldbeused and thrombocytopenia (30%). ORR was 48% (one CR, two in monotherapy or in combination. Looking at the emerging VGPR,ninePR,andsevenMR)forall40enrolledpatients, tumor biology, combination therapy has the potential benefit 52% (16/31) at the MTD [7]. of suppressing and eliminating more subclones at the same After these encouraging results, phase II studies tested the time, but patients with refractory disease may be more efficacy of bendamustine in combination with bortezomib debilitated and unable to tolerate aggressive combination and steroids. treatments. Among patients with early relapse, the use of In 79 patients with relapsed/refractory MM, bendamus- 2 a 3-drug regimen (bortezomib, thalidomide, and dexam- tine was given at 70 mg/m on days 1 and 4, bortezomib ethasone) improved overall response rate (ORR), depth of 2 1.3 mg/m on days 1, 4, 8, and 11, and dexamethasone 20 mg response, and progression-free survival with a trend toward on days 1, 4, 8, and 11, every 28 days up to eight cycles (BBD). improved overall survival [6]. Ongoing phase 3 studies will With this regimen, grades 3 and 4 anemia and leukopenia provide further evidence to address if 3-drug based regimens were seen in 18.7% of patients, while grade 4 thrombocy- are better than 2 drugs, using other new agents such as car- topenia was observed in 6%. Grades 3 and 4 infections were filzomib (carfilzomib/lenalidomide/dexamethasone versus observed in 20% of patients, with two deaths (3%) because lenalidomide/dexamethasone), panobinostat (panobinostat/ of infection. In addition, a doubling of the incidence of self- bortezomib/dexamethasone versus bortezomib/dexam eth- assessed grade 2 neurotoxicity from baseline to cycle 8 was asone), elotuzumab (elotuzumab/lenalidomide/dexameth- documented and grade 3-4 neuropathy was observed in 7% asone versus lenalidomide/dexamethasone), and poma- of patients at the last treatment cycle. BBD induced a very fast lidomide (pomalidomide/bortezomib/dexamethasone versus response with an ORR of 75.9% (including 15% CR), and PFS
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