IMWG consensus on maintenance therapy in multiple myeloma

Department of Medicine I, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria.
Blood (Impact Factor: 10.45). 01/2012; 119(13):3003-15. DOI: 10.1182/blood-2011-11-374249
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Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.

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Available from: Heinz Ludwig, Oct 12, 2015
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    • "Achievement of complete response (CR) or at least very good partial response (VGPR) at the end of the ASCT procedure was considered one of the key features for improved outcome 4-6. Nevertheless, MM remains an incurable disease, characterized by a high relapse rate, and several strategies were developed to increase the VGPR plus CR rate, including improvements in the induction regimen and the recent development of the concept of consolidation and/or maintenance phases post ASCT 3, 7. "
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    ABSTRACT: The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.
    Journal of Cancer 03/2014; 5(3):248-52. DOI:10.7150/jca.8541 · 3.27 Impact Factor
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    • "Despite advances in treatment strategies, MM remains an incurable disease, with about 20,000 newly diagnosed cases and over 10,000 deaths per year in the U.S. (26). Novel therapies have improved survival over the last decade, including autologous hematopoietic stem cell transplantation (HSCT) and the use of new drugs (27). Allogeneic stem cell transplantation can be curative, but is often associated with high transplantation-related mortality (28). "
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    ABSTRACT: Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma.
    Frontiers in Immunology 12/2013; 4:481. DOI:10.3389/fimmu.2013.00481
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    • "Multiple myeloma (MM) is a malignant plasma cell (PC) disorder, accounting for approximately 1% of neoplastic diseases and 13% of hematological cancers [15], and evolving from a monoclonal gammopathy of undetermined significance (MGUS) that progresses to smoldering myeloma (SMM) and, finally, to symptomatic MM. In recent years, the introduction of autologous hematopoietic stem cell transplantation (HSCT) and the availability of novel drugs such as thalidomide, lenalidomide and bortezomib, have prolonged overall survival [16,17]. Importantly, MM tumor cells are susceptible to immune recognition in the form of graft-versus-myeloma effect, as suggested by the therapeutic efficacy of allogeneic HSCT. "
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    ABSTRACT: Background Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment. Methods We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8+ T cells. Results KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4+CD25+FoxP3+ Treg cells and the contraction of NY-ESO-1-specific CD8+ T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4+ T cells into bona fide CD4+CD25hiFoxP3hi Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by d,l-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO+ myeloma disease compared with patients having IDO- MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity. Conclusions These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.
    Journal of Translational Medicine 12/2012; 10(1):247. DOI:10.1186/1479-5876-10-247 · 3.93 Impact Factor
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