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• W2115655276 abstract "International Journal of Hematologic OncologyVol. 3, No. 1 EditorialFree AccessMaintenance therapy for multiple myeloma after an autologous transplant: what have we learned?Kehinde Adekola & Muzaffar QazilbashKehinde AdekolaThe University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030, USASearch for more papers by this author & Muzaffar Qazilbash* Author for correspondenceThe University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030, USA. Search for more papers by this authorEmail the corresponding author at mqazilba@mdanderson.orgPublished Online:12 Feb 2014https://doi.org/10.2217/ijh.13.70AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Current treatment for newly diagnosed multiple myeloma (MM) can be divided into different phases: induction, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT), consolidation and maintenance. The use of auto-HSCT, immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) in the treatment of MM have greatly improved the progression-free survival (PFS) and overall survival (OS) of these patients in the last 10–15 years [1]. Even with recent progress in therapy, almost all MM patients eventually relapse. To overcome this problem, approaches such as post-auto-HSCT consolidation and maintenance are being explored to prolong the duration of remission and delay disease progression [2–4].Maintenance therapy for MM is primarily used to prolong the remission duration and, hence, survival after induction therapy and/or auto-HSCT [5–7]. An ideal maintenance drug should be easy to administer, safe and well tolerated over prolonged periods, and improve OS. In this editorial, we will review the evolution and current status of maintenance therapy after auto-HSCT, and offer recommendations based on the available data.Prior to the availability of IMiDs and PIs, interferon and corticosteroids were used as maintenance therapy, mainly after induction, with modest benefit [8,9]. Their use was limited by significant toxicity and a high rate of discontinuation in the case of interferon [8].After IMiDs and PIs became available, thalidomide, lenalidomide and bortezomib have been used for maintenance after an auto-HSCT. Thalidomide, with or without corticosteroids, has been used in post-auto-HSCT maintenance in at least six randomized clinical trials thus far [4,10–14]. With the exception of the Canadian trial [4], the other five trials demonstrated an improvement in PFS; however, only two studies, IFM 99 [10] and the Australian study [12], demonstrated an improvement in OS. A meta-analysis of these trials by the International Myeloma Working Group (IMWG) confirmed an improvement in PFS (hazard ratio [HR]: 0.65), but concluded that the trials were too heterogeneous to confirm an OS benefit [7]. These trials differed in induction therapy, thalidomide dose and duration, and concurrent use of corticosteroids. In the IFM trial [10], benefit of thalidomide maintenance was restricted to patients with less than a very good partial response and absence of del13 on metaphase cytogenetics. Thalidomide use was associated with significant peripheral neuropathy and venous thromboembolism, which limited its long-term use. Taken together, although thalidomide does prolong PFS, its use is limited by significant toxicity, dose reduction and early discontinuation.Lenalidomide, the second-generation IMiD, is active at a lower dose than that used for induction, and is better tolerated than thalidomide. It was studied in two large Phase III post-auto-HSCT maintenance trials [14,15]. In the CALGB 100104 trial, 460 patients received induction and a single auto-HSCT and were then randomized to lenalidomide maintenance or placebo until progression or unacceptable toxicity. The median time to progression was significantly prolonged in the lenalidomide arm (46 vs 27 months; HR: 0.48; p < 0.001). After a median follow-up of 34.5 months, OS in the lenalidomide vs placebo arms was 85 vs 77% (p = 0.03). In the IFM 2005–02 trial, 614 patients were randomized to lenalidomide or placebo after induction, one or two auto-HSCTs, and two cycles of lenalidomide consolidation. After a median follow-up of 36 months from randomization, median PFS was significantly better in the lenalidomide arm (41 vs 24 months; HR: 0.5; p < 0.001). The 3-year OS, however, was similar in the two groups (80 in lenalidomide vs 84% in placebo group; HR: 1.25; p = 0.29). In both trials, the lenalidomide arm was marked by a higher incidence of grade 3–4 neutropenia, thrombocytopenia and more thromboembolic events. One notable finding was an increase in second primary malignancies (SPM) in the lenalidomide arm of both trials (7.5 vs 2.6% in CALGB; 7 vs 3% in IFM). Despite this increase in SPM, there was almost a 65% reduction in the risk of relapse in both trials [7]. In summary, lenalidomide maintenance was associated with longer PFS in both trials, but improved OS in the CALGB trial only. There were differences between the two trials in terms of induction therapy, post-auto-HSCT consolidation (IFM trial only) and duration of maintenance [3,14].Bortezomib has shown encouraging results in post-auto-HSCT maintenance in one randomized trial thus far. In the HOVON-65/GMMG-HD4 trial patients in one arm received thalidomide-based induction, auto-HSCT and thalidomide maintenance, while patients in the other arm received bortezomib-based induction, auto-HSCT and bortezomib maintenance, with maintenance in both arms continuing for 2 years [2]. Both PFS and OS were significantly longer in the bortezomib arm. Since bortezomib was used for both induction and maintenance, the positive impact of bortezomib as maintenance could not be ascertained. Overall, 64% of patients in the thalidomide arm and 47% in the bortezomib arm discontinued treatment due to adverse events. Notably, bortezomib maintenance demonstrated superior outcome in patients with renal insufficiency and high-risk FISH abnormalities including del17p [15].Based on the available data as reviewed above, the consensus on post-auto-HSCT maintenance is still emerging, and the decision to offer maintenance should be individualized. Lenalidomide is better tolerated than thalidomide, improves outcome in all risk groups and can be given for a longer duration. Patients should be counseled about the risk of SPM. In patients opting for lenalidomide maintenance, we recommend a starting dose of 10 mg to be continued until progression or intolerance, with dose adjustments as needed. If thalidomide is chosen, then the lowest effective dose (50–100 mg) should be used, and the treatment should not be continued beyond 2 years owing to peripheral neuropathy and other adverse events. The benefit of bortezomib as maintenance is reported in one trial only, which was confounded by its use in induction. However, it may be considered for maintenance in patients with renal insufficiency or high-risk FISH abnormalities.Financial & competing interests disclosureM Qazilbash is a member of the advisory committee for Celgene and Millenium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Kumar SK, Rajkumar SV, Dispenzieri A et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood111(5),2516–2520 (2008).Crossref, Medline, CAS, Google Scholar2 Sonneveld P, Schmidt-Wsolf IG, van der Holt B et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized Phase III HOVON-65/GMMG-HD4 trial. J. Clin. Oncol.30(24),2946–2955 (2012).Crossref, Medline, CAS, Google Scholar3 Attal M, Lauwers-Cances V, Marit G et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med.366(19),1782–1791 (2012).Crossref, Medline, CAS, Google Scholar4 Stewart AK, Trudel S, Bahlis NJ et al. A randomized Phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National cancer institute of Canada clinicals trials group myeloma 10 trial. Blood121(9),1517–1523 (2013).Crossref, Medline, CAS, Google Scholar5 McCarthy PL. Part I: the role of maintenance therapy in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. J. Natl Compr. Canc. Netw.11(1),35–42 (2013).Crossref, Medline, CAS, Google Scholar6 Child JA, Morgan GJ, Davies FE et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N. Engl. J. Med.348(19),1875–1883 (2003).Crossref, Medline, CAS, Google Scholar7 Ludwig H, Durie BG, McCarthy P et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood119(13),3003–3015 (2012).Crossref, Medline, CAS, Google Scholar8 Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann. Oncol.11(11),1427–1436 (2000).Crossref, Medline, CAS, Google Scholar9 Berenson JR, Crowley JJ, Grogan TM et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood99(9),3163–3168 (2002).Crossref, Medline, CAS, Google Scholar10 Attal M, Harousseau JL, Leyvraz S et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood108(10),3289–3294 (2006).Crossref, Medline, CAS, Google Scholar11 Barlogie B, Tricot G, Anaissie E et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N. Engl. J. Med.354(10),1021–1030 (2006).Crossref, Medline, CAS, Google Scholar12 Spencer A, Prince HM, Roberts AW et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J. Clin. Oncol.27(11),1788–1793 (2009).Crossref, Medline, CAS, Google Scholar13 Lokhorst HM, Van Der Holt B, Zweegman S et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood115(6),1113–1120 (2010).Crossref, Medline, CAS, Google Scholar14 Morgan GJ, Gregory WM, Davies FE et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood119(1),7–15 (2012).Crossref, Medline, CAS, Google Scholar15 Neben K, Lokhorst HM, Jauch A et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood119(4),940–948 (2012).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 3, No. 1 Follow us on social media for the latest updates Metrics Downloaded 379 times History Published online 12 February 2014 Published in print February 2014 Information© Future Medicine LtdFinancial & competing interests disclosureM Qazilbash is a member of the advisory committee for Celgene and Millenium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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