Treatment of newly diagnosed multiple myeloma: early autologous stem cell transplantation versus novel agents
Schweden, A.M.C., supervised by Nijhof, I., Department of hematology VUmc
Background: Multiple myeloma is still incurable, nevertheless, the field of treatment has made major advances in the past two decades. Compared to conventional chemotherapy the best results are yet to be achieved with high dose melphalan and autologous stem cell transplantation (HDM-ASCT). However, HDM-ASCT causes much treatment-related problems, such as toxicity and hospitalization. The past years novel agents have been developed, with a better tolerability and no mandatory hospitalization. Those novel agents have been compared to HDM-ASCT in a few trials in terms of progression-free survival and overall survival, although, there has not been a systematic review since the most recent study publications.
Objective: To analyze whether the HDM-ASCT procedure is superior to novel agents, as first-line treatment of multiple myeloma in transplant-eligible patients £65 years.
Methods: A literature search was performed in PubMed and Embase, based on MeSH and TiAb terms of: “multiple myeloma”, “autologous stem cell transplantation”, “conventional chemotherapy”, “novel agents”, “progression-free survival” and “overall survival”.
Results: The search strategy provided five prospective articles and four retrospective articles, which included 1698 patients in the HDM-ASCT group and 1685 patients in the novel agent group, respectively.
The mean complete response (CR) is statistically significantly improved in HDM-ASCT, 42.62% vs 33.28%, P<0.0001. Likewise, the progression-free survival (PFS) is statistically significant improved in favor of the HDM-ASCT, P<0.0001. However, the mean overall response rate (ORR) is not statistically significantly different, P=0.087, so is the overall survival. The difference in OS is not statistically significant due to too short follow-up. Despite the superiority in CR and PFS, ASCT patients had more side effects during treatment, as expected. Conclusion: The HDM-ASCT procedure is in favor in terms of CR and PFS compared to the novel agents group. The ORR and OS did not statistically significantly differ. Additionally, side effects occurred more frequently in the HDM-ASCT group. Subsequently, this systematic review states that autologous stem cell transplantation is at this moment the best option to treat newly diagnosed transplant eligible multiple myeloma patients. Keywords: multiple myeloma, autologous stem cell transplantation, high dose melphalan, novel agents, progression-free survival, overall survival Introduction Multiple myeloma (MM) is the second most common hematological malignancy, and still incurable. MM accounts for 1% of all cancers, yet for 10% of all hematological malignancies. (1) The past two decades, much research has been performed to prolong or even cure multiple myeloma, which let to adjustment of the standard treatment.(2) Due to all novel agents, the median survival of MM patients improved from three/four years up to seven/eight years but eventually, all patients will relapse.(3) Ineligible patients were formerly treated with conventional chemotherapy (CC) and transplant-eligible patients received high-dose melphalan + autologous stem cell transplantation (HDM-ASCT). Many trials compared CC vs HDM-ASCT and the best results are yet to be achieved with the HDM-ASCT treatment in terms of survival, however, the HDM-ASCT treatment leads to much toxicity and deaths during treatment and requires hospitalization.(4, 5) Even after HDM-ASCT, the median overall survival of multiple myeloma patients remained shortly, namely 14.8 months.(6) However, less toxic, better tolerable, orally administered novel agents such as immunomodulatory agents, proteasome inhibitors and antibody therapy have been discovered in the past two decades, which improved overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) as maintenance or induction therapy.(7-10) Therefore, the burning question arises whether novel agent consolidation treatment could substitute the standard consolidation treatment with autologous stem cell transplantation until relapse. Since the introduction of novel agents, some meta-analysis and systematic reviews have been published. However, these did not include retrospective studies and as it concerns a rapid evolving field, new important trial outcomes have been published since then. The primary endpoint of this systematic review is to analyze whether the HDM-ASCT consolidation is superior to novel agent consolidation in terms of PFS and OS in newly diagnosed transplant-eligible patients. The secondary endpoint is the comparison between the groups in terms of the incidence of adverse events and the impact on ORR. We hypothesize that novel agents could substitute the HDM-ASCT treatment until relapse. Methods Selection PubMed and Embase Selection PubMed The PubMed search strategy was performed the 5th of December 2017 and the Embase search strategy was performed on the 12th of January 2018. To identify articles related to the comparison of early autologous stem cell transplantation and novel agents as treatment of transplant-eligible newly diagnosed multiple myeloma patients. According to the PICO model, the following terms should be included in the search: multiple myeloma, autologous stem cell transplantation, novel agents, progression-free survival and overall survival. All MeSH terms were included which lead to search strategy shown in Appendix 1 (PubMed) and Appendix 2 (Embase). The search strategy has been altered in Embase, specifically, the novel agents which were specified to multiple myeloma specific agents, additionally the article should have been published between 2008 and 2018 and must concern an article or conference abstract and be written in English or Dutch. Data-extraction 1652 articles were found in PubMed and 519 in Embase, all were screened on title and abstract to assess the relevance and eligibility for this systematic review. Articles that did not meet the inclusion criteria were obviously excluded. Subsequently, the articles with a positive judgment were read in full text and assessed again by the same author on eligibility, quality and relevance. Additionally, all references of the eligible articles have been checked, based on the same criteria. The data extraction consisted of first name of author, publication year, study design, patient characteristics, disease, follow-up, treatment regimen, complete response (CR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and side effects. Inclusion and exclusion criteria The articles were judged on quality, relevance and eligibility. To be included in this systematic review the articles had to comply with the following requirements: age £65 years, newly diagnosed multiple myeloma, be transplant-eligible and the article should be written in Dutch or English. Both prospective and retrospective studies are included. Exclusion criteria were categorized in 5 groups, patient (which included wrong age but also relapsed /refractory multiple myeloma), language (only English or Dutch), availability (no abstract or article), disease (only multiple myeloma was included, all other diseases were excluded) and relevance (off-topic). Results Study selection The study selection is exposed in the PRISMA flowchart, figure 1. Initially, 1652 articles were found in PubMed and 519 articles in Embase. 96 duplicates have been removed, so a total of 2075 articles have been checked on title and abstract by one author. 2042 articles were excluded based on title and abstract, specified in figure 1. 33 articles were read in full, to judge for eligibility, relevance and quality. After reading all full-text articles, five articles were excluded based on age, six did not report the variable of interest, four were irrelevant, one article could not be opened in full text, one article did not include a description of the regimen and seven were a precursor of an included article. All references of included articles were judged, however, no new article was found. Leading to a total of nine studies eligible for inclusion in this systematic review. Figure 1: PRISMA flowchart 1: Excluded on population: age ³ 65 years and refractory and relapsed multiple myeloma, relevance: the article wasn't about autologous stem cell transplantation vs novel agents or was a systematic reviews or meta-analysis, language: excluded if the articles weren't in Dutch or English, disease: excludes all articles not about multiple myeloma as disease, precursor new studies: the new version of the study is included already in this review Prospective studies Five prospective studies were included as presented in table 1.(11-15) All patients were treated with novel agents or autologous stem cell transplantation, however the regimen of novel agents differed between studies. The outcomes of each study were: PFS, OS, CR and ORR. The CR and ORR are represented in figure 2 and 3 and Appendix 3. Patients prospective studies The 5 prospective trials randomly assigned 2823 patients to either novel agent therapy or autologous stem cell transplantation, 1310 patients were randomized to novel agent therapy and 1513 patients received autologous stem cell transplantation. The age of the patients included in Palumbo et al., (2014)(12) and Gay et al., (2015)(13) varied from 51 to 56. In one study the age range was much wider, namely from 29 to 66.(15) and another two studies did not report the age range.(11, 14) The median age of four studies is 58, one prospective study was excluded because no median age was reported.(11)