Treatment of multiple myeloma based on autologous stem cell transplant: An overview of systematic reviews.

1. Introduction

Multiple myeloma (MM) [ 1 ] is a malignant plasma cell disease in which tumor cells originate from plasma cells in the bone marrow. Clonal growth of plasma cells in the bone marrow leads to one or more myeloma-defining events; its characterized by hypercalcemia, renal failure, anemia, or bone disease [ 2 ] and has been associated with plasma cell disorders. [ 3 ] Myeloma accounts for approximately 10% of all hematological malignancies. [ 4 ] There are differences in the incidence of MM among different races, with myeloma being twice as common in African Americans than in whites, and less common in Asians. [ 5 , 6 ] The estimated global 5-year prevalence is approximately 230,000. [ 7 ] In the Western world, the age-standardized incidence has been reported to be approximately 5 cases per 100,000 people. [ 8 ] The median age of patients at diagnosis is approximately 66 to 70 years, with 37% of patients below 65 years. [ 5 ] MM is extremely rare in individuals below 30 years of age (a reported frequency of 0.02%–0.3%) and appears to occur slightly more frequently in men. [ 9 ] Although MM is more frequent in high-income countries, its incidence has increased in low-income countries over the past decade, possibly owing to a lack of approval of effective drugs and stem cell transplants. [ 10 ]

From the early 1960s to the early 2000s, melphalan chemotherapy, together with steroids (prednisone or dexamethasone), formed the basis for treating MM. Melphalan has also been used in conditioning chemotherapy, which ablates the bone marrow before autologous stem cell transplantation (ASCT), and for the treatment of patients considered ineligible for transplantation. Recently, progress has been made in the treatment of myeloma with the development of new targeted therapies including thalidomide, lenalidomide, and bortezomib. [ 4 ] With the approval of multiple novel drugs, the treatment of MM has advanced from ASCT to novel drug combinations such as proteasome-inhibitors (PI) and immunomodulatory (IMID) drugs, contributing to significant improvements in patient survival. [ 11 ] The guidelines suggest that patients eligible for transplantation should receive pretransplantation and induction therapy with IMID drugs, PI, and steroids before transplantation. First-line treatments that do not meet the requirements for transplantation include bortezomib or lenalidomide with low-dose dexamethasone, or lenalidomide with low-dose dexamethasone and bortezomib. [ 12 ]

Despite the emergence of new active agents, ASCT remains an important part of the treatment of previously untreated MM patients. Although it is commonly used in early treatment, its treatment can be diversified, including early or delayed, single or series treatment, and even salvage treatment. [ 13 ] In the new drug era, the addition of new drugs before or after ASCT resulted in improved complete response (CR) rates, delayed progression, and prolonged overall survival (OS). [ 14 ] A large number of drugs have been added to clinical practice, and drugs such as PI and IMID [ 15 ] have improved prognosis. Induction therapy, mobilization and conditioning therapies, consolidation, and maintenance approaches are being refined. Recent studies have shown that maintenance therapy with the immuno modulatory drug lenalidomide following ASCT can improve progression-free survival (PFS) and OS. [ 16 ] Daratumumab is a monotherapy for adult patients with relapsed or refractory MM. [ 17 ] The options for older patients are fewer; however, some trials have demonstrated an improvement in PFS and/or OS with melphalan. [ 18 ] Although many treatment options are available, there is still a need to find more effective treatment options since the difficulty in getting completely cured, and high morbidity and mortality rates still exists.

In recent years, several systematic reviews, and meta-analyses on treatment protocols related to drug therapy, including ASCT for MM, have been published. High-quality systematic reviews and meta-analyses provide reliable evidence for clinical application. [ 19 ] The Multiple Systematic Review Assessment 2 (AMSTAR 2) scale [ 20 ] is a validated instrument with 16 domains and a total score that provides a framework to better assess the methodological quality of reviews. In addition, preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist [ 21 ] was used to ensure transparency of the characteristics reported in reviews. To assess the quality of evidence of the included reviews, the grading, assessment, development, and evaluation of recommendations (GRADE) methodology [ 22 ] was implemented. Therefore, this overview aims to use AMSTAR 2 tool, PRISMA checklist, and GRADIE approach to critically synthesize and evaluate the methodological quality of the effects of the included studies on the complete response rate, survival period, quality of life, and adverse events of patients with MM based on ASCT.

2. Methods

2.1. Search strategy

Electronic literature was searched in 4 international electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) from inception to February 28, 2023, without language restrictions. The retrieval strategy adopted a combination of subjects and free words. English search terms included “MM plasma cells,” “ASCT,” and “meta-analysis.” Additional references from identified studies, reviews, unpublished work, or relevant citations provided by experts were manually checked to include potentially missed studies. Adjustments were made according to the specific database.

2.2. Criteria for inclusion and exclusion

The inclusion criteria for this overview were as follows: the study must be a meta-analysis of randomized controlled trials (RCTs) and the language was limited to English; included patients were diagnosed with MM, with no restrictions on sex, age, race, occupation, course of the disease or the severity of disease; the type of intervention involved ASCT; the efficacy of the treatment was measured by at least 1 experimentally quantifiable outcome.

Articles were excluded if: they were duplicate publications; they were only published in conference proceedings or protocols; the participants had other diseases besides MM.

Outcome indicators: at least the following indicators were reported: PFS, OS, stringent complete response (SCR), The Risk of severe infection, and CR of the repeated publications were retained.

2.3. Literature screening and data extraction

The selection was performed independently by 2 authors (L.J. and Y.Y.). All the retrieved articles were imported into Endnote X9 software, and duplicated publications were excluded. According to the inclusion criteria formulated in advance, the titles and abstracts were read independently for preliminary screening, and the inclusion of the remaining reviews was decided after careful reading of the full text. Disagreements were resolved through discussion and consensus between the 2 review authors; if no agreement was reached, the third member of the review team (J.C.H.) was then consulted.

2.4. Report quality evaluation

The quality of reporting norms of the included literature was evaluated with the PRISMA statement [ 23 , 24 ] and scored: the scores were 1, 0.5, and 0 for “complete reporting,” “partial reporting” and “not reported” respectively, with 15 and below considered having serious reporting deficiencies, 15.5 to 21 having some reporting deficiencies, and 21.5 to 27 with relatively complete reporting.

2.5. Evaluation of methodological quality

Two reviewers (L.J. and Y.Y.) independently assessed the methodological quality of the literature using the Systematic Review Assessment Measurement Tool 2 (AMSTAR-2) [ 25 ] ; the key items are 2, 4, 7, 9, 11, 13, and 15. Disagreements were resolved through discussion and, when necessary, through the participation of a third reviewer (J.C.H.). Review reliability was classified as high (no or 1 noncritical weakness), moderate (more than 1 noncritical weakness), low (one critical flaw with or without noncritical weaknesses), or critically low (more than 1 critical flaw with or without noncritical weaknesses).

2.6. Evaluation of evidence quality

Furthermore, the GRADE system [ 26 ] was used to evaluate the quality of evidence for each of our chosen outcome measures. We assessed the overall certainty of the summarized evidence by focusing on primary outcomes. According to the GRADE score, the quality of evidence was classified as high, moderate, low, and very low.

3. Results

3.1. Literature search and study inclusion

A total of 139 meta-analysis were retrieved; 32 articles were from PubMed, 62 articles were from Web of Science, 2 articles were from Cochrane Library and 43 articles were from Embase. In total, 49 duplicates were excluded by filtration, 72 articles by title and abstract screening, and the remaining 15 articles were assessed through full texts. After review by 2 independent reviewers, 11 reviews were included (Fig. 1 ).

3.2. Characteristics of the included reviews

All included meta-analyses were published between 2007 and 2020. This overview included 190 original RCTs and 57,142 participants. Seven reviews [ 27 – 33 ] discussed the efficacy and side effects of various drugs in combination with ASCT. Four reviews [ 34 – 37 ] focus on ASCT. Study characteristics are presented in Table 1 .

3.3. Reporting quality evaluation results

PRISMA scores of the 11 included articles are shown in Table 1 . The main reasons for the deduction are as follows: Only 1 review provided a complete list of search terms, while the rest of the reviews only provided partial search terms and do not illustrate the entire electronic search strategy for at least 1 database; Eight reviews were not assessing data from individual studies for bias and their use in combining results; The outcome measures used in the combination and analysis of the results were not detailed in 1 review; Seven reviews did not report how to evaluate the possible bias between studies (publication bias and selective reporting bias); Only 2 reviews provided the registration number of the systematic review and protocol.

3.4. Methodological quality evaluation results

The methodological quality of the included meta-analyses was evaluated using the AMSTAR2 scale. The research questions and inclusion criteria of all the included reviews consist of PICO elements, and the research types were clarified. There are 10 reviews used 2 independent reviewers for literature screening and data extraction, and appropriate statistical methods were used to explain the sources in case of any conflict of interest. Only 1 study did not use double screening. The Cochrane risk of bias assessment tool was used to evaluate all 11 reviews and only 1 study used an unsatisfactory technique for assessing the risk of bias. Three references described the funding of the study. There are 5 reviews analyzed the studies they included and checked for publication bias using funnel plots. There are 7 reviews explained and analyzed the heterogeneity of the results, but, none of the reviews provided a list of excluded reviews or explained the reasons. In conclusion, the 11 meta-analyses included had many flaws in key items 7 and 15. The evaluation results are presented in Table 2 .

3.5. Evidence of quality evaluation results

The GRADE was performed on the outcome indicators of the 11 reviews. According to GRADE guidelines, high-quality evidence means that the true effect is close to the effect estimate and there is high confidence in the result. For moderate-quality evidence, there is moderate confidence in the results, and the true effect is likely closer to the estimated effect but might also be significantly different. There were 6 medium, 16 low, and 3 critically low evidence outcomes. The summary of evidence quality and results is shown in Tables 3 – 5 .

3.6. Outcome indicators

Progression-free survival (PFS)

Lenalidomide maintenance with melphalan-prednisone lenalidomide induction (MPR-R) (control group is thalidomide maintenance and melphalan–prednisone–thalidomide induction [MPT-T]) [ 32 ] ; serial high-dose therapy (HDT/ASCT) (control group is standard-dose therapy [SDT]) [ 28 ] ; patients with early SCT (control group is patients with SDT/late ASCT) [ 35 ] ; single autograft at an early stage (control group is upfront SDT) [ 37 ] all have a better PFS for MM and can effectively improve the survival time.

Overall survival (OS)

Lenalidomide, bortezomib, and dexamethasone (control group is traditional triplet regimens) [ 27 ] ; ASCT in older patients (≥65 years of age) (control group is Non-ASCT) [ 34 ] ; HDT/ASCT (control group is SDT) [ 28 ] ; Continued addition of bortezomib (control group is conventional therapy,) [ 33 ] can effectively improve OS.

Stringent complete response (SCR)

The SCR of ASCT was higher than Non-ASCT. [ 34 ]

The risk of severe infections

Compared to thalidomide, bortezomib-based induction therapy, and lenalidomide maintenance therapy were associated with an increased risk of severe infection. [ 30 ]

Complete response (CR)

Patients treated with bortezomib, thalidomide, and dexamethasone (VTD) had a significantly higher CR than bortezomib, cyclophosphamide, and dexamethasone. [ 31 ]

The response rate

A good partial response rate was approximately 1.5-fold significantly higher in the post-ASCT consolidation plus lenalidomide maintenance (CON + LEN) group than in the LEN alone group. [ 29 ] Patients treated with VTD presented a very good partial response rate than bortezomib, cyclophosphamide, and dexamethasone. [ 31 ]

4. Discussion

This overview was developed to summarize the basic characteristics and assess the methodological quality of evidence of published meta-analysis on the treatment of MM with autologous stem cell transplant. In evidence-based medicine, data from systematic reviews based on randomized controlled trials are generally considered the highest level of evidence. However, several methodological weaknesses in published systematic reviews and meta-analyses have been identified. [ 38 ] Therefore, this overview used the AMSTAR-2 scale and the GRADE system to assess methodological quality, quality of evidence, and strength of recommendations of included meta-analyses. A total of 11 systematic reviews were identified for this overview. Moderate quality evidence shows that the combination of drugs (such as PI and IMID) [ 39 ] and ASCT can help enhance the clinical efficacy of MM, mainly in terms of OS, progression free survival and overall response rate.

The Evaluation of the included meta-analysis showed that the quality of meta-analysis methods still needs to be improved. The main challenges were as follows: Incomplete search strategy: none of the literature considered gray literature, and some of the literature had no reasonable explanations on language and time restrictions, which might cause a certain degree of bias; No list of excluded literature: the 11 included reviews only described the reasons for the exclusion of the literature but, did not provide the list of the excluded literature; Incomplete basic information of the included studies: most of the literature failed to describe in detail the basic information of the included literature, such as drug dosage for the intervention and control groups; incomplete reporting of funding sources: most of the literature did not include the funding sources of the individual studies; incomplete explanation and discussion of heterogeneity: some of the literature tested for heterogeneity, however most of the literature did not analyze and explain the heterogeneity; Publication bias was not adequately investigated: most of the literature did not consider publication bias in the results.

The PRISMA statement showed the following deficiencies in the quality of the included meta-analyses: most individual studies were biased; bias was not assessed; no prior protocol registration information was provided; some of the studies failed to analyze the source of heterogeneity.

The GRADE scores showed that the quality of outcome indicators of each meta-analysis was uneven (19 medium, and 6 low evidence outcomes). The reasons for these discrepancies are not dependent only on the researchers methods, such as heterogeneity, accuracy, and publication bias, but also the quality of the original RCTs. For instance, the RCT included in the literature might have errors in randomization, blinding methods, and distribution.

The following aspects should be considered when conducting treatment-related meta-analyses, including ASCT for MM: Literature search should include gray literature and specialized registries. A list of excluded literature during screening should be included in addition to reasons for screening out; Basic information of included literature should provide relevant information, such as the drug dosage for the intervention and control groups. Whether heterogeneity exists in the studies should be considered. If heterogeneity exists, it should be reasonably explained and analyzed. The existence of publication bias should be considered, and reasonable strategies should be formulated to reduce such bias.

There are some limitations to our overview. Firstly, considering our inclusion criteria, we may have missed some relevant reviews. To ensure consistency, we only included reviews in English, which may have influenced our results. Secondly, the methodological quality of the included reviews was limited, partly due to the diversity of treatment options and the quality of relevant RCTs. Lastly, due to lack of a unified standard, there is a large heterogeneity among the included studies, making it difficult to compare and analyze the results.

5. Conclusion

This overview using the AMSTAR 2, PRISMA, and GRADE approach to evaluate the methodological quality and quality of evidence on the treatment of MM based on autologous stem cell transplant. All the included studies reported the beneficial effects of different treatment schemes on MM, but due to the limited quality of the methods, the results should be inferred with care. The prospects are great in MM treatments, and while a “cure” remains a dream. [ 40 ] Our overview suggests that the combination of drugs has improved patient survival rates, efficacy, and safety compared to the standard regimen, may improve the clinical efficacy of MM treatment and enhance the patients quality of life. The quality of the methodology used in these meta-analyses needs to be further improved. Therefore, it is necessary to consider higher quality before proceeding systematic reviews. Future researchers should design, perform, and report meta-analyses according to the AMSTAR 2 and PRISMA checklists, in order to improve the quality of the studies.

Acknowledgments

We thank all the participants and clinical researchers involved in the publications cited in this systematic review.

Author contributions

Conceptualization: Juan Liang, Wanjun Zhang.

Data curation: Juan Liang, Ying Yang, Wanjun Zhang.

Formal analysis: Juan Liang, Ying Yang.

Funding acquisition: Conghua Ji.

Investigation: Shenyun Lin.

Methodology: Shenyun Lin.

Project administration: Conghua Ji.

Resources: Juan Liang.

Software: Juan Liang.

Supervision: Peijie He, Oscar Onayi Mandizadza.

Writing – original draft: Juan Liang, Ying Yang.

Writing – review & editing: Oscar Onayi Mandizadza, Shenyun Lin, Conghua Ji.

Abbreviations: ASCT autologous stem cell transplantation CON + LEN post-ASCT consolidation plus lenalidomide maintenance CR complete response GRADE grading, assessment, development, and evaluation of recommendations HDT high-dose therapy IMID immunomodulatory MM multiple myeloma OS overall survival PFS progression-free survival PI proteasome-inhibitors PRISMA preferred reporting items for systematic reviews and meta-analyses RCT randomized controlled trial SCR stringent complete response SDT standard-dose therapy VCD bortezomib, cyclophosphamide, and dexamethasone

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

The authors have no conflicts of interest to disclose.

This work was supported by the Health Commission of Zhejiang Province (No. 2021KY616), the People’s Republic of China.

How to cite this article: Liang J, Yang Y, He P, Mandizadza OO, Zhang W, Lin S, Ji C. Treatment of multiple myeloma based on autologous stem cell transplant: An overview of systematic reviews. Medicine 2023;102:40(e35456).

Contributor Information

Juan Liang, Email: liangjuan97@163.com.

Ying Yang, Email: yingyangdoc@126.com.

Peijie He, Email: zjhpj1009@163.com.

Oscar Onayi Mandizadza, Email: oscarmandizadza@yahoo.com.

Wanjun Zhang, Email: 1977594454@qq.com.

Shengyun Lin, Email: lsyww2012@163.com.

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