Review Article, J Clin Exp Oncol Vol: 14 Issue: 4

Efficacy of interventions for newly diagnosed multiple myeloma: An umbrella review

Yimeng Li^1*, Mengmeng Ji^2*, Mark A. Fiala³, Enkhjin Gansukh¹, Natalia Neparidze^{4, 5}, Martin W. Schoen^{6, 7}, Xiaomei Ma^{1, 5}, Graham A. Colditz², Su-hsin Chang² and Shi-Yi Wang^{1, 6}

¹Department of Chronic Disease Epidemiology, Yale School of Public Health, USA

²Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, USA

³Division of Oncology, Washington University in St. Louis, St. Louis, USA

⁴Department of Internal Medicine, Section of Hematology, Yale School of Medicine, USA

⁵Cancer Outcomes, Public Policy and Effectiveness Research (COPPER) Center, Yale University, USA

⁶Department of Medicine, Saint Louis University School of Medicine, St Louis, USA

⁷Medical Service, St Louis Veterans Affairs Medical Center, St Louis, USA

*Corresponding Author:

Yimeng Li
Department of Chronic Disease Epidemiology, Yale School of Public Health, USA
E-mail: yimeng.li@yale.edu

Received: 05-Jun-2025, Manuscript No. jceog-25-168171; Editor assigned: 06- Jun-2025, PreQC No. jceog-25-168171 (PQ); Reviewed: 20-Jun-2025, QC No. jceog-25-168171; Revised: 27-Jun-2025, Manuscript No. jceog-25-168171 (R); Published: 03-Jul-2025, DOI: 10.4172/2325-9620.1000345

Citation: Li Y, Ji M, Fiala MA, Gansukh E, Neparidze N, et al. (2025) Efficacy of Interventions for Newly Diagnosed Multiple Myeloma: An Umbrella Review. J Clin Exp Oncol 14: 345

Abstract

Introduction

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. Over the last three decades, the introduction of autologous hematopoietic cell transplantation (HCT) and the availability of novel agents have changed the management of myeloma and extended median overall survival to 8-10 years.[1,2] However, MM is still considered incurable and virtually all patients will relapse, require multiple regimens for treatment, and die from MM or its sequalae. The proliferation of therapeutic targets for MM have stimulated a considerable surge in published randomized controlled trials (RCTs). Likewise, the relative number of systematic reviews (SRs), to meticulously collate and analyze RCTs, has increased tremendously. The contributions of SRs in generating high-quality evidence that inform clinical practice and research directions are undeniable.[3] However, the influx of these resources can be overwhelming, potentially leading to a duplication of efforts, and may present contradictory findings. The ensuing complexity makes it challenging to navigate the landscape of MM research, emphasizing the critical need for an umbrella review to synthesize existing SRs and provide a comprehensive overview of the current evidence. An umbrella review, an essential tool in modern evidence-based medicine, is an SR of SRs. It can help in effectively navigating the research maze by serving as an overarching guide. To our knowledge, only two umbrella reviews for MM have been performed.[4,5] These umbrella reviews, however, are outdated. For example, newly FDA-approved agents for patients with MM, such as daratumumab which has become a backbone treatment in recent years, were not included. Furthermore, there has no comprehensive quality assessment of existing SRs. Therefore, we conducted an umbrella review to 1) summarize the findings from existing SRs of MM treatment efficacy, which can provide a comprehensive overview of the evidence for clinicians, researchers, and policymakers; and 2) identify evidence gaps and weaknesses in the current SRs, thereby informing and guiding future SRs.

Methods

Literature search: We followed the PRISMA Statement for this umbrella review [6]. We conducted a comprehensive literature search for SRs and/or meta-analyses on MM in PubMed, Embase, Web of Science, and Cochrane. The search was performed from January 1, 1990 to July 10, 2023. The search strategies for the four databases can be found in Appendix 1.

Inclusion and exclusion criteria

To be included in our review, the articles had to 1) be SRs with or without meta-analyses; 2) be published in English; 3) assess systemic treatments for the newly diagnosed MM (including smoldering MM) population only; that is, articles involving relapsed/refractory MM (RRMM) or other malignancies were excluded; and 4) report efficacy outcomes, including overall survival (OS), progression-free survival (PFS), and response rates (overall response rate [ORR], complete response rate, or very good partial response rate). As we intended to assess the quality of existing SRs, articles were included even if they included non-RCT studies or did not report a clear search strategy. To exclude narrative reviews, articles which did not perform a meta-analysis had to contain the word “systematic” in the main text to be included. Reviews which only reported adverse events or outcomes not within our pre-specified outcome list or conference abstracts were excluded.

Data extraction

Two authors (Y.L and M.J) independently screened the titles and abstracts to identify potential pertinent articles. Two authors (Y.L and S.W) reviewed the full-text articles, determined the eligibility, and assessed each study’s quality. Disagreement was resolved by consensus through discussion. For each SR, we abstracted information on the name of the first-author(s), year of publication, country, funding source, multiple myeloma type (e.g., transplant-eligible MM [TEMM], non-transplant-eligible MM [NTEMM], or unspecified), the intervention(s) of interest, the comparator(s), study type (whether a meta-analysis, network meta-analysis or individual participant data [IPD] meta-analysis was performed), inclusion of non-RCT data, the main findings, and their assessment of strength of evidence. For each SR, we not only abstracted the number of head-to-head RCTs included, but also reviewed these RCTs to identify any discrepancies between the SRs and the included RCTs.

Quality assessment

The Assessment of Multiple Systematic Reviews (AMSTAR) evaluation tool was utilized to evaluate the methodological quality of SRs and meta-analyses that qualified for inclusion in this umbrella review. [7] We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument to assess the strength of evidence [8].

Results

After removing duplicates, the literature search identified a total of 1241 potentially relevant records (Figure 1). Furthermore, 893 studies were excluded after screening titles and abstracts. Upon full-text reviews, 87 articles met the inclusion criteria. The population of interest was smoldering MM (SMM) in five reviews, TEMM in 36 reviews, NTEMM in 22 reviews, and unspecified NDMM (including reviews combining TEMM and NTEMM) in 24 reviews (Table 1). Nine reviews did not include meta-analyses, five performed IPD meta-analysis and 21 were network meta-analyses. Fifteen reviews addressed the question related to transplant, and 19 to consolidation/maintenance therapy. Twenty-six reviews were funded by industry. Detailed study characteristics can be found in Appendix 2.

Table 1: Review characteristics (N = 87)

Methodological quality of SRs

The methodological quality of reviews is displayed in Appendix 3. Forty-one reviews (47%) of the reviews provided an “a priori” design, indicating the existence of a protocol or ethics approval. Seventy-eight reviews (90%) executed a comprehensive literature search, and 39 studies (45%) described the included reviews in adequate detail. In terms of quality assessment [67] studies (72%) employed an existing checklist to evaluate the quality or risk of bias of included studies in their review. Only seven reviews assessed the strength of evidence [9–14] all except one using the GRADE instrument. These findings highlight the varying approaches and methodologies employed across the reviewed studies. Based on our assessment, strength of evidence was moderate or high in 53 SRs (60%; Appendix 4).

Evidence/Evidence gaps from SRs

Evidence addressed by the SRs and the potential evidence gaps are presented here according to the type of patient population (Table 2).

Table 2: Evidence and evidence gaps

SMM

We identified five SRs, including 3 with meta-analyses [15–17] and 2 without [18,19] The number of RCTs included in each SR ranged from 2 to 8. Alkylators with MP can inhibit disease progression, but did not have impact on overall survival [20] Early treatment with immunomodulatory drugs (IMiDs) looks promising as two RCTs demonstrated early treatment with lenalidomide or zoledronic acid plus thalidomide improved PFS.[21,22] No evidence of benefits on OS of lenalidomide was found.22 We downgraded the level of evidence from moderate to low because patients on the control arm in QuiRedex trial were not provided lenalidomide on progression, nor was lenalidomide available outside of the trial, which does not reflect the standard of care during the study period nor current care; thus, the benefits of early treatment of lenalidomide would be overestimated. Additionally, this trial, beginning in 2007, did not routinely use free light chain assays to monitor early signals of progression, and the algorithm for identifying a patient as high risk was outdated.[23] As multiple risk stratification models have been developed to determine a patient’s risk of progression and the corresponding treatment,[24–27] future SRs examining the impact of IMiDs across different risk groups are needed. Also, daratumumab is very effective in MM treatment and has been evaluated in two trials; thus, comparisons between daratumumab and IMiDs would be of interest/importance.[28,29]

TEMM

We identified 37 SRs examining the treatment efficacy for TEMM, including 10 for induction therapy,[30–38,15] for transplant,[10,39–52] 10 for consolidation/maintenance therapy,9–61] and two for others. Because SRs may include observational studies only, the number of RCTs included in each SR ranged from 0 to 13. Regarding induction regimens, bortezomib-based regimens were included in seven reviews [31–36,38] and daratumumab was included in one review.[37] Evidence suggested that triplets (such as bortezomib-thalidomide-dexamethasone [VTD] or bortezomib-lenalidomide-dexamethasone [VRD]) improves OS and PFS [32,33,36]. Dara-based regimens have demonstrated improved ORR and minimal residual disease (MRD) [37].While the CASSIOPEIA trial did use PFS as an endpoint, [62] the standard of care in the control maintenance arm of CASSIOPEIA was not adequate for US standards. Longer follow-up in the GRIFFIN trial is needed to confirm whether a PFS and OS benefit will be achieved. Additionally, more studies evaluating the high-risk subset of TEMM would benefit this population with an unmet need. Regarding transplant, nine SRs compared autologous HCT vs chemotherapy/deferred HCT, [10,41,42,44,45,47,49,52] 3 tandem vs single autologous HCT, [43,47,51] and 4 autologous-allogenous HCT [19,39,40,46]. While high dose chemotherapy (HDC) plus autologous HCT, compared to convention chemotherapy, improved PFS, it did not improve OS [41,44,49]. Additionally, patients with high-risk cytogenetics appear to benefit from early rather than delayed HCT.42 Tandem HCT (vs single HCT) and autologous-allogenous HCT (vs autologous- autologous HCT) did not improve PFS or OS. Evidence also suggested that HDC with bortezomib, lenalidomide, and dexamethasone plus HCT improved PFS but not OS [47]. Transplant is the standard of care for patients with TEMM, but comparisons between novel treatments, such as chimeric antigen receptor T-cell (CAR-T) therapy [63–66] or bispecific T-cell engager therapy [67] vs transplant could help inform treatment recommendations. There were three SRs for consolidation therapy, [9,55,59] six for maintenance therapy, [53,56–58,60,61] and one for both consolidation and maintenance therapies.[54] While evidence regarding consolidation therapy was insufficient, evidence suggests that IMiD maintenance therapy for patients with MM after HCT improved PFS and OS [53,57,58,60]. Additionally, lenalidomide maintenance seemed to be better than thalidomide maintenance regarding PFS improvement [68]. Future research should examine whether consolidation therapy can improve outcomes; and if yes, identify the best consolidation regimens. From the value-based practice perspective, it would be important to determine if maintenance therapy could be stopped for patients who reach MRD-negativity, given the high cost of lenalidomide.

NTEMM

We identified 22 SRs examining the efficacy of induction therapy for NTEMM, including one IPD meta-analysis and 15 network meta-analyses. Evidence suggested that daratumumab plus vincristine, melphalan, and prednisone (Dara-VMP), daratumumab plus lenalidomide and dexamethasone (Dara-RD), VRD, bortezomib-melphalan-prednisone-thalidomide induction and bortezomib-thalidomide maintenance (VMPT-VT) were more effective and could improve PFS and OS, compared to other regimens [11–74]. Additionally, compared with the bortezomib-based regimens, carfilzomib-based regimens did not improve OS and PFS [75]. Regarding maintenance therapy for NTEMM, lenalidomide or ixazomib maintenance improved PFS but not OS [13]. Ongoing research will evaluate if Dara-RD or VRD-lite (i.e., revised VRD with lower intensity of therapy) is the preferred induction regimen and whether the addition of a fourth drug is beneficial among patients with NTEMM.

Unspecified NDMM

We identified 23 SRs examining the efficacy of different interventions for unspecified NDMM. Old bisphosphonate drugs, such as etidronate, clodronate, pamidronate, and ibandronate, had no impact on MM mortality,[76] whereas zoledronic acid improved OS [77]. Evidence suggested that daratumumab-based regimens improved PFS for patients with TEMM and NTEMM [14]. While one network meta-analysis concluded that lenalidomide maintenance appears to be the best treatment option, compared with thalidomide- or bortezomib-based regimens, the results in fact were not statistically significant [78]. Also, ixazomib maintenance therapy, compared to no maintenance therapy, improved PFS for patients with TEMM and NTEMM [79]. Future research comparing daratumumab or ixazomib with lenalidomide-based maintenance therapy is needed.

Concerning issues in SRs

We identified five concerning issues (Table 3). First, six reviews made some errors during the data abstraction stage [13,15–18,35]. Four reviews included duplicate studies, [15–18] even though the authors stated that two reviewers independently conducted data abstraction. Riccardi 1994 [80] is a subset study of Riccardi 2000 [20], and Musti 2003 [81] of D’Arena 2011 [82]; yet these were included as separate studies. One SR stated that it only included RCTs in their review, [35] yet an included study was in fact a retrospective matched case-control analysis [83]. One SR examined maintenance therapy for NTEMM, [13] but the population in one RCT was eligible to transplant [84].

Table 3: Concerning issues in existing systematic reviews

Second, five reviews applied an inappropriate meta-analytic approach [34,38,52,55,85]. Specifically, these authors calculated the outcomes of interest (complete response rate or PFS) for two groups in which patients were from different studies, and made conclusions based on the comparisons between the estimates. The conclusions are invalid as these reviews not only ignored the clustering within some head-to-head trials, but also did not account for the differences in baseline characteristics between the two groups.

Third, nine reviews [9,54,55,59,61,86–89] included RCTs in which patients who received two different consolidation/maintenance treatments but underwent different and non-comparable pre-maintenance therapies, and no stratification was performed. Given that the final outcomes could be related to the combined effect of both induction and maintenance in these trials, these RCTs are inappropriate for evaluation of consolidation/maintenance therapies.

Fourth, 24 reviews examined the efficacy of different interventions for unspecified NDMM [14,68,76–79,85,87–103]. The authors of these SRs did not separate TEMM and NTEMM, partially because the enrollment eligibility criteria of the original research included both TEMM and NTEMM. However, 13 SRs combined TEMM and NTEMM without conducting subgroup analyses by transplant status, which implicitly assumed that the treatment effect is similar for both groups [76,77,87,90–92,94,95,97,99–101,103]. Thus, the results of these SRs need to be interpreted with caution.

Fifth, 17 reviews included observational studies or single arm trials in their meta-analysis [9,10,34,35,38,39,46,50,52,55,56,85,99,100,104–106]. It is well known that for SRs of treatment efficacy, RCTs are more appropriate than observational studies, which are subject to selection bias.8 Thus, the conclusions based on these SRs may not be accurate. Furthermore, only two [9,10] of these 17 reviews assessed the strength of evidence (very low level of evidence in one [10] and unclear assessment in another [9]), making it difficult for appropriate interpretation of the reviews’ conclusion.

Discussion

This umbrella review systematically summarized and appraised the evidence for NDMM treatments. Eighty-seven reviews on NDMM treatments were included in the analyses, which showed that bortezomib-based induction regimens for transplant-eligible patients, daratumumab in the induction regimens for transplant-ineligible patients, and lenalidomide maintenance for NDMM were supported by a moderate or high level of evidence. Meanwhile, we identified five concerning issues which may compromise the validity of the review’s conclusion. Building upon two previous overviews^4,5, this study provides updated evidence regarding treatment efficacy for NDMM, which can help physicians make treatment recommendations. The results of this umbrella review were largely consistent with the National Comprehensive Cancer Network (NCCN) guidelines (category 1 or 2B) [107]. This includes VRD or Dara-VRD as the induction therapy for TEMM, autologous HCT for TEMM, VRD, Dara-RD, or Dara-VMP as the primary therapy for NTEMM, and lenalidomide or ixazomib for maintenance therapy. There are, however, some discrepancies between NCCN guidelines and our review. First, VMPT is not listed as one of the primary therapies for NTEMM in NCCN guidelines, even though there is moderate evidence to support its use. This is largely because the NCCN is a US-based guideline alliance, and US practices seldom, if ever, use melphalan or thalidomide in the era of novel agents due to toxicity profiles. Second, meta-analyses of two RCTs demonstrated the benefits of adding daratumumab for induction therapy in TEMM patients, [14,62,108] yet daratumumab-based regimens were not listed in category 1/2B regimens for TEMM. This is partly because GRIFFIN was a phase 2 trial and was not powered for PFS or OS. The PFS benefits were mainly driven by the CASSIOPEIA trial conducted in Europe, which utilized thalidomide [62]. It is worth examining the role of daratumumab induction for TEMM in the US, where lenalidomide is part of the standard care. Lastly, although carfilzomib is primarily seen as a replacement for bortezomib, evidence suggested that carfilzomib-based regimens do not improve OS and PFS compared to bortezomib-based regimens for NTEMM [75] or TEMM [109]. One caveat to note is that the ENDURANCE trial excluded patients with high-risk cytogenetics. Thus, the existing data does not completely inform us of the comparative efficacy of carfilzomib versus bortezomib-based triplet in this subset of patients. Our study indicated that most existing systematic reviews had some weaknesses that need attention. First, only 8% of the SRs identified assessed the strength of evidence. Even among the SRs published after 2014 (as the GRADE instrument was introduced in 2011), [8] 10% of them evaluated the strength of evidence. We identified five concerns compromising the review's validity. Although the SRs’ quality was fair based on the AMSTAR checklist, the issue of inappropriate data abstraction wasn't easily identified. Addressing this requires journal editors and reviewers to thoroughly review all eligible studies, highlighting the challenges in evaluating SR quality. We're not against SRs of observational studies. When data from RCTs are unavailable, well-conducted observational study SRs offer the best evidence. Yet, SRs of observational studies, without assessing evidence strength, can lead to inappropriate interpretation, especially concerning treatment efficacy.

Opportunities for future research

Our study identified important gaps in the literature which warrant further research (Table 3). As treatments for MM have evolved rapidly, effective treatments documented from early trials/SRs are likely to be outdated. Since novel agents are used as the standard of care, future research could examine new combinations that improve outcomes. Additionally, ongoing and future research should examine whether new regimens could be used earlier, such as daratumumab for SMM, and CAR-T or bispecific T-cell engager therapy for TEMM to replace transplant. Furthermore, the ongoing debate regarding the relative efficacy of quadruplet versus triplet regimens is a significant point of contention within the field. Unfortunately, a scarcity of systematic reviews exists on this topic, primarily due to the short-term follow-up for quadruplets and many trials still being in the early phase. Only a handful of SRs conducted meta-analyses or subgroup analyses by patients’ characteristics [10,15,39,42,110]. Future research should examine the treatment efficacy by an individual’s risk due to the current movement towards personalized medicine. Collaborative effort in conducting IPD meta-analyses is needed since they are more appropriate than traditional meta-analyses, with or without meta-regression for subgroup analyses. As MM diagnostic and classification criteria evolve [111–113] future studies must consider these changes to ensure consistent interpretation and application of research findings in a clinical setting. Diagnostic and risk-stratification criteria changes can influence the patient population included in trials and the generalizability of study outcomes. For example, recent inclusion of biomarkers like involved/uninvolved free light chain ratio and percentage of bone marrow plasma cells in MM diagnostic criteria has led to more SMM patients being diagnosed with clinical multiple myeloma [114]. These shifts must be accounted for in future studies to capture the disease’s full spectrum accurately, thereby better informing the development and implementation of treatment strategies and ultimately improving patient outcomes. The treatment landscape is evolving with innovative therapies, yet international disparities in drug approval and usage persist due to varying regulatory environments, drug availability, and differences in healthcare systems and funding mechanisms. For instance, lenalidomide plays a crucial role in the treatment protocols for newly diagnosed and relapsed MM patients in the United States, [115] serving both as an induction and maintenance therapy. Yet the National Institute for Health and Care Excellence (NICE) has limited the use of lenalidomide to specific scenarios due to cost-effectiveness concerns [116,117]. This discrepancy underscores the need for ongoing comparative research to understand how the same evidence base can lead to different treatment landscapes in different countries and their impact on patient outcomes worldwide. While the present umbrella review is the most comprehensive overview for treatment for NDMM, several potential limitations should be acknowledged. First, despite our search strategy encompassing multiple databases, we cannot eliminate the possibility of missing relevant systematic reviews. Second, evidence summarized in our overview was limited to results of published SRs. For example, results from well-conducted individual RCTs which have not been analyzed in SRs were not included, even though these RCTs could provide evidence with moderate strength. Nevertheless, this overview’s evidence base has a degree of overlap among the included SRs, which allowed us to compare and corroborate the results and conclusions from different studies. Third, our overview did not evaluate side effects from interventions for NDMM, nor efficacy of interventions for RRMM. Future umbrella reviews of these topics could help treatment decision-making.

Conclusion

Our overview reveals that treatment strategies for NDMM are evolving rapidly with significant advancements in therapeutics. We identified several methodological issues in existing SRs, indicating the need for further robust and systematic investigation. Because SRs play a pivotal role in clinical guideline development, future SRs should avoid the issues we have identified.

Acknowledgments

This work was supported by U01 CA265735 from the National Cancer Institute of the National Institutes of Health. The sponsor had no role in the design and conduct of the study, collection, management, analysis, or interpretation of the data, or the preparation, review, or approval of this manuscript.

Declaration of interest

Dr Schoen reported receiving personal fees from Pfizer and ConcertAI outside the submitted work. Dr Ma served as a consultant for Bristol Myers Squibb. Dr Colditz reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Wang reported receiving grants from the American Cancer Society outside the submitted work. Dr Neparidze received research funding (institutional) from Janssen and GSK. None of these interests were related to the development of this manuscript. The remaining authors declare no competing financial interests.

Data Availability Statement

The data underlying this article are available in the article and PubMed database.

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