A network meta-analysis of randomized clinical trials in lenalidomide-exposed or -refractory multiple myeloma patients.

Introduction

Over the past few decades, the therapeutic landscape of multiple myeloma (MM) has undergone significant advancements, driven by the introduction of a wide array of novel agents. The integration of these agents into clinical practice has substantially improved patient survival outcomes in both the frontline and relapsed/refractory (RR) settings. 1

Lenalidomide, an immunomodulatory drug (IMiD), represents a therapeutic milestone in MM treatment. It is an integral component of first-line therapy for transplant-eligible (TE) younger patients undergoing first-line therapy with daratumumab–bortezomib–lenalidomide–dexamethasone (DaraVRd), 2 as well as for transplant-ineligible (TI) patients, where it is commonly combined with daratumumab and dexamethasone (DRd), 3 bortezomib and dexamethasone (VRd), 4 isatuximab, bortezomib, and dexamethasone (IsaVRd), 5 or DaraVRd. 6 Despite the prolonged progression-free survival (PFS) and depth responses achieved with these regimens, 7 , 8 disease relapse remains common.

In the RRMM setting, proteasome inhibitors (PIs), such as carfilzomib and ixazomib, 9 , 10 the IMiD, pomalidomide, 11 , 12 as well as monoclonal antibodies (mAbs), including daratumumab, isatuximab, and elotuzumab, 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 have become key components of salvage therapy. Moreover, the treatment armamentarium has expanded with the advent of novel drugs such as selective inhibitors of nuclear export (selinexor), drug-conjugated mAbs (e.g. belantamab mafodotin), bispecific antibodies (BsAbs), and chimeric antigen receptor T-cell (CAR-T-cell) therapies, which have recently gained regulatory approval, as monotherapies or in combination regimens, providing additional promising therapeutic choices. 21 , 22 , 23 Despite the growing availability of therapeutic agents, there remains a paucity of data from large-scale clinical trials to guide an optimal treatment selection upon disease relapse. Indeed, for patients progressing after lenalidomide-based therapy, a range of lenalidomide-sparing regimens are available, including the doublet carfilzomib–dexamethasone (Kd), 24 and several triplet combinations such as daratumumab–bortezomib–dexamethasone (DVd), 25 daratumumab–carfilzomib–dexamethasone (DKd), 26 pomalidomide–bortezomib–dexamethasone (PVd), 27 selinexor–bortezomib–dexamethasone (SVd), 28 and more recently, belantamab mafodotin-based combinations such as belantamab mafodotin–bortezomib–dexamethasone (BVd) 29 and belantamab mafodotin–pomalidomide–dexamethasone (BPd). 30

Previously, we conducted a network meta-analysis (NMA) of lenalidomide-sparing regimens in RRMM patients who were either lenalidomide exposed or refractory. 31

Given these evolving treatment options, we conducted an updated systematic review and NMA incorporating recently published phase II/III randomized clinical trials. This study aims to provide a comprehensive comparative assessment of second-line lenalidomide-sparing regimens in patients with RRMM previously exposed or refractory to lenalidomide, integrating both direct and indirect evidence to support optimal treatment selection. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31

Materials and methods

Search strategy

A systematic electronic search was conducted using PubMed, Embase, Ovid, the Cochrane Collaboration database, and proceedings from major international hematology and oncology meetings. Only prospective studies were included in this analysis. 32 The following search terms were used: ‘multiple myeloma’, ‘relapse’, ‘refractory’, ‘randomized clinical trial’, ‘management’, ‘lenalidomide-exposed’, ‘lenalidomide-refractory’, and ‘therapy’ in different combinations (e.g. ‘relapsed/refractory multiple myeloma’). Titles and abstracts were screened for relevance. Additionally, reference lists, related articles, and Google Scholar citations were reviewed to identify additional relevant publications. Only English-language articles were considered. The final literature search was last conducted on 31 December 2024. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 33 , 34

Inclusion and exclusion criteria

To be eligible, studies had to meet the following inclusion criteria:

Enrolled patients diagnosed with RRMM receiving second-line treatment.

Randomized controlled trials (RCTs), regardless of blinding status.

Abstracts or unpublished data that provided sufficient details on study design, patient characteristics, interventions, and outcomes.

Experimental arms investigated novel or unconventional regimens, while control arms comprised standard RRMM treatments.

Studies were excluded if they:

Were non-comparative or non-prospective.

Did not report relevant outcomes.

Had an unclear methodology.

Focused solely on patients receiving treatment beyond the second-line treatment.

Data extraction and quality assessment

Three independent reviewers (EAM, GC, and MG) assessed the literature based on predefined criteria.

The following data were extracted:

Study details (first author, year).

Patient characteristics (sample size, prior exposure to lenalidomide).

Treatment regimens and outcome measures including hazard ratios (HRs) for PFS.

Each reviewer independently recorded data in separate databases, which were subsequently cross-checked to minimize bias through consensus discussions. The database was reviewed by three investigators (EAM, GC, and MG), and duplicates were removed. Any discrepancies were resolved by discussion.

Study quality was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions, 35 by assigning 1 point for each of the following criteria: randomization, allocation concealment, blinding, withdrawal/dropout reporting, and follow-up adequacy. Studies were classified as high quality (A: 4-5 points), moderate quality (B: 2-3 points), or low quality (C: 0-1 point). 36 , 37 Publication bias was assessed by using Egger’s test 38 or Begg’s test, 39 along with visual inspection of funnel plots.

NMA framework

To ensure a comprehensive assessment of treatment efficacy, both Bayesian and frequentist NMA approaches were independently conducted by GC and DL. The Bayesian framework generated probabilistic treatment rankings, while the frequentist method served as a cross-validation tool to ensure the robustness of findings.

The Bayesian NMA was carried out with STATA software (2023, Stata Statistical Software: Release 18, StataCorp LLC, College Station, TX) by using the mvmeta package. NMA integrates direct and indirect comparisons, allowing treatments to be ranked according to their relative efficacy. PFS was used as the primary outcome, and Bayesian NMA was carried out using a random effects (RE) model with a Markov Chain Monte Carlo simulation (30 000 iterations).

Loop inconsistency and heterogeneity were assessed by evaluating the logarithm of the ratio of two odds ratios (RoR) from direct and indirect evidence. 40 , 41 RoR values close to 0 indicate good agreement between direct and indirect evidence. The heterogeneity of the loop was then assessed through the restricted maximum likelihood method. 40 , 41

Relative treatment effects are reported as HRs for PFS with corresponding 95% credible intervals (CrIs), the Bayesian equivalent of 95% confidence intervals (CIs). Ranking probabilities and surface under the cumulative ranking curve (SUCRA), which provides a numerical summary of the rank distribution of each treatment schedule on the different endpoints, were used to provide hierarchy probabilities. 39 , 40 , 41 The higher SUCRA values (closer to 1) indicate superior efficacy.

Given the limited number of included trials, a sensitivity analysis using a frequentist approach 42 was carried out to assess the robustness of our primary Bayesian NMA. This analysis was conducted using the netmeta package in R 43 and employed an RE model to the same dataset. HRs for PFS, with corresponding 95% CIs, were used for pairwise treatment comparison. Treatment ranking was based on P-scores, a metric analogous to SUCRA, 37 while inconsistency was evaluated using a modified DerSimonian–Laird estimator for τ 2 . In order to summarize the results, a heatmap was generated using GraphPad.

The present NMA was not registered in the PROSPERO international prospective register of systematic reviews.

Results

Study selection

The PRISMA flowchart illustrating RCT selection and the search strategy is shown in Supplementary Figure S1 , available at https://doi.org/10.1016/j.esmoop.2025.105514 . Over 11 years (from 2014 to 2025), the systematic literature search initially identified a total of 3328 items including full articles and abstracts from meetings, which, after an initial screening, were reduced to 2420 potentially relevant studies following the exclusion of 908 review articles. Further refinement of the selection process led to the removal of 2155 studies due to the absence of an appropriate comparator, study overlap, or reliance on Surveillance, Epidemiology, and End Results (SEER)-based analyses. A full-text evaluation was conducted on 265 studies, of which 257 were excluded due to trial design limitations. Ultimately, only eight trials, including 3952 patients, met the inclusion criteria and were incorporated into the NMA ( Table 1 ).

Quality assessment

To assess the methodological robustness of the included studies, a risk-of-bias evaluation was carried out using the Cochrane risk-of-bias tool ( Figure 1 A and B). The assessment revealed that most trials exhibited a low risk of bias, particularly in key domains such as randomization, allocation concealment, and outcome assessment. However, certain studies displayed an unclear or high risk of bias, mainly due to limitations in blinding and incomplete reporting of outcome data. These methodological weaknesses necessitate a cautious interpretation of findings, especially when relying on indirect treatment comparisons.

Network meta-analysis for progression-free survival

The total population size across studies varied, with the largest trial, ENDEAVOR, enrolling 929 patients, while the smallest, IKEMA, includes 302 patients ( Table 1 ). A key aspect of the various trials is the distinction between lenalidomide-exposed and lenalidomide-refractory populations. While all patients in these trials had prior exposure to lenalidomide, the proportion of those classified as refractory varies significantly. In particular, the OPTIMISMM trial, evaluating PVd versus bortezomib–dexamethasone (Vd), includes the highest number of lenalidomide-refractory patients (200 and 191 in the respective arms), reflecting a patient cohort with a more challenging disease biology. Similarly, the DREAMM-8 trial has a high proportion of refractory patients (125 and 111 in the BPd and PVd arms, respectively), suggesting that these regimens were tested in a heavily pretreated population. In contrast, studies such as IKEMA 44 and CANDOR have lower proportions of lenalidomide-refractory patients, which may influence the relative efficacy outcomes in these subgroups.

The inclusion of diverse treatment regimens, ranging from PI-based combinations (e.g. PVd, Vd) to mAb-containing regimens (e.g. IsaKd, DKd), underscores the evolving treatment landscape in RRMM. Notably, trials such as CASTOR and DREAMM-7 include daratumumab-based combinations, while BOSTON evaluates the addition of selinexor, reflecting the increasing incorporation of novel agents into standard-of-care backbones.

Figure 1 summarizes the risk-of-bias evaluation for the included trials using the Cochrane risk-of-bias tool. Figure 1 A illustrates the overall distribution of risk across key methodological domains. Most studies exhibited a low risk of bias in random sequence generation, allocation concealment, incomplete outcome data, and selective reporting. However, high risk was observed in the blinding of participants and personnel (performance bias) and the blinding of outcome assessment (detection bias), indicating potential limitations in study blinding procedures. Figure 1 B provides a study-level breakdown of bias across individual trials. While most studies demonstrated methodological rigor in randomization and allocation, a consistently high risk was noted for blinding-related domains. These findings highlight potential concerns regarding the influence of knowledge of treatment assignment on outcome assessment, which may affect the reliability of reported results.

A network plot was constructed to illustrate the direct and indirect comparisons between the evaluated therapeutic regimens ( Figure 2 ). The structure of the network highlights the heterogeneity in available evidence, with some treatment pairs having more direct comparisons than others.

A critical component of the analysis was the ranking of treatments based on PFS using SUCRA values. The SUCRA-based heatmap allowed a comparative assessment of treatment efficacy, with regimens achieving higher SUCRA values indicating superior performance in delaying disease progression. The heatmap visualization ( Figure 3 ) highlights a clear ranking gradient, with the most effective regimens at the top and the least ones at the bottom.

As depicted in Figure 3 , all triplet regimens included in this NMA demonstrated superior efficacy in terms of PFS compared with the doublet regimen Vd, with this benefit observed in both lenalidomide-exposed and lenalidomide-refractory patient populations. Conversely, the other doublet Kd exhibited comparable efficacy across both populations. Notably, the triplet regimen BVd emerged as the most effective treatment strategy in both subgroups, demonstrating a statistically significant advantage over other regimens. In the lenalidomide-exposed cohort, BVd achieved the highest ranking, with a SUCRA value of 100%, followed by DVd (SUCRA 87.1%), IsaKd (SUCRA 75.3%), and BPd (SUCRA 62.5%). In the pairwise comparisons, BVd demonstrated significant superiority over other regimens, as highlighted in the diagonal comparison of relative HRs ( Supplementary Figure S2A , available at https://doi.org/10.1016/j.esmoop.2025.105514 ). Specifically, when compared with DVd and IsaKd, BVd demonstrated a statistically significant progression risk reduction of 89% (HR 0.11, 95% CrI 0.10-0.11) and 90% (HR 0.10, 95% CrI 0.09-0.11), respectively. To note, although DVd showed a higher SUCRA ranking, no statistically significant difference was observed between DVd and IsaKd in terms of PFS. The comparison between BVd and BPd yielded even greater statistical significance (HR 0.08, 95% CrI 0.08-0.09). A similar trend was observed in the lenalidomide-refractory population ( Supplementary Figure S2B , available at https://doi.org/10.1016/j.esmoop.2025.105514 ). BVd remained the top-performing regimen, again achieving a SUCRA value of 100%, and a probability best value of 100%, followed by BPd (SUCRA 87.5%), DVd (SUCRA 74.6%), and IsaKd (SUCRA 62.8%). Looking at the relative HR, BVd maintained a statistically significant advantage across all pairwise comparisons, demonstrating an HR of 0.31 (95% CrI 0.27-0.35) compared with the second-best regimen, BPd.

Sensitivity analysis

To validate the Bayesian-derived treatment rankings and assess the impact of statistical assumptions, we conducted a frequentist NMA, which yielded results that were largely consistent with the primary Bayesian approach. Compared with Vd, all other regimens exhibited a significant benefit in terms of PFS ( Figure 4 ), with BVd demonstrating the greatest effect in both lenalidomide-exposed (HR 0.13, 95% CI 0.07-0.21) ( Figure 4 A) and lenalidomide-refractory patients ( Figure 4 B) (HR 0.16, 95% CI 0.08-0.33).

Treatment rankings based on P-scores were consistent with those obtained using SUCRA in both patient populations, reinforcing the robustness of our primary findings and further corroborating the superior efficacy of the triplet regimen BVd ( Supplementary Figure S3 , available at https://doi.org/10.1016/j.esmoop.2025.105514 ). In pairwise comparisons, the trends observed in the Bayesian analysis were essentially confirmed, although the HRs from the frequentist analysis were generally slightly higher ( Supplementary Figure S4 , available at https://doi.org/10.1016/j.esmoop.2025.105514 ). Specifically, in the lenalidomide-exposed subgroup, BVd achieved a significant reduction in the risk of progression with an HR of 0.33 (95% CI 0.23-0.48), when compared with the second-best combination DVd, while in the lenalidomide-refractory cohort, BVd demonstrated a statistically significant advantage over all other regimens except for BPd, where the HR was 0.56 but the 95% CI (0.24-1.28) crossed the threshold for statistical significance.

Discussion

Lenalidomide has long been the backbone of treatment for newly diagnosed MM (NDMM) patients. In TI patients, the MAIA study demonstrated that the triplet combination of DRd significantly improved PFS and overall survival (OS) compared with lenalidomide plus dexamethasone (Rd) alone. 45 Similarly, long-term follow-up of the SWOG S0777 trial confirmed the superiority of VRd over Rd, further reinforcing the role of triplet regimens in this setting. 46 As a result, DRd and VRd are now established as preferred treatment options for TI-NDMM patients. 1

In TE-NDMM patients, lenalidomide maintenance after autologous stem-cell transplantation is recommended by the European Society for Medical Oncology (ESMO) guidelines, 1 based on randomized trials demonstrating prolonged PFS and OS compared with placebo. 7 , 47 However, given the continuous nature of lenalidomide-based therapy until disease progression, a high rate of patients at first relapse are considered lenalidomide refractory. This evolving treatment paradigm challenges the conventional classification of ‘lenalidomide exposed’ versus ‘lenalidomide refractory’. True ‘lenalidomide-exposed’ patients are those who discontinue therapy due to toxicity rather than disease progression, whereas the majority of relapsed patients today are genuinely lenalidomide refractory.

Our updated NMA, incorporating recently available phase II/III RCTs, provides a comprehensive assessment of lenalidomide-sparing regimens for RRMM patients as second-line therapy. By integrating direct and indirect evidence, this study offers a nuanced evaluation of relative treatment benefits, addressing a crucial gap in the literature.

The results indicate that BVd emerged as the most effective treatment option for both lenalidomide-exposed and lenalidomide-refractory patients, achieving the highest SUCRA ranking. BVd outperformed other triplet regimens, including DVd, IsaKd, and BPd, highlighting the role of anti-B-cell maturation antigen (BCMA) therapies in improving disease control in patients who have exhausted lenalidomide-based regimens. Although DVd achieved a higher SUCRA ranking, no statistically significant difference in PFS was observed when directly compared with IsaKd.

This apparent discrepancy may reflect inherent limitations of the NMA methodology, which relies predominantly on indirect comparisons derived from individual RCTs. Such indirect evidence, while methodologically valid, can introduce potential biases due to heterogeneity across studies. In particular, differences in the proportion of lenalidomide-refractory patients among the included trials may have influenced treatment effects, despite overall similarity in baseline characteristics. These methodological considerations should be carefully weighed when interpreting the comparative efficacy of DVd and IsaKd.

A key unmet need remains in the lenalidomide-refractory setting, as current guidelines lack a definitive sequencing algorithm for second-line therapy. While drug class-switching is generally recommended, the absence of direct head-to-head comparisons between available therapies complicates clinical decision making.

To address this, our NMA included all approved lenalidomide-free regimens for RRMM patients, providing an evidence-based hierarchy of treatment efficacy. BVd consistently demonstrated superior PFS benefits in lenalidomide-refractory patients, reinforcing its role as a preferred treatment option in this challenging population.

Beyond BVd, the combination of daratumumab, pomalidomide, and dexamethasone (DPd) has shown clinical efficacy, as demonstrated in the APOLLO trial, where it reduced the risk of progression or death by 37% compared with pomalidomide–dexamethasone (Pd) alone. 48 However, although DPd is currently approved for use in the second-line setting, it was not included in our NMA, as its comparator arm (Pd) was not commonly employed in the other included trials, which predominantly used Vd or Kd as control arms. This limited its suitability for indirect treatment comparisons within the network. Notably, the 12-month PFS in APOLLO was 52%, whereas, in DREAMM-7, 29 it was 78%, suggesting a significantly better outcome with BVd. Nevertheless, while these results highlight DPd as an active regimen, the absence of a more widely used comparator makes it challenging to integrate within a broader treatment hierarchy.

Looking ahead, novel agents such as cereblon (CRBN) E3 ligase modulators (CELMoDs), including iberdomide and mezigdomide, offer promising alternatives for lenalidomide-refractory patients. 49 , 50 Ongoing trials, such as EXCALIBER RRMM and SUCCESSOR-1, are evaluating iberdomide- and mezigdomide-based regimens to overcome resistance mechanisms associated with prior lenalidomide exposure.

Similarly, the advent of BCMA-targeted CAR-T-cell therapy is reshaping the RRMM treatment landscape. Landmark trials such as KARMMA-3 51 and CARTITUTE-4 52 have demonstrated unprecedented PFS benefits in earlier lines of treatment. In CARTITUDE-4, which included lenalidomide-refractory patients from the second to the fourth line, median PFS was not reached at 15.9 months of follow-up, with a 30-month OS of 76.4% in the cilta-cel arm. 53 Given the design of the CARTITUDE-4 trial, which employed a heterogeneous ‘physician’s choice’ control arm, it was not feasible to include it in our NMA. As an increasing number of immunotherapy clinical trials adopt similar control strategies, future meta-analyses may face methodological limitations in deriving reliable indirect comparisons. Overall, these findings position CAR-T as a potential standard for fit patients at first relapse, particularly for those achieving sustained minimal residual disease negativity and seeking treatment-free intervals.

Beyond CAR-T-cell therapy, BsAbs have emerged as a transformative class, with three Food and Drug Administration-approved T-cell engagers (TCEs), demonstrating significant efficacy in heavily pretreated and triple-class refractory MM. 22 , 54 , 55 , 56 , 57 Although BsAbs are currently approved for third-line therapy and beyond, ongoing trials such as MajesTEC-3 ( NCT05083169 ) are investigating their use in earlier treatment lines, particularly for lenalidomide-refractory patients naive to anti-CD38 mAbs. 58 The expansion of BsAbs into earlier lines of therapy may further refine treatment sequencing strategies and offer novel options for patients with limited alternatives.

Although TCEs may represent a breakthrough in RRMM treatment, BVd remains a valuable option in resource-limited settings, where the access to new immunotherapies is restricted.

The increasing use of DRd in first-line therapy has led to a growing population of patients refractory to both lenalidomide and daratumumab (double refractory). With the approval of quadruplet regimens, such as DaraVRd and IsaVRd, as first-line therapy, this phenomenon may extend to TE patients as well. Unfortunately, data on double refractory patients remain scarce, relying mainly on real-world evidence and indirect comparisons. 10 , 15 , 16 , 17 , 18 , 19 , 20

Recently completed and ongoing trials—including MagnetisMM-5, 59 MajesTEC-9, 60 SUCCESSOR-2, 61 and MagnetisMM-32 62 —are investigating teclistamab-, elranatamab-, and mezigdomide-based regimens with the aim of defining therapeutic strategies for this difficult-to-treat population.

Both the Bayesian and frequentist approaches to NMAs yielded largely consistent results, reinforcing the robustness of our findings. While Bayesian estimates were more stable due to the integration of prior distributions, the frequentist approach showed greater uncertainty in sparse networks. Nevertheless, both methods consistently ranked BVd as the most effective regimen, with DVd, IsaKd, and BPd among the top treatments.

In conclusion, our NMA underscores the growing preference for triplet-based regimens over doublet combinations, with BVd emerging as the most effective option for lenalidomide-exposed and -refractory RRMM patients. Nevertheless, considering the known toxicity profiles associated with belantamab mafodotin and bortezomib—namely, ocular toxicity and peripheral neuropathy, respectively—real-world studies are warranted to assess the feasibility and tolerability of the BVd combination at full doses or according to scheduled administration. Additionally, evaluating the clinical effectiveness of reduced dose-intensity regimens would be of clinical relevance, given the need to balance efficacy with patient quality of life in routine practice. 63 , 64 A further limitation of our analysis lies in the underlying assumption that patient characteristics and clinical management strategies were sufficiently comparable across the included trials.

As the treatment landscape evolves with CAR-T, BsAbs, and CELMoDs, sequencing remains a critical challenge. Future studies should focus on refining treatment algorithms, integrating novel agents earlier, and assessing real-world outcomes to guide optimal RRMM management.

Acknowledgments

Funding

This work was partially supported by the Italian Ministry of Health—Ricerca Corrente Annual Program 2025 (no grant number).

Disclosure

The authors have declared no conflicts of interest.

Data sharing

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Contributor Information

A. Neri, Email: antonino.neri@ausl.re.it.

E. Vigna, Email: ernesto.vigna@aocs.it.

M. Gentile, Email: massimo.gentile@unical.it.

Supplementary data

Supplementary Data

References

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