Multiple myeloma (MM) is a rare, incurable hematologic malignancy that demands ongoing innovation in treatment approaches given frequent disease relapse and refractory treatment. Recent regulatory approvals for label expansions of MM products such as idecabtagene vicleucel (ABECMA®) [1] and ciltacabtagene autoleucel (CARVYKTI®) [2] have targeted relapsed/refractory MM, while approvals for isatuximab (SARCLISA®) [3] and daratumumab in combination with bortezomib, lenalidomide, and dexamethasone (DARZALEX FASPRO®) [4] have targeted newly diagnosed patients. The generation and incorporation of real-world data and evidence (RWD/E)—evidence derived from routine clinical practice rather than interventional trials (e.g., electronic health records [EHR])—has gained momentum in regulatory applications and decision-making. This trend is particularly evident in MM, a disease characterized by frequent cycles of remission and relapse and a rapidly evolving standard of care (SoC) that increasingly challenges the feasibility and relevance of traditional randomized clinical trial (RCT) designs.

Passage of the 21st Century Cures Act in late 2016 opened the door to use of RWE in support of regulatory applications [5]. Additionally, both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have issued guidelines [6, 7] outlining the application of RWE in regulatory contexts, including initial marketing authorization, post-approval studies, and label expansions. One purpose of RWE is to support applications in areas where traditional trial designs may be challenging. The FDA has indicated that RWE may be particularly useful in oncology and other rare diseases [8]. Given that MM comprises <2% of all cancers and has limited treatment options in advanced stages [9], it is particularly well-suited for regulatory approaches that leverage RWE. For example, approvals based on evidence from single-arm trials can be strengthened by comparing them to a non-interventional group of patients receiving standard care in routine clinical settings. Additionally, demonstrating unmet need for oncologic treatment may require the use of routinely collected longitudinal clinical data, such as that found in EHR systems [10].

Two common pre-authorization applications of RWE in MM include the natural history study (NHS) and external comparator arm (ECA). A NHS consisting of longitudinal RWD may be particularly helpful in demonstrating limited treatment options and unmet need in MM, a requirement to pursue accelerated approval pathways. For example, in the 2022 marketing application of ciltacabtagene autoleucel submitted to EMA, the sponsor provided RWE sourced from EHR retrospective chart review data to demonstrate limited treatment options and worse outcomes for patients diagnosed with multiple myeloma refractory to anti-CD38 monoclonal antibodies (MAMMOTH study) [11, 12]. In their review, EMA acknowledged the contribution of the RWD study in providing important context for interpreting the trial results.

In MM, conditional product approval may be granted based primarily on results from single-arm Phase 2 trials with supportive evidence from an ECA comprised of RWD. Recent examples of this ECA approach, including the Phase 2 trials for idecabtagene vicleucel (KarMMA-3) [13], elranatamab (MagnetisMM-3) [14, 15], and invoseltamab (LINKER-MM1) [16], reflect regulatory acceptance of single-arm trials in heavily pre-treated multiple myeloma populations where there is high unmet need and limited treatment options. In such cases, the role of the ECA is typically to “benchmark” or indirectly compare the trial results in the absence of a trial control arm, which may be infeasible or unethical.

The increasing trend in the use of RWD/E in MM is highlighted by the number of recent regulatory approvals that were informed by sponsors who submitted RWE as part of the application. An analysis of MM approvals and accompanying regulatory reviews by FDA and EMA between January 2021 and April 2025 demonstrates that of 27 drug marketing applications for products treating MM approved during this time (FDA: n = 13, EMA: n = 14), 12 (44.4%) used RWE to support regulatory approval (Fig. 1). Of these 12 approvals, 8 (66.7%) included evidence from a NHS and 4 (33.3%) included evidence from an external comparator arm (Fig. 1). Table 1 shows the 7 products approved during the study period by approvals in line of therapy. Approximately half (50%) of the individual therapies were originally approved in later lines of therapy but had successive approvals in earlier lines of therapy during the study period. MM approvals including RWE in their application were predominantly in advanced lines of therapy, with 10 (83.3%) of approvals in the fourth-line of therapy or higher (Table 1). Supplementary Table 1 highlights RWE-related study details used in the 12 approved drug marketing applications.

Fig. 1: FDA and EMA MM Drug Approvals With RWE (January 2021–April 2025).
figure 1

FDA U.S. Food and Drug Administration, EMA European Medicines Agency, MM multiple myeloma, RWE real-world evidence.

Full size image
Table 1 Use of RWE in FDA and EMA Drug Approvals in MM by Regulatory Review Pathway and Line of Therapy (January 2021–April 2025).
Full size table

The ability of RWD to inform and support regulatory applications heavily depends on data quality. Regulators have indicated that data to support regulatory submissions must be both relevant (containing the appropriate study population and key study variables) and reliable (data must be complete, accurate, and traceable) [17]. In studies of MM, this means that sources of RWD must clearly and completely capture critical treatment variables such as line of therapy, eligibility criteria that indicate evidence of progression or disease stage, as well as endpoints such as real-world overall response rate and progression-free survival. Additionally, as companies seek competitive advantage of their treatment in the market, a treatment’s safety profile becomes increasingly relevant, which relies on the RWD source’s ability to identify treatment-emergent adverse events.

Promises of RWE in MM notwithstanding, RWE is not always well-received by regulators due to poor data quality, data source heterogeneity, and other methodologic limitations. For example, in the 2021 BLA submission of idecabtagene vicleucel (Abecma®), the sponsor included a global non-interventional retrospective study (NDS-MM-003) to compare the outcome of the MM-001 trial [13] with a real-world cohort of relapsed and refractory myeloma patients treated with standard therapies. Patient level data from clinical sites, registries and research databases was pooled into a single dataset. FDA flagged concerns with pooling multiple heterogeneous data sources as well as differences in follow-up time and response assessment between the studies, and concluded the RWD was inadequate to provide contextualization of the outcomes of the MM-001 trial [18]. In the years since Abecma’s FDA approval in 2021, FDA has developed additional industry guidance and publications around RWE, including final draft guidances in RWE to support regulatory decision-making and the Oncology QCARD [8]. A consistent theme in these publications is the importance of demonstrating a particular source of RWD is fit-for-purpose by its ability to effectively demonstrate the relevance, reliability, and generalizability for a particular use case. The data quality bar for regulatory use cases is high, and few available data sources provide sufficient capture of key variables needed for RWE studies in MM. Both FDA and EMA acknowledge that RWE may be better used as supportive evidence versus substantial evidence in an application, which may compel a sponsor not to prioritize inclusion of RWE in an application unless they believe the evidence would strengthen their application. Moreover, in settings where a traditional RCT is more feasible—such as earlier lines of treatment—a sponsor may have less need to rely on RWE, unlike in later lines of therapy where conducting an RCT may be impractical.

In conclusion, the contribution of RWE to MM development programs will continue to play a vital role in informing and shaping future treatment approaches. In alignment with FDA and EMA guidances, sponsors interested in leveraging RWE in their drug development programs for regulatory decision-making are strongly encouraged to engage with health authorities early and often around the intended use case. Fit-for-purpose and feasibility assessments demonstrating how a RWD source is relevant, reliable, and generalizable are critical for successful early engagement with regulators around potential use cases in MM. High-quality data that supports robust real-world evidence (RWE) will remain essential in advancing MM therapy development, offering critical insights and context in areas where data are scarce and patient needs are most urgent.