Real-world evidence in the multiple myeloma treatment landscape

July 15, 2021

Authors: Dawn Marie Stull, PharmD, BCOP, Scientific Director, Global Medical Affairs, Takeda Oncology and Dasha Cherepanov, Associate Director, Global Outcomes Research, Takeda Oncology

In our time at Takeda Oncology, we’ve had the opportunity to observe how real-world evidence (RWE) obtained outside of randomized controlled trials (RCTs) has been playing an increasingly important role in understanding treatment options for patients, especially in the field of multiple myeloma research. We’ve been involved in Takeda’s global INSIGHT MM study – the largest prospective, observational study in multiple myeloma to date – as well as Optum electronic health record (EHR) database studies, which have allowed us to see the importance of RWE in understanding the full patient journey firsthand.1-2 In recent years, there has been an increase in recognition of the need for RWE across the spectrum of health care information users, with organizations and companies undertaking RWE initiatives that further inform treatment research.

While both provide distinct value on their own, jointly assessing data from RWE studies and RCTs helps provide a comprehensive understanding of treatment effectiveness and safety and ultimately, better informed prescribing decisions. Looking at RWE in combination with RCT data can be particularly helpful in uncovering key evidence around how multiple myeloma patients respond to their treatments and how these treatments impact their day-to-day lives. RWE is complex, and as with RCT data, understanding the utility and limitations of RWE study results is critical to proper application of these understandings to the goal of improving patient care for those battling multiple myeloma.

The Current State of RWE

RCTs remain the gold standard for evaluating a treatment’s safety and efficacy in highly-selected patient populations, while observational studies provide insights into treatment effectiveness in heterogenous patient populations.3 While the strict inclusion and exclusion criteria of RCTs allows researchers to measure the efficacy of an intervention without the interference of external factors,4-5 RWE has the ability to bridge the gaps inherent to the highly structured nature that exists within RCTs.

Differences Between Randomized Clinical Trials and Real-World Evidence Studies

Clinical Trials3

Real-World Evidence Studies3

  • Evaluate treatment efficacy in select patient populations and have good internal validity
  • Stringent inclusion / exclusion criteria
  • Under-representation of elderly, comorbid and patients from lower socioeconomic backgrounds
  • Under-representation of community centers
  • Protocol-driven dose modification may lead to better tolerability and longer duration of therapy
  • Less likely to experience selection bias due to blinded and randomized design
  • Provide insight into treatment effectiveness in heterogeneous patient populations
  • Includes patients with more comorbidities and trial-ineligible patients
  • Capture patient and physician preference and motivation
  • Incorporate different distribution of academic vs. community centers
  • Capture tolerability / convenience factors that contribute to premature discontinuation
  • More likely to include selection bias and confounding variables

Additional RWE benefits include:

  • Broader Patient Inclusion Criteria: Approximately 25% to 73% of people living with multiple myeloma are ineligible for RCTs for reasons such as advanced age, frailty, comorbidities, organ dysfunction and lack of accessibility – factors that are often characteristic of the typical myeloma patient.2-3,6-13 The freedom to enroll a broader patient population for RWE studies – not just those who are healthy or local enough to participate in RCTs – allows for the generation of more data, including critical information for frail and unfit patients excluded from RCTs
  • Patient-Focused Findings: By eliminating the rigorous protocol-driven RCT management, RWE allows research to capture the reality of how a treatment can impact patients’ everyday lives. RWE findings thus allow patients to be involved in their treatment and provide direct insights
  • Timely Results: RWE studies can be completed relatively promptly for broad patient populations, which allows its complementary data to be available within a shorter timeline compared to RCTs, further providing valuable insights into optimizing individualized patient care

Despite its many benefits, RWE is still often misunderstood and can be incorrectly viewed as unreliable. Though real-world studies are becoming more commonly relied upon by healthcare decision-makers, questions remain regarding the validity of RWE, with many citing a lack of a centralized, standard methodology. Although these concerns are understandable, it’s important to note that both the European Medicines Agency (EMA) and the United States (U.S.) Food and Drug Administration (FDA) have recently developed guidance for RWE in an effort to validate the importance of these studies and provide additional structure for their implementation.14-15

Different Types of RWE Observational Study Designs

It is important to understand that not all RWE is created equal. The term encompasses a variety of different data sources and study design types, each of which can be used to answer different research questions and possess different advantages and disadvantages.

RWE studies are typically observational studies, including cross-sectional, prospective and retrospective cohort study designs. All three of these types of studies provide value in understanding treatment effectiveness and other patient outcomes, and it is important to design the study appropriately to address research questions of interest. Real-world studies can tell different parts of the story by drawing on a variety of existing data sources, such as product and disease registries, insurance claims databases and EHRs.

Advantages and Disadvantages of Observational Designs

Observational Study  Design


Advantages Include:

Disadvantages Include:


  • Collects data at a single point in time
  • Most time efficient
  • Inability to examine cause and effect16


  • Follows up with patients longitudinally and collects data over a period of time16
  • Examines patient outcomes over time, as their characteristics and circumstances evolve 16
  • Time consuming
  • Confounding and information bias
  • High likelihood of loss of patients to follow up16


  • Conducted when patient follow‑up has already occurred16
  • Quicker data collection or access, execution of statistical analyses & results16
  • Relatively higher risk of confounding and information bias16

While cross-sectional, prospective or retrospective study designs are most commonly used, these categories don’t necessarily capture designs of real-world studies but represent those that are commonly used. Through its many forms, RWE provides an extensive resource of information and can be used in conjunction with what is learned through RCTs to tell the full story of a patient’s treatment experience and help optimize and individualize patient care.

Continuing to Embrace RWE in the Multiple Myeloma Space

As with any form of growth or change, adjusting to a healthcare landscape that uses RWE in decision making will not be a simple, nor a linear process. We all must work together to find ways to effectively incorporate this information to facilitate drug development and optimize treatment selection for patients.  We must continue to innovate, acknowledging the challenges with RWE but also understanding the benefits it provides by highlighting important aspects of patient care that may be difficult to address and thus are commonly not captured in the context of RCTs.

As we work with our peers and colleagues in the industry to align on a common understanding of the opportunities and challenges RWE presents, we think of the nearly 450,000 people around the world currently living with multiple myeloma and are reminded that there are patients who still have critical treatment needs.17 RWE allows us to continue to improve care for all patients within the multiple myeloma space, particularly the many whose personal journeys are not addressed by RCTs. We invite you to join us in embracing new methods of understanding the patient story as we continue to discover new ways to provide transformative solutions for multiple myeloma patients.



1Costello C. et al. INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma. Future Oncol. 15,13. 2019:1411-1428.

2 Chari A. et al. Real-world outcomes and factors impacting treatment choice in relapsed and/or refractory multiple myeloma (RRMM): a comparison of VRd, KRd, and Ird. Expert Rev Hematol. 4. 2020:421-433.

3 Richardson, P.G., San Miguel, J.F., Moreau, P. et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer Journal. 8,109. 2018

4 Garrison LP Jr et al. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 10,5. 2007;326-35.

5 Makady A. What Is Real-World Data? A Review of Definitions Based on Literature and Stakeholder Interviews. Value Health. 2017;20:858-65

6 Lawrence, Ryan. Healio. Recommendations are ‘call to action’ for African American inclusion in myeloma trials. https://www.healio.com/news/hematology-oncology/20210223/recommendations-are-call-to-action-for-african-american-inclusion-in-myeloma-trials?utm_source=selligent&utm_medium=email&utm_campaign=news&M_BT=5055199939669. Accessed on March 5, 2021.

7 Mohty, Mohamad et al. Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study. Clinical lymphoma, myeloma & leukemia.18,10 2018: e401-e419.

8 Terpos, E., Mikhael, J., Hajek, R. et al. Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life. Blood Cancer J. 11, 40. 2021.

9 Malecek MK et al. Multiple Myeloma Patients Ineligible for randomized Controlled Trials Have Poorer Outcomes Irrespective of Treatment. 18, 9. 2018: e363-e364.

10 Knauf W. et al. Survival of non-transplant patients with multiple myeloma in routine care differs from that in clinical trials-data from the prospective German Tumour Registry Lymphatic Neoplasms. Annals of Hematology. 97,12. 2018: 2437-2445.

11 Hungria HTM, et al. Real-World (RW) Multiple Myeloma (MM) Patients (Pts) Remain Under-Represented in Clinical Trials Based on Standard Laboratory Parameters and Baseline Characteristics: Analysis of over 3,000 Pts from the Insight MM Global, Prospective, Observational Study. Blood 134(Supplement_1):1887. 2019

12 Wagner Lynne I. Clinical Outcomes and Health-Related Quality of Life (HRQoL) Among Randomized Clinical Trial (RCT)-Eligible and RCT-Ineligible Patients: Results from the Connect® MM Registry. Blood 134,1. Abstract 1843. 2019

13 Shah JJ et al. Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes. Clin Lymphoma Myeloma Leuk. 17,9. 2017:575-583.

14 Czarska-Thorley, D. 2020. Guideline on registry-based studies. https://www.ema.europa.eu/en/guideline-registry-based-studies. Retrieved March 19, 2021

15 https://www.fda.gov/media/120060/download.

16 Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emergency Medicine Journal. 20. 2003: 54-60. http://dx.doi.org/10.1136/emj.20.1.54

17 International Agency for Research on Cancer. Globocan 2018: Estimated Cancer Incidence, Mortality and Prevalence in 2018. 2020. https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf.  Accessed on March 5, 2021.