Real-World Noninterventional Studies: Multiple Myeloma Paves the Way for Improved Clinical Trial Design

June 2021, Vol 12, No 3
Robert M. Rifkin, MD, FACP
Medical Director of Biosimilars
Associate Chair of Hematology Research
The US Oncology Network
Rocky Mountain Cancer Centers
Denver, CO

According to the American Cancer Society, nearly 35,000 new patients with multiple myeloma are diagnosed annually in the United States, with more than 12,000 deaths attributed to this cancer.1 However, with the introduction of several novel therapies, the outcomes for patients with newly diagnosed multiple myeloma have improved substantially over the past decade.

Recent data showed that the risk for death was 35% lower among patients newly diagnosed with multiple myeloma between 2011 and 2014 compared with patients diagnosed between 2006 and 2010.2 Although this noteworthy development coincides with the advent of novel agents and new treatment protocols, the 2017 results of the prospective, observational cohort study Connect MM Registry showed that more than 40% of patients newly diagnosed with multiple myeloma were not eligible to participate in clinical trials, based on common randomized controlled trial (RCT) exclusion criteria.3

Expanding RCT Eligibility with Real-World Evidence Studies

The growth of novel, personalized therapies and the complexity of the oncology landscape offer an opportunity to address the disparities associated with RCT eligibility criteria through the expanded use of real-world patient populations to capture data on the day-to-day benefits of drug therapies.

Evidence from real-world studies enables physicians to deliver efficient, cost-effective patient care by providing actionable insight into how treatments perform in clinical practice. Such care can be practice-changing, especially in the community oncology setting, where the delivery of high-quality services to large patient populations in a timely fashion is paramount.

Our recent study investigating the use of daratumumab (Darzalex) in US patients with multiple myeloma provides an excellent example of how real-world evidence can be used in combination with RCT data to bolster clinical knowledge.4,5 Daratumumab, a human immunoglobulin G1 kappa monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action, is approved for use in many lines of therapy for multiple myeloma throughout the patient’s journey.6 Since daratumumab’s approval, 2 additional approaches have been explored, including a split-dose treatment schedule and a shift to subcutaneous daratumumab.

Real-World Implications of Dosing Schedule Changes

Staffing and logistical issues can make long infusion times impractical in the outpatient setting. To manage the duration of the first infusion of daratumumab, my team developed a split-dose schedule to facilitate the administration of the first infusion during 2 consecutive days.4 Our retrospective, observational cohort study was designed to provide real-world insight into patients with multiple myeloma who are receiving daratumumab in a community oncology setting and to compare the infusion time and safety of a first split-dosing versus a single-dosing schedule for daratumumab.4

The study used the iKnowMed oncology electronic health record system, which captures outpatient medical histories from community oncology practices in The US Oncology Network that together manage approximately 1 million patients annually. A total of 622 patients with multiple myeloma from The US Oncology Network were included in the analysis, of whom 364 patients had a split first-dose schedule and 258 patients had a single-dose schedule.4

Although the total administration time of daratumumab was longer (median duration, 8.7 hours vs 6.5 hours) among patients who received the split-dose schedule, this study demonstrated that a shorter day-1 infusion schedule offers a viable treatment option for community oncology clinics and supports a more convenient approach to infusion for patients with multiple myeloma.4

These real-world results were validated in the multicenter, single-arm, open-label phase 2 LYRA clinical trial, which evaluated the depth of response and duration of treatment with the combination of daratumumab, bortezomib (Velcade), cyclophosphamide, and dexamethasone (DARA-CyBorD) in patients with newly diagnosed or relapsed multiple myeloma.7 The LYRA study showed that this 4-drug combination offered a safe and effective treatment option for patients with multiple myeloma. The study also demonstrated that the split-dose protocol is feasible and facilitates the administration of daratumumab in the community setting.7

An updated analysis of the LYRA study, which was presented at the 2019 American Society of Hematology annual meeting, concluded that maintenance treatment with daratumumab alone for 12 months after the DARA-CyBorD regimen increased the complete response rate in patients with newly diagnosed or relapsed multiple myeloma.8 These results were consistent with those of previous studies, that showed that extended maintenance of daratumumab treatment improves the depth of response.9-15 Of note, the increase in the complete response rate was linked to a durable progression-free survival (PFS) and overall survival.8

The 24-month PFS rates in patients with newly diagnosed or relapsed multiple myeloma were similar to the PFS rates observed with the combination of daratumumab, bortezomib, melphalan, and prednisone, as well as with daratumumab plus bortezomib and dexamethasone in patients with newly diagnosed or with relapsed or refractory multiple myeloma.8

Implications of Route of Administration

Long infusion times may have an adverse impact on a patient’s quality of life. In addition, infusion-related reactions are rather common for patients who are receiving daratumumab intravenously for multiple myeloma.6 The COLUMBA trial demonstrated that subcutaneous daratumumab was noninferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma.16 The indications for daratumumab therapy have now advanced into the front lines, and further advancements will likely incorporate real-world evidence.

Real-World Evidence Is Key to Improving Study Design

The ineligibility of patients for prospective clinical trials is not unique to multiple myeloma. Significant disparities exist in clinical trial participation, with oncology clinical trial populations skewing younger and healthier than the real-world patient populations.17

Although RCTs remain the gold standard for the assessment of drug safety and efficacy, clinical trials alone are not sufficient to accelerate desperately needed advances in cancer care. Real-world evidence must play an increasing role in drug development and evaluation, by providing critical information about how new oncology treatments perform in real-world clinical settings.

Real-world evidence has been used successfully to support new and supplemental indications, and may also have the ability to inform postmarketing use and safety monitoring, because adverse events for new drugs may not emerge until the treatments are available in clinical practice.

Observational real-world studies offer the ability to test treatment options on more representative patient populations, with fewer exclusions for common conditions that could affect outcomes in clinical practice. Such studies may augment new clinical data and support the ability to reduce the number of subjects assigned to the control arm in a randomized trial, or to conduct smaller randomized trials.

As pragmatic studies continue to demonstrate that real-world data can be analyzed and compared with the outcomes expected with an RCT in other areas of medicine, it is reasonable to expect that they can be effectively used in oncology as well. This observation will allow us to design broader clinical trials that will include more representative patient criteria than the current clinical trials population. These data can be used as the basis of a stand-alone analysis or as part of the RCT.

Real-world studies are poised to serve as the foundation for improved clinical trial designs that will allow researchers to look at a broader patient population, with the goal of enhanced patient care and treatments. This has the potential to improve our ability to recruit patients for RCTs and to complete them, as well as to accelerate the development and manufacturing of new oncology drugs to make them available to patients earlier.


  1. American Cancer Society. Key statistics about multiple myeloma. Revised January 12, 2021. Accessed March 10, 2021.
  2. Maiese EM, Evans KA, Chu BC, Irwin DE. Temporal trends in survival and healthcare costs in patients with multiple myeloma in the United States. Am Health Drug Benefits. 2018;11(1):39-46.
  3. Shah JJ, Abonour R, Gasparetto C, et al. Analysis of common eligibility criteria of randomized controlled trials in newly diagnosed multiple myeloma patients and extrapolating outcomes. Clin Lymphoma Myeloma Leuk. 2017;17:575-583.e2.
  4. Rifkin R, Singer D, Aguilar KM, et al. Daratumumab split first versus single dosing schedule among patients with multiple myeloma treated in a US community oncology setting: a retrospective observational study. Clin Ther. 2019;41:866-881.e7.
  5. Xu XS, Moreau P, Usmani SZ, et al. Split first dose administration of intravenous daratumumab for the treatment of multiple myeloma (MM): clinical and population pharmacokinetic analyses. Adv Ther. 2020;37:1464-1478.
  6. Darzalex (daratumumab) injection, for intravenous use [prescribing information]. Janssen Biotech; August 2020.
  7. Yimer H, Melear J, Faber E, et al. Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study. Br J Haematol. 2019;185:492-502.
  8. Rifkin RM, Melear JM, Faber E, et al. Daratumumab (DARA) maintenance therapy improves depth of response and results in durable progression-free survival (PFS) following Dara plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction therapy in multiple myeloma (MM): update of the Lyra study. Blood. 2019;134(suppl_1):863.
  9. Dimopoulos MA, Oriol A, Nahi H, et al; for the POLLUX investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
  10. Dimopoulos MA, White DJ, Benboubker L, et al. Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of Pollux. Blood. 2017;130(suppl 1):739.
  11. Palumbo A, Chanan-Khan A, Weisel K, et al; for the CASTOR investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
  12. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974-981.
  13. Chari A, Usmani SZ, Krishnan A, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma (MMY1001): updated results from an open-label, phase 1b study. Blood. 2017;130(suppl 1):3110.
  14. Facon T, Lonial S, Weiss BM, et al. Daratumumab in combination with pomalidomide and dexamethasone for relapsed and/or refractory multiple myeloma (RRMM) patients with ≥2 prior lines of therapy: updated analysis of MMY1001. Blood. 2017;130(suppl 1):1824.
  15. Spencer A, Hungria VTM, Mateos MV, et al. Daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of Castor. Blood. 2017;130(suppl 1):3145.
  16. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7:e370-e380. Erratum in: Lancet Haematol. 2020;7:e710.
  17. Ludmir EB, Mainwaring W, Lin TA, et al. Factors associated with age disparities among cancer clinical trial participants. JAMA Oncol. 2019;5:1769-1773.

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