Over the past two decades, the treatment of Multiple Myeloma (MM) has changed dramatically with the introduction of novel immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, an antibody-drug conjugate, and most recently, a novel chemotherapy drug. Despite these advancements and gains in survival, the disease remains incurable, and a variety of new drugs are under investigation.
Well-designed, expertly-executed clinical studies are critical for fulfilling the unmet medical needs of patients with MM. In this article, we explore lessons learned from Precision for Medicine’s extensive MM trial experience and offer strategies for optimizing five key aspects of study conduct.
1) Site Selection
Sites are the nexus of data generation in every clinical trial, so it follows that site performance is typically the most important determinant of study success. Identification of qualified, interested sites with access to the target patient population requires a blend of art and science. Previous experience and past performance in MM trials serve as objective, top-line measures for evaluating sites. However, these criteria alone are not enough.
The art of site selection lies in using the study design, objectives, and endpoints to reverse engineer the profile of an ideal site, which may vary depending on the patient population and type of therapy under investigation. For instance, if study eligibility is molecularly-defined, sites would need to have enough patient throughput to support enrollment after filtering criteria. For cellular therapeutics, which are complex and can be quite toxic, sites would need to have the training, processes, and resources required to handle therapy administration and adverse events.
2) Enrollment Support
The key to facilitating enrollment is making it easy for sites to screen potential study participants and document that they qualify. Identifying CRAs with experience in MM and having them engage closely with sites can facilitate site initiation and study start-up. In a recent phase III registrational MM trial, Precision for Medicine found that implementing detailed patient enrollment plans—including in-person site interactions, investigator-led caucuses, and patient advocacy initiatives—was effective in boosting site engagement and exceeding enrollment expectations.
3) Disease Insights
Experience with other types of cancer does not provide preparation for MM trials because MM is unique with respect to disease manifestations and the assessment of response to treatment. In particular, disease assessment requires a synthesis of information from M protein in serum or urine plus radiologic data. There are also nuances involving the definition of eligible patients. These two factors are important aspects of the approach to identifying patients, capturing response data, and reviewing site-generated data for consistency with the study protocol.
The electronic case report form (eCRF) database must be carefully developed with expert medical guidance to allow for the capture of complex data and to support overall response assessment. This is critical to avoid errors and time wasted on clarifying ambiguous data. Project team members, especially CRAs must be fully trained to ensure familiarity with the International Myeloma Working Group (IMWG) guidelines to support confirmation of disease response.
4) Site Support
Given the nuances of MM trials, rigorous, hands-on training of sites and clinical research associates (CRAs) is critical for study success. Developing an onboarding curriculum that includes process checklists, product manuals, and trial-specific education modules helps ensure all procedures are executed properly. For therapies associated with serious adverse events, it is important to check that toxicity management protocols are in place. It may also be useful to perform practice runs of key study procedures during the site initiation visit. These run-throughs are useful for identifying and mitigating potential risks and for increasing the competence and confidence of site staff.
5) Data Quality
Even seasoned MM investigators and centers of excellence can get response assessment wrong. A risk mitigation approach is central to preventing errors and to early identification of worrisome data trends. In addition to traditional data management practices, the production of high quality data requires the implementation of additional processes to support a medically sophisticated review of all study data. Customizing the electronic case report form (eCRF) to the response criteria and supporting data required helps minimize the risk of oversights and errors.
The future of Myeloma treatment looks promising based on the availability of a growing list of approved drugs and a range of novel targets that are under investigation. However, this promise cannot be realized unless the unique aspects of MM are acknowledged and used to drive the planning and conduct of clinical trials. With ongoing translational research and carefully designed clinical trials, we can continue bringing hope to patients in need of new treatment options.
About the author: Al Blunt, MD is Senior Vice President of Medical at Precision for Medicine. Noted authority in the drug development industry, Dr. Blunt is a sought-after strategist providing guidance for and oversight of the design, conduct, and analysis of oncology trials. He is a hands-on leader for Precision’s team of oncology medical monitors with expertise in phase 1 to 3 clinical trials investigating a wide variety of anticancer drug classes and cancer types.