Phase I Clinical Trial 

The main goal of a phase I clinical trial is to determine the maximum tolerated dose (MTD) and safety profile of a new drug or a new combination of drugs. A phase I study may be the first testing of a new treatment in humans. However, when it comes to combination therapies, the individual drugs may have been well-tested in humans in prior studies. 

Generally, patients enrolled in phase I clinical trials have advanced myeloma that is refractory to standard treatment. A cohort may have 3–6 patients who are given the same treatment at the same dose. The first cohort typically gets a low dose. This dose is increased in each subsequent cohort until a set number of patients experience dose-limiting toxicity (DLT). The dose level used for the previous cohort is then taken to be the MTD. That MTD is used as the dose in a phase II trial.  

Phase II Clinical Trial  

A phase II trial is a study designed to determine the efficacy and safety of a new therapy tested in a phase I trial. Patients are usually required to have measurable disease refractory to standard treatment. If the results of a phase II study are clearly much better than the standard treatment, then the treatment may be approved without being tested in a phase III study. If results from a phase II study are promising, the treatment may then be tested in a phase III study. 

Phase III Clinical Trial  

A phase III clinical trial is a study that compares two or more treatments. The endpoint of a phase III study may be survival or progression-free survival (PFS). Phase III studies are usually randomized, so patients do not choose which treatment they receive. Some phase III trials compare a new treatment that had good results in a phase II study with a standard-of-care treatment; others compare treatments already in common use.  

Phase IV Clinical Trial  

Even after the FDA approves a drug for use in a particular indication, additional studies may be needed. For example, safety surveillance is designed to detect any rare or long-term side effects over a larger patient population and longer time than was possible during the phase I–III clinical trials.  

Measure of Efficacy  

Clinical trials vary greatly in size, from a single researcher in one hospital or clinic to an international multicenter study with hundreds of participating researchers at hospitals across several continents. The number of patients in a clinical trial can range from a few individuals to several thousand patients.

Overall survival (OS) is the median number of individuals in a group who are alive after a particular duration of time. OS is often used as a measure of treatment efficacy in clinical trials. The lengthening duration of OS in myeloma clinical trials makes OS a difficult endpoint to use, and this led to the effort to validate minimal residual disease (MRD) status as a new endpoint.

In April 2024, the FDA held an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the use of MRD as an endpoint in myeloma clinical trials, including considerations regarding timing of assessment, patient populations, and trial design for future studies that intend to use MRD to support accelerated approval of a new product or a new indication.

ODAC provides independent expert advice to the FDA on broad scientific topics or on certain products to help the agency make sound decisions based on the available science. If ODAC makes a non-binding recommendation, the FDA generally follows the recommendations but is not legally bound to do so.

The IMF and collaborative research group i2TEAMM (International Independent Team for Endpoint Approval of Myeloma MRD) were key applicants to the ODAC proceedings, along with Sylvester Comprehensive Cancer Center of the University of Miami, Florida.

For this meeting, the FDA convened the advisory committee to discuss the adequacy of available data to support the use of MRD as an endpoint to support accelerated approval of new therapies for patients with myeloma.

The IMF’s International Myeloma Working Group (IMWG) has established uniform response criteria for MRD for use in myeloma. MRD has been included as an exploratory endpoint and secondary endpoint to assess response to therapies in myeloma clinical trials. When the data is robust, MRD data has been included in the prescribing information.

MRD testing has been shown to be prognostic in both frontline and relapse settings. MRD test results have affirmed PFS results that are used as basis for several FDA approvals in phase III clinical trials.

Medical Insurance Coverage  

Health insurance policies usually cover tests and procedures considered standard of care. Some examples of these tests and procedures are routine blood tests, X-rays, and myeloma-specific measurements. 

The study sponsor pays for study-related tests and procedures. These may include the following: 

• additional bone marrow biopsies
• more frequent skeletal surveys (metastatic surveys)
• magnetic resonance imaging (MRI)
• positron emission tomography (PET) scans
• computed axial tomography (CAT or CT) scans
• pharmacogenomics-, pharmacodynamics-, and pharmacokinetics-related tests 

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