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 II 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 trials makes it a difficult endpoint to use. This has led to the effort to validate minimal residual disease (MRD) status as a new endpoint. 

MRD is the presence of residual tumor cells after treatment has been completed, and complete response (CR) has been attained. Response or remission are interchangeable terms to describe the complete or partial disappearance of the signs and symptoms of cancer. For myeloma, CR means the following factors are true: 

• negative immunofixation electrophoresis (IFE) on serum (blood) and urine tests 
• disappearance of any soft tissue plasmacytomas 
• 5% or fewer plasma cells in bone marrow 

CR is not the same as a cure.  

Even patients who have attained a stringent CR (sCR) may have MRD. sCR is CR plus a normal free light chain (FLC) ratio and the absence of clonal cells in bone marrow by immunohistochemistry (IHC) or immunofluorescence. MRD-negative status means that not even one myeloma cell is detected among 100,000 or 1,000,000 sampled bone marrow plasma cells (depending on the sensitivity of the specific test given to the patient).  

Very good partial response (VGPR) criteria include: 

• serum monoclonal protein (myeloma protein, M-protein) detectable by IFE but not by electrophoresis
• 90% or greater reduction in serum M-protein
• urine M-protein is less than 100 mg per 24 hours
• VGPR indicates a response level below that of CR (Complete Response)

Partial response (PR) criteria include: 

• At least a 50% reduction in serum M-protein
• A reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours 

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) 
• computed axial tomography (CAT or CT) 
• pharmacogenomics-, pharmacodynamics-, and pharmacokinetics-related tests 

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