Overcoming Limitations in Multiple Myeloma Trial Designs

The International Myeloma Working Group (IMWG) has drastically improved the diagnostic criteria and monitoring protocols for multiple myeloma (MM) trials. In fact, the discovery of novel biomarkers has made MM diagnosis and monitoring much easier and more efficient. The new protocols are complex, however, and they must be fully understood to maintain accuracy and efficiency in the diagnosis and monitoring of MM.

We talked to Marc Golightly, Ph.D., Professor of Pathology at Stony Brook University and Consultant at ICON Laboratory Services, for his take on the IMWG’s recent developments in MM care, as well as the challenges that sponsors face while developing MM protocols.

Dr. Golightly has been integrally involved in laboratory diagnosis of multiple myeloma at Stony Brook for more than 30 years. He is the director of the Medical Center’s Clinical Immunology Laboratory and Clinical Flow Cytometry Laboratory, and the University’s Research Flow Cytometry Core Facility. He has been a consultant with ICON for MM clinical trials and flow cytometry since 2000. Dr. Golightly recently co-hosted a webinar about laboratory considerations in multiple myeloma trials, which you can access here.

1. How has the IMWG recently evolved the diagnosis and monitoring of MM?

Recently, the IMWG added new criteria for diagnosing MM. These criteria include the detection of validated biomarkers (myeloma-defining events) prior to the onset of established CRAB features (high calcium levels, renal dysfunction, anemia, and destructive bone lesions), which indicate end organ damage.

The new biomarkers include: 1) a serum involved/uninvolved free light chain ratio of 100 or greater, as long as the involved light chain is present at a concentration of at least 100mg/L; and 2) more than one focal lesion on an MRI that is at least 5mm in size. These biomarkers, in fact, have been associated with the development of severe CRAB features. By examining these new biomarkers, a MM diagnosis can now be made before the appearance of end organ damage.

Additionally, the International Response Criteria for MM have been refined by adopting flow cytometric minimal residual disease (MRD) analysis (>4 color) and by analyzing one million cells. Moreover, the flow cytometry community has made efforts to refine these criteria even further by standardizing this analysis using 8 colors and examining 2-3 million cells.

2. How may these changes affect a trial’s enrollment process and subsequent monitoring for treatment response?

With knowledge of these new biomarkers, MM diagnoses can be made much earlier in a patient’s disease course, meaning patients can enroll in a trial before the onset of end-stage damage. Data has shown that early treatment can extend survival among high-risk smoldering MM patients.

Also, the inclusion of flow cytometric MRD analysis will greatly fine-tune the evaluation of these patients’ response to treatment.  

3. For MM trials, monitoring for disease progression and drug response can be complicated by a number of confounding factors and sometimes discrepant test results. What risks should sponsors be cognizant of?

By far, the largest complication in disease monitoring is the scenario where monoclonal proteins, most often IgAs, are present in the beta region in serum protein electrophoresis (SPE). In this situation, the antibody signal can be obscured by the underlying beta peak.

This issue does not normally arise at first presentation, since the antibody signal peaks are usually much larger than the beta peaks. However, as the antibody peaks diminish due to treatment, they disappear into the beta peak, making them difficult to discern, and in turn, the SPE becomes inaccurate and insensitive.

To resolve this issue, 92% of cases require immunofixation electrophoresis (IFE) and IgA quantitation via nephelometry to monitor the response to treatment. The IMWG has recognized this problem.

In addition, treatments themselves can interfere with the assessment of a patient’s response. Certain drugs, such as Elotuzumab and Daratumumab, have been shown to obscure the patient response to treatment, as their presence can appear in the SPE and IFE as monoclonal peaks themselves.

The sponsor should choose a trial laboratory that has experience working with these confounders and knows how to accurately distinguish between a patient’s response to treatment and other interfering signals.

4. How can smart bioanalytical strategies control these risks and protect the validity and accuracy of a trial?

Choosing a clinical trial laboratory that is aware of these confounding issues and has experience working with them could be a big step towards eliminating these issues. In addition, these confounders can be minimized by teaming up with an experienced myeloma clinical trial lab at the onset of a trial and seeking their input for study design.