ASH 2019: Liquid Biopsies? Tumor DNA in Blood Could Predict Early Outcomes in Relapsed or Refractory Myeloma

At the 2019 American Society of Hematology (ASH) Meeting in Orlando, a group of investigators from several institutions including: Harvard Medical School, Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, Massachusetts General Hospital, Newton-Wellesley Hospital, the University of Rochester, and the University of Michigan presented a prize winning poster entitled Circulating Tumor DNA in the Peripheral Blood As Early Predictor of Clinical Outcome in Relapsed/ Refractory Multiple Myeloma. The lead investigator was Johannes M. Waldschmidt, MD. The authors attempted to define “liquid biopsy” parameters that identify myeloma patients who do not benefit from a particular treatment before relapse becomes evident by blood markers. According to the investigators “Having such parameters at hand will potentially inform changes in treatment.”

The researchers studied 45 relapsed and refractory myeloma patients, who had been treated in a multi-center phase II trial, evaluating the combination of elotuzumab, pomalidomide, bortezomib and dexamethasone. Peripheral blood plasma samples were acquired for circulating tumor DNA (ctDNA) evaluation using a relatively new, highly sophisticated, genetic technique called low-pass whole genome sequencing at four different time points:

• the day the patient was first screened
• the first day of cycle 3 of treatment
• the 1^st day of cycle 5 of treatment
• the final day of treatment

The concentration, relative fraction, and copy number profile (defining mutations) of myeloma-derived circulating tumor DNA were determined at each of these time points. At the time of this preliminary analysis, 17 patients (35%) continued on treatment and 28 patients (58%) had developed progressive disease. 

Circulating tumor DNA levels at screening and on the first day of cycle 3 strongly correlate with progression-free survival (PFS). On the first day of cycle 3, patients with a residual circulating tumor DNA level less than 10% showed a significantly longer Progression Free Survival (median 17.6 months) as compared to those with circulating tumor DNA levels greater than 10% (median 5.9 months).

The circulating tumor DNA levels generally correlated with other blood markers such as M-protein and serum-free light chains. To test their hypothesis, the authors performed a subgroup analysis of all patients with minimal response/ stable disease at first follow-up on day 1 of cycle 3. In this group of 19 patients, having more than 10% of residual circulating tumor DNA fraction was linked to a significantly shorter median Progression Free Survival (1.6 months,) as compared to circulating tumor DNA levels less than 10% (5.8 months progression free survival). 

Based on the above results, the authors concluded:

1. “Liquid biopsy” evaluation of circulating tumor DNA may refine prognosis and provide added predictive value over current blood markers alone. 
2. While in the large majority of cases circulating tumor DNA has excellent agreement with M-protein and serum-free light chains for monitoring of multiple myeloma disease progression, circulating tumor DNA may identify patients where relapse is imminent before it can be detected by other blood tests.
3. This approach may complement or enhance physicians’ framework for treatment decisions. 
4. The circulating tumor DNA approach is highly scalable, cost-efficient, and provides information about the clonal evolution of multiple myeloma without the need for a bone marrow biopsy test.

Although complicated, this study suggests that this new, minimally invasive “liquid biopsy” test gives an earlier indication that the patient’s disease is at risk of progressing and treatment needs to be changed.

Thank you to our Myeloma Coach ASH 2019 sponsors: