Newsletter - The Exasperating Inflexibility of Clinical Trials

The Exasperating Inflexibility of Clinical Trials

A Message from Dr. Tony Blau

I have a love-hate relationship with clinical trials. For many patients with multiple myeloma, participation in a clinical trial represents their best option. Clinical trials provide the foundation for assessing whether new treatments are effective, and are grounded in the scientific method. Scientific advancement requires skepticism, the constant necessity of distinguishing between what we know and what we think we know, and very carefully and thoughtfully designed and executed experimentation. If any of these elements is lacking, the foundation upon which scientific progress is based turns to sand. 

Not surprisingly, the mandate of clinical trials to advance scientific progress is not uniformly aligned with the interests of individual patients. Designers of clinical trials must identify the features of patients most likely to benefit, however patients with few options may be willing to accept risks not permitted by a clinical trial’s inclusion and exclusion criteria. 

There are times when a trial’s entry criteria seem too rigid, as occurred earlier this month with All4Cure participant MM-1171 (registration required to view the dashboard). A retired professor, MM-1171 was diagnosed with multiple myeloma in 2013 and responded well to treatment with revlimid, velcade and dexamethasone followed by an autologous stem cell transplant in 2014, which was in turn followed by revlimid maintenance. In 2019 his myeloma recurred, and three additional lines of therapy produced much less satisfactory and shorter lived responses. MM-1171 is an All4Cure Pioneer - a participant in All4Cure’s patient advisory board, and it was at one of our meetings that I described All4Cure’s IRB approved protocol that allows leftover patient samples to be used for research testing, and for results to be posted on the patient’s dashboard. 

We developed All4Cure’s IRB approved protocol as the continuation of a trial initiated while I was still at the University of Washington for patients with metastatic triple negative breast cancer. I asked MM-1171 if he would like to participate in this trial, since this would allow me to engage researchers who are interested in applying their expertise to try to help patients with relapsed refractory myeloma identify treatments that might be effective. Professor Nitin Baliga leads this effort, and a manuscript describing their approach was recently published. To provide Nitin and his colleagues with the information they needed, a bone marrow sample from MM-1171 would need to undergo testing using DNA and RNA sequencing. Very generously, the digital health technology company Tempus agreed to perform the DNA and RNA sequencing on a research basis, and to provide Nitin and his team with the results for their analysis. 

The first results to come back from Tempus contained a surprise - MM-1171’s myeloma cells harbored an important mutation known as BRAFV600E. Occurring in only about 5% of patients with myeloma, this finding suggested that MM-1171 might respond to drugs that target this mutation. Unlike patients with myeloma, the BRAFV600E mutation is common in patients with a different form of cancer - metastatic melanoma, and two FDA - approved drugs used in combination, dabrafenib and trametinib, are often effective in these patients.

A clinical trial supported by the National Cancer Institute matches patients to treatments based on the molecular content of their tumors. Within this trial, patients with tumors containing BRAFV600E can receive dabrafenib and trametinib. A site for this clinical trial was open near where MM-1171 lives, and I thought to myself, "Bob’s your uncle!" But there was a glitch, and it was related to an important issue. If the BRAFV600E mutation were present in most or all MM-1171’s myeloma cells, then it was plausible that the combination of dabrafenib and trametinib might be effective. If, on the other hand, the BRAFV600E mutation were present in only a miniscule fraction of MM-1171’s myeloma cells, the likelihood of benefit from the dabrafenib/trametinib combination would seem much, much lower. To exclude patients unlikely to benefit from dabrafenib/trametinib, designers of the trial required that the BRAFV600E mutation be found at a “variant allele frequency" (VAF) of at least 5%. Hopes for enrollment into the trial were dashed when MM-1171’s Tempus report showed that the VAF of his BRAFV600E mutation was 4.8%.

Now I can accept a near miss, but in this case I believed that MM-1171’s exclusion from the trial was based on an incomplete understanding of his situation. The VAF is intended to approximate the number of tumor cells that contain the BRAFV600E mutation, but that is not what the VAF actually measures. Rather it counts all of the copies of the BRAF gene that are detected in a sample - both normal BRAF copies and mutated BRAFV600E copies, and from these numbers the percentage of BRAF copies containing the V600E mutation is calculated and reported as the VAF. 

Normal cells contain two copies of every gene, and every normal cell contains 2 normal copies of BRAF. Gene copy numbers can vary in tumor cells, but a reasonable approximation is that each one of MM-1171’s myeloma cells likely contains one copy of normal BRAF and one copy of the mutated BRAFV600E. Therefore, if 100% of the cells in the bone marrow sample sent to Tempus were myeloma cells, one would predict a VAF for BRAFV600E of 50%. However the large majority of cells contained in the sample sent to Tempus were normal cells, as the percentage of myeloma cells was estimated at only 25% by pathology review, and only 12% by flow cytometry. That means that even if all of MM-1171’s myeloma cells contained the BRAFV600E mutation, the maximal VAF one could have hoped for would be in the range of 6 - 12%. The measured VAF of 4.8% seems very close by comparison.

I emailed Professor Keith Flaherty, principal investigator of the trial, and promptly received a kind and thoughtful reply, acknowledging the logic of my reasoning but also citing his inability to deviate from the prespecified requirements of the trial.

In the meantime MM-1171 is exploring other options, and All4Cure is trying to help in whatever ways we can, including following up with Nitin and his team. One important avenue may be to try to access drugs off label. By using All4Cure to capture the outcomes of whatever treatments are chosen, we and MM-1171 hope that his experiences can be helpful to others.