July 14, 2020.
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Meg Seymour, a senior fellow at the center. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
Today, the committee is asked to discuss whether the benefits of belantamab mafodotin outweigh its risks for patients with relapsed or refractory multiple myeloma (RRMM) who have received at least 4 prior therapies. While patients clearly need new and better treatments for RRMM, these treatments need to also have meaningful benefits for patients, especially if they are associated with serious risks.
There is a reason why this drug is only being considered as a 5th line treatment for patients who have received at least 4 different types of prior therapies. Some people might think this is just a “Hail Mary” pass, and therefore worth considering as better than nothing. But we know that isn’t what will happen. If FDA approves this drug, it will be heavily promoted and inappropriately used as a 2nd and 3rd line and 4th line treatment as well, as has happened with other drugs in the past.
But let’s look at the data, starting with the risks.
The known risks are substantial. This is true particularly in regard to ocular toxicity, however there are also other risks associated with this treatment, such as gastrointestinal toxicity. Seventy one percent of patients in the proposed dosage group of 2.5mg/kg experienced keratopathy. This is alarming. Furthermore, one fifth of patients who completed the vision assessment and who had little to no baseline symptoms had to give up driving and had difficulty with or gave up reading. The Applicant did not identify therapeutic strategies that would mitigate this risk of ocular toxicity, and the data are not sufficient to say whether delaying or lowering doses mitigates the risk.
While this loss of vision disrupted patients’ lives, limiting their freedom, it might be a risk that is acceptable to some patients. But, such a risk should be acceptable only if there is a reasonable chance of meaningful benefits, such as longer life or improved quality of life. However, the benefits of this treatment are not clear.
What about the benefits?
The benefits are questionable because the DREAMM-2 study is an open label, single arm, phase 2 clinical trial, comparing two doses of the same drug, with no other active comparison group. This is completely inadequate for a cancer drug.
Although the Applicant met its primary endpoint with an overall response rate of 31%, there is a lack of crucial data regarding overall survival and quality of life. Given the available data and the study design, we agree with the FDA’s assessment that the Applicant is unable to claim that patients were satisfied with the treatment and maintained a stable quality of life. If patients do not receive a benefit in terms of overall survival, they may be taking on unnecessary risks and complications that make their final days miserable.
Moreover, replication is the key to science, because differences in the patients enrolled, medical practice, and even chance can affect the results. Interpretation of this study is further complicated by comparison to a historical control, which may have very different study populations, timing of assessments, and changes in treatment options. These limitations make it difficult to evaluate the benefits and risks and determine their generalizability.
There is a need for new treatments for RRMM. Patients may be willing to accept more uncertainty and more risks for new treatments. But their need should not be the basis for approving treatments whose benefits do not outweigh the risks. Based on the data discussed today, it is difficult to determine how well the treatment in question works and whether its effect is clinically meaningful. To approve a treatment for which the benefits do not clearly outweigh the risks creates additional risk for those who are already suffering. At the same time, FDA would have lowered their standards for cancer drugs so that FDA will no longer be the gold standard that patients and their physicians can rely on.