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Multiple Myeloma an incurable disease, but I have spent the last 25 years in remission using a blend of conventional oncology and evidence-based nutrition, supplementation, and lifestyle therapies from peer-reviewed studies that your oncologist probably hasn't told you about.
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OS vs. PFS in Myeloma Trials
OS vs. PFS in Myeloma Trials? Which is more important to you- your overall survival aka length of life or your progression-free survival aka your first remission?
You’ve been diagnosed with an incurable blood cancer called multiple myeloma. The only think your oncologist has told you is that “your cancer is incurable but very treatable.” What the hell does that mean??? That’s what I wondered when I was first diagnosed…
In short, incurable but treatable means that you will undergo regimen after regimen and go into and out of remission. Some MM patients will reach complete remission and some will reach various degrees of partial remission.
In the video linked below, a well-meaning oncologist talks about the dream of finding a cure for MM. Why then, are so many clinical trials testing progression-free survival and not overall survival?
What are clinical trials in myeloma?
As a MM survival myself, I think OS is much more important than PFS. But I’m only one person. What do you think? What is more important to you- first remission or how long you live?
Email me at David.PeopleBeatingCancer@gmail.com and tell me what you think.
Good luck,
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Why Overall Survival Should Be The Oncology Trial Endpoint
The use of surrogate endpoints to predict overall survival in oncology trials has been vigorously debated in the oncology community.
In multiple studies, we have shown that the correlation of surrogate endpoints with overall survival has been weak and, in most cases, inadequate. However, others have made arguments against using overall survival as the gold standard endpoint for cancer drug trials. These arguments include claims that overall survival is not a feasible endpoint for pivotal cancer drug trials and that negative overall survival results may be unreliable
In this column, we counter some of these arguments from the perspective of an oncologist who treats cancer and is engaged in oncology research and a patient advocate with lived experience of cancer.
Argument: Overall survival is not the only meaningful clinical endpoint. Response rates and progression-free survival also are important clinical endpoints because patients feel good when their tumor shrinks or they have more time without disease progression. Both situations can improve patients’ quality of life.
Response: On the face of it, this argument sounds reasonable, but it treats response rates and progression-free survival as clinical endpoints rather than surrogate endpoints that need to be validated. A patient would surely welcome news that treatment has reduced the size of their tumor and would feel dismayed if the tumor is growing. However, these reactions rest on the belief that these changes signal recovery in the case of a shrinking tumor, or worsening symptoms in the case of a growing tumor, neither of which may be true.
“Disease progression” and “progression-free survival” were developed as technical terms to signify whether a therapy in a phase 2 clinical trial was sufficiently promising to advance to phase 3.
The terms were not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. In clinical trials, a progression event is defined as an increase in the sum of tumor diameters by more than 20%, or the appearance of a new lesion. These are both arbitrary benchmarks that in no way imply that a patient’s subjective experience of symptoms or their survival time would differ widely between a tumor growth of 19% vs 21%, or if a new, tiny lesion develops.
Of course, disease progression sometimes does affect a patient’s quality of life, but trials treat all progression events equally. An event in the brain that affects the patient’s ability to walk and an asymptomatic tumor growth in the lung from 1 cm to 1.3 cm are both considered disease progression in trials.
Patients care about progression-free survival because they mistakenly believe that an improvement will probably lead to improved overall survival or quality of life. But overall survival and quality of life can actually be affected detrimentally, despite progression-free survival gains, because the patient may experience treatment-related physical and financial toxicity without clinical benefit. Conversely, it is possible to have better overall survival and quality of life without any improvement in progression-free survival.
With response rates, the relationships to overall survival and quality of life are even weaker. Because progression-free survival and response rates do not represent clinical benefit, they cannot be considered clinical endpoints. They are surrogate endpoints that need to be validated.
A patient will reasonably welcome a treatment-related change that improves the prospect of living a longer life or enduring less suffering but should not be misled when these outcomes have not been demonstrated as being clinically beneficial.
Argument: It is not ethical to wait for overall survival when there is an unmet need.
Response: The phrase “unmet need” is used to represent the lack of effective treatment options for a particular condition. Regulators may expedite approval of a new drug that is intended to fulfil the need because waiting for overall survival may not seem ethical in these settings.
In reality, however, the term is used inconsistently, both when the need is either questionable (the indication is indolent) or the need is real but one or more treatment options already exist.
When the need for a drug with clinical benefit is genuinely unmet, presenting patients with just any drug is unethical; their need will continue to exist despite drug approvals if survival is not improved. In fact, approving ineffective drugs can impede the development of drugs that work.
Argument: Overall survival is not a practical endpoint for drug trials for rare cancers.
Response: This argument has some practical validity because the low prevalence of a rare cancer may limit study recruitment opportunities. From an equity perspective, however, patients with rare cancers are no less deserving of treatments based on meaningful evidence of safety and efficacy than are patients with common cancers. Like any other patient with cancer, they should know those treatments have shown the potential for an overall survival or quality of life benefit before undergoing potentially toxic treatments.
Several trials, such as FIRM-ACT, VIT-0910, AEWS0031, and rEECur, have shown that international collaboration makes randomized clinical trials with an endpoint of overall survival possible for most rare cancers. We support offering early access via accelerated approval when scientific evidence suggests a drug has potential benefit for patients, but the trial should be followed to confirm an overall survival benefit and the drug should be withdrawn if an overall survival benefit is lacking.
Argument: The point of measuring overall survival is to ensure that the treatment does not worsen overall survival.
Response: This argument is frequently made, even by regulators. However, unless a drug is tested in a justified noninferiority design trial where the aim is to determine whether it provides compensatory benefits — easier administration, lower cost, or fewer side effects than the alternative — the goal of new cancer drugs is to improve survival. Merely “not worsening survival” is incongruent with medicine’s fundamental goal of benevolence. All drugs have toxicities, some of which can be fatal. Recommending a treatment with toxicities because it did not worsen survival would harm patients and go against the Hippocratic Oath.
Argument: Overall survival in this trial was negative, but this was probably a false-negative finding. We expect future trials will be positive.
Response: When a drug fails to improve overall survival, some experts will argue that it was a false-negative result and a future trial will be positive. For instance, to explain the negative overall survival findings in a 2020 confirmatory trial, the researchers cited a subgroup analysis in which the drug received accelerated approval based on early exploratory results. However, the subgroup analysis violated the statistical plan and raised the likelihood that the early trial’s favorable outcome was false-positive.
A second trend that increases the likelihood of false-positives is when the same anticancer medications are studied across multiple trials. If we run dozens of trials of the same drug, some of them will eventually be positive by chance alone.
Dismissing a negative overall survival finding as a statistical artifact puts patients at risk because oncologists may continue to use the drug, despite it providing no discernable clinical benefit to patients.
Argument: The overall survival was negative because of crossover so that patients in the control arm received the therapy at progression.
Response: Highly effective drugs will continue to show overall survival gains despite crossover — that is, when patients in the control arm receive the experimental drug at the time of progression.
For example, a trial evaluating the addition of pertuzumab in first-line HER2-positive metastatic breast cancer allowed crossover and still showed a significant overall survival benefit. Another trial evaluating sunitinib vs placebo in advanced gastrointestinal stromal tumors showed a significant overall survival improvement despite 80% of patients in the placebo arm crossing over to sunitinib at progression.
However, in the SONIA trial, receiving cyclin-dependent kinase 4/6 inhibitors as first-line treatment of metastatic hormone receptor–positive breast cancer did not improve survival and added toxicities compared with receipt of the same agents as second-line treatment.
If crossover negates an overall survival benefit, this implies that patients in the experimental arm who received the drug upfront and patients in control arm who get the drug only at progression have no difference in survival times. If the survival outcomes in the groups are similar, that is evidence that the new drug should be given only to those who need treatment at the time of progression and not to everyone upfront.
Giving patients the drug at the time of progression would spare patients toxicities, preserve efficacy, and save health systems costs.
Argument: Although overall survival is negative in the confirmatory trial, the clinical practice guidelines recommend using the drug, and the guidelines should be followed.
Response: We cannot ignore results of a confirmatory trial just because the drug is already in the guidelines. Guidelines should be updated on the basis of the latest evidence, rather than clinical practice being dictated by outdated guidelines. When a drug given accelerated approval appears in the guidelines, the confidence level of the evidence should be rated low until confirmatory results are available. If a confirmatory trial shows that overall survival does not improve, the guidelines should be quickly updated. However, even if they are not, physicians should not just blindly follow the guidelines.
Furthermore, practitioners should be aware that members of oncology guidelines committees often have financial conflicts of interest with pharmaceutical companies, which the literature shows can bias guideline recommendations.
The Bottom Line
We believe that despite arguments put forward against relying on or measuring overall survival, it continues to be the most patient-centric marker of clinical benefit. Patients deserve to know that the cancer drugs their oncologists recommend will contribute to a longer or better life.
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