A few months back, good news hit the multiple myeloma community: the U.S. Food & Drug Administration voted to accept a new endpoint — MRD, or measurable residual disease — for accelerated approval of treatments for this cancer.

What does this mean for myeloma patients?

Everything, per Fred Hutch Cancer Center hematologist-oncologist Rahul Banerjee, MD, who treats patients diagnosed with this slow-growing cancer of plasma cells.

“Myeloma is considered incurable — but patients can be in remission for a long time,” Banerjee said. “Until now we’ve had an historic obsession with the M-protein and we typically check it. We don’t frequently look at the cancer cells themselves. We look at the proteins they’re producing to see if it’s going up or going down — like a PSA in prostate cancer.”

The problem is the M-protein can take six months or longer to clear after therapy. And sometimes, this protein doesn’t ever go away, even in patients who are asymptomatic. Despite this, disease remission — also known as a complete response to treatment — has traditionally been defined as having zero M-proteins in the blood and in the urine. The absence of M-proteins has also been a desired endpoint when trialing new therapy drugs.

What’s an endpoint? It’s how scientists demonstrate whether whatever it is they’re studying — a screening modality, a targeted treatment, an immunotherapy, etc. — is a boom or a bust. With this new decision, trials using MRD to assess benefit can now be considered by the FDA to approve novel drugs.

“In brief, it’s not about the M-protein anymore,” Banerjee said. “MRD is measuring cells in the bone marrow. This directly tells us how patients are doing with the myeloma, not indirectly how the protein is doing. It’s a much more sensitive endpoint.”

Endpoints matters

Why the change? Banerjee said it’s because myeloma patients are living longer and longer.

“Historically, we haven’t had good treatments,” he said. “The prognosis for patients was three to five years, although now it’s easily more than 10 years for many patients in the U.S. Patients don’t have the time to wait five to seven years to see a difference in treatments. That’s the crux of MRD as an endpoint. It’s quicker, and it’s much more sensitive.”

When MRD is used as a clinical trial endpoint, Banerjee said, “it means the FDA can approve a drug sooner and we can get it into the hands of patients faster.” MRD — which also stands for minimal or molecular residual disease — is also an incredibly useful tool for the de-escalation of treatment.

“If someone is MRD-negative, and thus their myeloma is under good control, you can drop the number of treatments from, say, once a week to once a month,” Banerjee said. “That can help with clinical toxicity — side effects — as well as time toxicity. Myeloma is notoriously bad for time toxicity. Some patients need to come in for once-a-week injections —sometimes forever.”

Using MRD negativity as an endpoint for remission, he said, “could identify patients who don’t need that kind of treatment indefinitely.”

OS? PFS? TTP? DFS? How about TTF or pCR?

The acronyms scientists use to signify what endpoints measure can sometimes read like a bowl of alphabet soup. But they convey crucial information.

“An endpoint is something we measure on every patient on a clinical trial and distill it into a number,” said biostatistician Megan Othus, PhD. “It can range from how long they live to a measure of their quality of life. When we do a randomized trial, we compare the endpoints measured in one group versus another.”

Overall survival, or OS, defined as the length of time a patient is alive after the start of a treatment, is considered the “gold standard” endpoint in cancer clinical trials. But as the FDA puts it, demonstrating overall survival in a clinical trial “can be lengthy, costly and otherwise challenging.”

“This is an old problem in treatment trials,” said Fred Hutch biostatistician Ruth Etzioni, PhD, holder of the Rosalie and Harold Rea Brown Endowed Chair. “We want to know quickly whether something works. But if we look for survival, we have to wait a long time.”

That’s where short-term “surrogate” endpoints come in. Cancer researchers use a variety of them in treatment trials, including:

  • PFS     progression-free survival

  • TTP     time to progression (time it takes for the cancer to spread or grow)

  • DFS     disease-free survival

  • TTF      time to treatment failure

  • TTNT   time to next treatment

  • DoR      duration of response

  • ORR     objective response rate

  • CR       complete response (disappearance of all signs of cancer in response to treatment)

  • pCR     pathological complete response (absence of cancer in tissue samples after treatment)

“Whether the surrogate endpoint can actually substitute for the survival endpoint is the tricky part,” Etzioni said, noting that one of the first and most well-known papers to address this from a statistical perspective was written by Fred Hutch professor emeritus Ross Prentice, PhD.

“He came up with a way of deciding whether a short-term endpoint was good enough to be a surrogate for survival,” she said. “His Prentice Criteria provided a blueprint for interrogating historical trials where you have both endpoints to decide if the short-term endpoint is adequate.”

Evolving endpoints

Selecting the right endpoint is crucial, Othus said. 

“It’s important to define endpoints well because the endpoints are what the conclusion of the trial is based on,” she said. “What do you measure? When do you measure? These are questions that researchers and clinicians struggle with.”

But just as cancer patients’ prognosis has changed over time due to new, better therapies, endpoints are changing, too.

“They’ve evolved over time,” Othus said. “Patients are living longer and longer. At the same time, we have even more drugs we want to study and new technologies that let us measure and evaluate cancer in different and potentially better ways. If we have to wait and see how long people live and they’re living longer, it takes longer and longer to get the answer.”

Case in point: when Othus first joined Fred Hutch in 2009, she worked in melanoma research, where there were few effective treatments.

“Back then, life expectancy was months in our trials for patients with advanced melanoma,” she said. “If I saw anybody alive after a year, I knew [that therapy] was going to be a big deal. Because life expectancy was so short, it didn’t take that long to see that people would live longer.”

Now, melanoma patients are living decades due to improved treatments such as checkpoint inhibitors, “so a trial that would have taken less than a year in 2009 will take five years because people are living longer,” Othus said.

Longer survival is one of the main reasons researchers have devoted a great deal of time and energy trying to find better — read shorter-term — endpoints.

“Overall survival as an endpoint is not feasible or helpful if it’s going to take us 20 years,” Othus said. “Nobody’s going to care about the results of a trial in 20 years. We want to move on and test the next good thing to keep patients going.”

But some health insurance companies require complete or “mature” overall survival data before they can justify reimbursement.

An international mix of clinicians, advocates and health economists discussed this impasse in a 2021 paper published in Cancer Management & Research.

“If payers wait for long-term OS data, patients have to wait to access the new treatment, even when regulators have decided that it is safe and effective,” they wrote. “As a result, some patients may die while waiting ... [but] if payers do not have long-term OS data, they risk paying for a treatment that is not as effective as they had hoped.”

Fortunately, this doesn’t necessarily apply when the FDA is involved.

“One of the big things with the myeloma decision is that if the FDA has said MRD, measurable residual disease, is good enough, then payers have to follow the FDA rules,” Othus said. “If the FDA says we’re going to issue accelerated approval for a new drug combination based on this, then payers generally have to pay for it.”

Another endpoint issue involves RECIST, or Response Evaluation Criteria in Solid Tumors, the standardized method of determining a patient’s response to treatment, based upon changes in tumor size as determined by CT scans and/or MRI.

What if the scans don’t pick up the cancer, which can happen with prostate, lobular breast and other cancers that tend to grow in a diffuse pattern? If you can’t see it, you can’t measure it.

Modified criteria, say advocates and researchers, are needed for cancers that “resist RECIST.”

Confusing, but key

Though endpoints in clinical trials are extremely important for patients — new study results can lead to new drug approvals and changes in treatment — they’re byzantine enough that many don’t understand their nuances.

A study by the FDA published in Oncologist in 2020 convened a series of cancer survivor focus groups to gauge familiarity with three common research terms: overall survival, progression-free survival and response rate. “Participants had misconceptions,” they wrote, “… and tended to expect that all endpoints were a variation on living longer.”

Stephanie Walker, a retired North Carolina nurse diagnosed with de novo metastatic breast cancer in 2015, said she pays close attention to endpoints when results from clinical trials come in.

“Endpoints absolutely matter for patients,” she said. “They may give us another option for treatment and they also let us know what to steer clear of. If too many people die on a drug, I don’t want that one.”

Walker said she was at ASCO 2023 when the DESTINY04 clinical trial results were announced. “The overall survival was so good, there was a standing ovation,” she said.

DESTINY researchers trialed a drug combination called an antibody drug conjugate on breast cancer patients with low expression of the biomarker HER2. The results — a statistically significant and clinically meaningful benefit in PFS and OS — meant a brand-new effective therapy was on its way to patients.

Walker acknowledged terms like OS, ORR, DFS, and the like can be confusing, but she’s clear about what matters to her.

“I’d take progression-free survival for a surrogate endpoint in a heartbeat,” she said. “It means I’ll live longer, although it’s also important to look at the side effects of a drug. I want quality of life and will choose quality over quantity every time. I’ve seen friends who go on treatment after treatment after treatment and in the end, they have no quality time to spend with family and loved ones. I don’t want to be incapacitated for any reason. Patients have their own endpoint, as well.”

Banerjee said his patients are absolutely satisfied with the new MRD endpoint.

“Right now, with the newer therapies, I might tell patients ‘This treatment might make you MRD negative faster, but I don’t know for sure it will make you live longer or feel better, but it’s possible it may,’” he said. “My patients take that and run with it.”

Endpoints for screening trials?

Endpoints (and surrogates) are also used in cancer screening trials, which can take far longer than treatment trials.

National thought leaders like Etzioni are currently trying to sort out how scientists can determine if the new multi-cancer detection tests — blood tests that detect circulating tumor DNA — will save as many lives as more traditional cancer screening modalities.

To do this, she’s evaluating and assessing the reliability of new cancer screening tests, via a series of studies and through the National Cancer Institute’s new Cancer Screening Research Network (Fred Hutch is the data coordinating and communication center).

In April, she and others published a meta-analysis of screening trials to determine whether incidence of a later cancer stage diagnosis (such as stage 3 or stage 4) could be an alternative endpoint for cancer-specific mortality in some of the tests, often referred to as “liquid biopsies.”

The research team whittled down more than 1,200 publications to 41 randomized clinical trials which included 12 trials for lung cancer, six for breast cancer, 11 for colorectal cancer, four for prostate, four for ovarian and four other trials that covered liver, oral and other cancers.

After analysis, they found that using incidence of late-stage cancer diagnosis rather than death by cancer as an endpoint worked for some cancers, particularly lung and ovarian. But not so much for the others.

“Stage III-IV cancer incidence is unlikely to be a suitable alternative endpoint to cancer-specific mortality in screening trials for breast, colorectal, and prostate cancers,” she and her colleagues wrote in JAMA.

In a paper published in May in Lancet, however, Etzioni and co-authors concluded that ”despite challenges, there is great potential for the sensible use of surrogate [endpoints] to accelerate the translational pathway by stopping trials of ineffective screening technologies early and by progressing implementation research (or even pilot programs) of promising screening strategies while awaiting cancer mortality results.”

Research of this nature is difficult, but absolutely essential, Fred Hutch experts said.

“This work is really hard, but what really matters is whether patients live longer,” Othus said. “In myeloma, they had years of data on overall survival and when they looked at patients who had become MRD-negative through a variety of trials, they all told the same story. People who are MRD-negative on average live longer.”

But with new technologies cropping up, Othus said it’s becoming harder and harder to figure out the rules.

“With liquid biopsies, the question is will finding a cancer using a liquid biopsy help people live longer?” she said. “All of these tests are a little different including the things they measure. It’s fascinating, but it feels a little bit like the Wild West right now. The rules aren’t clear.”

Those rules could clear up relatively soon. Just this week, a House panel began contemplating a bill that would enable Medicare to cover the use of multi-cancer blood tests for preventive screening.

Diane Mapes is a staff writer at Fred Hutchinson Cancer Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at dmapes@fredhutch.org.

This article was originally published June 28, 2024, by Fred Hutch News Service. It is republished with permission.