About 15 years ago, Carl Ola Landgren, M.D. Ph.D., noticed an encouraging yet potentially concerning trend in the treatment of multiple myeloma. Drugs had become so increasingly efficacious that they could induce tumor responses in nearly 90% of newly diagnosed patients.
It was good news for patients, as more could enjoy tumor shrinkage. But Landgren saw a potential downside around the corner: As standard treatments improved, it would take ever longer for new meds to prove that they could provide benefits based on traditional clinical measurements.
“I said, ‘If we don’t take action, we will not be able to move the field forward,’” Landgren recalled.
So, Landgren, who was then working at the National Cancer Institute, helped launch an interagency initiative involving the FDA and the National Heart, Lung and Blood Institute. In 2012, the group held a roundtable at the FDA’s headquarters in Silver Spring, Maryland, to consider a more stringent tumor measurement in myeloma—minimal residual disease (MRD).
Now, after nearly a decade of work, Landgren and other researchers will share research that aims to substantiate a link between MRD negativity and improved clinical outcomes such as delayed tumor progression or death in multiple myeloma. A team led by Landgren, now with the Sylvester Comprehensive Cancer Center, and another International Myeloma Foundation-backed group known as i2TEAMM, will present their separate meta-analysis studies of MRD in myeloma at an FDA advisory committee meeting this Friday.
The experts’ hope is that the findings could support MRD as a surrogate endpoint for granting accelerated approvals of novel multiple myeloma drugs, thereby bringing new treatments to patients earlier.
Bringing drugs to patients faster
“[MRD] can really play a critical role in accelerating drug development, especially in a setting like the newly diagnosed patients,” Craig Tendler, M.D., vice president of late development and global medical affairs at Johnson & Johnson Innovative Medicine, explained in an interview with Fierce Pharma.
Today, the endpoint of overall response rate can support full approvals in late-line myeloma settings. In contrast, as front-line therapies’ overall response rates approach 100%, longer-term endpoints such as progression-free survival (PFS) are used to support those FDA approvals. But existing standard-of-care, first-line regimens already help patients live around a median seven years without disease progression.
“If we had to rely solely on those endpoints as the basis for an approval, any novel agents that [we] would have brought into these settings would take a long time for those studies to mature,” Tendler said.
At the American Society of Hematology annual meeting in December, Peter Voorhees, M.D., from Atrium Health raised a hypothetical phase 3 trial that pits a bispecific antibody against a combination of either J&J’s Darzalex or Sanofi’s Sarclisa with Takeda’s Velcade, Bristol Myers Squibb’s Revlimid and the steroid dexamethasone (VRd) in first-line patients who’re eligible for stem cell transplants.
To be statistically powered to show a PFS benefit, the trial would need to enroll more than 1,700 patients and would take nearly 10 years to reach the final PFS analysis, according to Voorhees’ calculation.
“Clearly, we need a surrogate endpoint for longitudinal outcomes that reads out earlier than progression-free survival if we’re going to continue to make progress for this group of patients,” Voorhees said during his presentation.
A study doesn’t necessarily have to reach the final PFS analysis in order to read out and provide researchers and regulators with actionable knowledge. But it would take a very strong regimen to show a benefit early on, and the timeline likely would still look daunting. A phase 3 trial dubbed PERSEUS, which randomized just about 700 patients, detailed a statistically significant PFS win for the Darzalex-VRd regimen against VRd alone in December, five years after the trial’s initiation.
Conversely, Rahul Banerjee, M.D., a physician-researcher at the Fred Hutch Cancer Center who specializes in multiple myeloma, estimated that in some cases, a separation of treatment effects based on MRD could start to show just four months after treatment.
J&J’s Tendler noted that an MRD readout usually doesn’t require as many patients as a PFS analysis, and therefore doesn’t have to wait for a trial powered for PFS to be fully enrolled. Landgren said he believes a meaningful, statistically significant MRD improvement could read out just three years after a trial’s start.
The utility of MRD
With MRD, researchers measure disease burden with the most sensitive techniques such as flow cytometry and next-generation sequencing (NGS), Tendler explained. Today, these techniques can detect malignant clones in 1 in 100,000 cells (10-5) and have sensitivity down to 1 in a million cells (10-6). MRD negativity means no sign of cancer cells as tested by the assays, and it represents an even deeper level of tumor clearance than a complete response.
The concept of MRD first emerged in the 1990s, and it attracted wider attention in the clinical world in 2016 with the publication of consensus criteria for measuring MRD by the International Myeloma Working Group, Banerjee recalled in an interview with Fierce Pharma.
In 2018, the FDA used MRD status to define patients with another type of blood cancer, B-cell precursor acute lymphoblastic leukemia, who need additional treatment. The agency approved Amgen’s Blincyto in those patients who are in remission but still have MRD at 0.1%.
Doctors are already using MRD to guide their treatment decisions. For myeloma patients who’ve achieved MRD negativity as measured by two negative readouts at least six months apart, Banerjee considers stopping treatments, especially for meds that carry significant toxicities. Some first-line patients may also consider potentially forgoing stem cell transplants if they’ve achieved MRD negativity, Banerjee said.
This practice has been reflected in clinical trials, too. In the ongoing PERSEUS trial, patients are allowed to discontinue Darzalex after they’ve reached MRD negativity for a year.
Even without seeing data from Landgren’s team or the i2TEAMM group, Banerjee, who’s not involved in either study, said he’s ready to embrace a drug approved by the FDA based on the MRD endpoint. That’s partly because he’s experienced with MRD in clinical care, and because patients are already asking about it after doing their own disease research.
“I would use it, and I would be very excited about trials that use MRD as an endpoint to get more drugs to our patients sooner,” Banerjee said.
But Banerjee cautioned that he tends to be more open-minded when it comes to accepting new concepts in multiple myeloma compared with some of his peers. Many physicians still have doubts about PFS despite FDA approvals, he noted. These doctors wouldn’t be persuaded until they see overall survival data. But Banerjee believed that decision should be in the hands of the patient.
“I would argue with MRD negativity, the same logic applies,” Banerjee said. “I’d say, look, the trial has shown that adding this regimen […] makes more people MRD-negative. Will that make you live longer? I don’t know. And I’m okay with that. And certainly, I think our patients, I can counsel them about it.”
Supporting MRD as a surrogate endpoint
Banerjee’s confidence in MRD also comes from past studies that have pointed to a correlation between MRD negativity and improvements in longer-term clinical outcomes such as PFS and overall survival. Landgren and colleagues first published such a meta-analysis in 2016 and have performed other similar assessments after that.
In 2020, a large meta-analysis—involving 44 multiple myeloma clinical studies with PFS data from nearly 8,100 patients—published in the journal Blood Advances showed that achieving MRD negativity could slash the risk of disease progression or death by 67%. And among 23 studies with overall survival data from nearly 4,300 patients, MRD negativity was linked to a 55% improvement in death risks, according to the paper.
The research made a big splash in the academic world, but the FDA wasn’t persuaded. Still, the fact that the agency is convening the advisory committee meeting to review the new data is a good sign, Banerjee said.
Unlike those earlier studies, the criteria to support regulatory decisions will be more stringent, Landgren noted. His new study, dubbed EVIDENCE, includes only “high-quality” data with the MRD sensitivity bar set at 10-5, Landgren said.
For years, Landgren’s team previously worked with the FDA to develop a statistical analysis plan, which was agreed upon at the end of 2021. For example, Landgren said finding the right time to capture MRD in a consistent manner across trial arms was critical to avoid bias. The trials included in the meta-analysis also can’t have too many missing data.
In an article published last year in Clinical Cancer Research, FDA officials, including oncology chief Richard Pazdur, M.D., flagged several problems with past blood cancer drug applications utilizing MRD. As the FDA staffers pointed out, MRD data collected in registrational trials were often not fit for inclusion in the label.
Among the cancer types evaluated, multiple myeloma “had one of the lowest acceptance rates for MRD data despite having the highest number of submissions,” the FDA noted in its study. The main problem, the FDA pointed out, stemmed from the assays used to detect MRD. In many cases, NGS-based assays failed to identify a malignant clone suitable for tracking. These missing data rendered the overall results uninterpretable, the FDA said.
Banerjee, Landgren and Tendler all said that NGS assays have advanced significantly in recent years; they're now able to capture MRD signatures in more than 90% of cases, according to the experts.
“The assay is very reliable,” Landgren said, “and pharmaceutical companies, it’s in their best interest to do the studies right and to capture the correct data, the correct samples and so forth. So, when those two things are paired together, then you have good datasets coming in.”
What happens now?
Landgren’s team submitted the results from EVIDENCE about a year ago and has held follow-up discussions with the FDA since then. The agency is expected to share those new analyses by Landgren and i2TEAMM, as well as its initial thoughts on the topic, on Wednesday.
During Friday’s meeting, a team of external advisers to the FDA will discuss whether MRD can serve as an endpoint to support accelerated approvals in multiple myeloma, including considerations regarding timing of assessments, patient populations and trial designs. The agency doesn’t have to follow its panel’s opinion, but it typically does.
By the FDA’s criteria, a surrogate endpoint needs to be at least “reasonably likely” to predict a clinical benefit. To prove that, Landgren said, the endpoint must have a plausible biological mechanism; must demonstrate a prognostic value for clinical outcomes; and must have evidence from clinical trials to prove a pattern.
“MRD has all those features, we feel, for myeloma,” Landgren said.
“It’s very important to emphasize that these are two independent studies that investigate the role of MRD as an early clinical endpoint in myeloma,” Landgren said, later adding that “the results of these two independent studies are very consistent, and they support each other.”
While the overall results support the MRD endpoint's clinical relevance, the strength of correlation varies across each trial included in the analysis, Tendler said. This raises the question of whether any isolated cases would weaken MRD’s case. But the J&J exec argued that the bigger analysis is what matters.
“There’s a risk in any accelerated approval,” Tendler said. “But the whole point of doing this meta-analysis, and now by two different applicants showing very similar results, is to increase that statistical certainty.”
Banerjee said he hopes that enough studies support the larger trend that the more people become MRD-negative, the better they do on long-term survival outcomes. If some cases buck that trend, it would be important to characterize the issue and take it into account, he argued.
Safety would be an obvious topic for consideration. He noted the phase 3 BELLINI trial, which showed a big PFS benefit for AbbVie and Roche’s Venclexta in patients with previously treated multiple myeloma but eventually linked the BCL2 inhibitor to an increased risk of death because of serious infections.
If the expert panel and the FDA eventually adopt MRD as an approveable endpoint, J&J could benefit. The large pharma company is testing its Legend Biotech-partnered CAR-T therapy Carvykti in first-line multiple myeloma.
Meanwhile, Sanofi could be among the first to take advantage of MRD in a regulatory filing. The French pharma is very encouraged by the results of a phase 3 trial coded IsKia, Peter Adamson, M.D., Sanofi’s global head of oncology development, said in an email interview. The study, which uses MRD as the primary endpoint, recently showed that a combination of Sanofi’s Sarclisa, Amgen’s Kyprolis, Revlimid and dexamethasone (KRd) was significantly better than KRd alone at improving MRD negativity rate in first-line myeloma patients. That readout came about three years after the trial had kicked off in Fall 2020.
Without detailing Sanofi’s regulatory plan, Adamson said “Sanofi is committed to exploring every option to support patients with multiple myeloma.”
“We know the FDA has been quite clear about minimizing the risk of deleterious long-term effects that might only be identified through overall survival data,” Adamson said. “However, we believe the preponderance of data support MRD being an appropriate surrogate endpoint for this disease.”
Allowing MRD as an intermediate endpoint to facilitate accelerated approval fits the FDA’s Project Frontrunner, Tendler argued. The FDA initiative aims to open up accelerated approval to cancer drugs for earlier treatment lines with the same randomized trial supporting both accelerated approval and a full nod.
“It’s one of those inflection points in myeloma drug development,” Tendler said, “which can have a significant and meaningful impact on being able to hopefully bring new promising agents earlier to patients and, in this framework, still be able to conduct the appropriate trials to prove the clinical benefit.”