After ODAC, What’s Next for MRD Testing in Multiple Myeloma?

More than 20 years after the first papers on the topic appeared, use of minimal residual disease (MRD) negativity is poised to become a common surrogate end point in accelerated approvals for therapies for multiple myeloma and perhaps for other blood cancers.¹ That's according to experts who appeared at a session to conclude the first day of the International Myeloma Society 21st Annual Meeting & Exposition, held in Rio de Janiero, Brazil.

Cochaired by Brian G.M. Durie, MD, of Cedars-Sinai, Los Angeles, and chair of the International Myeloma Foundation, and Jean-Luc Harousseau, MD, of Institut de Cancerologie de L’ouest France, the session, “MRD Is an End Point: Our Success Story,” explored the April 12, 2024, action of FDA’s Oncologic Drug Advisory Committee (ODAC). The panel voted unanimously that MRD-negative complete response (CR) could be used as a surrogate end point for accelerated approval.

Shaji Kumar, MD | Image credit: Mayo Clinic

As Shaji Kumar, MD, of Mayo Clinic explained in a presentation on the ODAC vote, the decision doesn’t mean FDA will be any less stringent in its oversight. This view was shared by panelist Carl Ola Landgren, MD, PhD, director of the Sylvester Comprehensive Cancer Center of the University of Miami. Landgren's work on the EVIDENCE meta-analysis² that led to the ODAC vote began in 2009, when he was with the National Institutes of Health. Including MRD negativity as an end point is, Kumar explained, is a recognition of the gains made in multiple myeloma and the need for a new way to measure efficacy of drugs. Speakers on the panel called it a hard-won victory that took years of trips to FDA and countless hours of work and collaboration.

The Price of Progress

The need for surrogate end points has arisen with better treatments, Kumar said; even transplant-ineligible patients are seeing progression-free survival (PFS) beyond 5 years, and virtually all phase 3 trials 3 have shown superior MRD negativity in investigational arm. “We haven't reached the median for some of the newer trials,” he said, adding, “It is only going to continue to improve as we have new therapies.”

“The price of the progress is that trying to design a clinical trial now to show an improvement of PFS from 60 months to 72 months—let’s say one year improvement—it’s going to take 1500-plus patients, follow-up of over 5 years in order to demonstrate that there is actually a meaningful improvement with a new therapy, and it's going to be increasingly impossible to do this in the newly diagnosed myeloma setting.”

At the same time, he said, similar challenges are emerging in the relapsed setting, “where we now have triplet regimens, [and] a first relapse with PFS that exceeds 3 years. So clearly, we need to have something else to measure” that can accurately represent PFS over a shorter period.

Enter the surrogate end point. MRD negativity measures whether myeloma cells can be detected in the bone marrow; testing has become increasingly sensitive over the past 2 decades, and MRD is now routinely a secondary end point in clinical trials; it's even the primary end point in some.

What ODAC examined, Kumar said, were 2 things; first, the petitioners had to show that MRD negativity could predict PFS at the patient level. Then, “There has to be what we call a trial level surrogacy,” which means “that the surrogate can actually be used to reliably predict the effect of treatment on the final end point.”

Still Lots of Questions

Nikhil Munshi, MD | Image credit: Dana-Farber

Nikhil Munshi, MD, of Dana-Farber Cancer Institute, and Jesus San Miguel, MD, PhD, of Clinica Universidad de Navarra, then took the audience through a high-level discussion of the evidence presented to ODAC on how the dozens of studies—83 in all—helped MRD negativity meet the bar as a surrogate both at the patient and at the trial level. Durie and Harousseau asked questions, and San Miguel and Munshi offered responses in the early discussion before they fielded questions with Landgren in an open session with the audience.

San Miguel discussed the value of MRD negativity relative to the traditional criterion of complete response (CR). He displayed a data set that showed when patients who have achieved CR but are MRD positive are removed taken out of the numbers, the remaining patients are similar to those who are very good partial responders. “In fact, we consider that MRD negativity is the new CR.”

Jesus San Miguel, MD, PhD | Photo credit: ESMO

Munshi next discussed the issue of sensitivity—in other words, how low do we need to go? Although published studies now record levels MRD negativity to 10^-6 and even 10^-7, the agreed-upon standard for FDA is a threshold of 10^-5, which means a test must detect the presence of myeloma cells in the bone marrow with a sensitivity of 1 in every 100,00 healthy cells.

Is more sensitivity ever needed based on patient population? San Miguel answered this question with a meta-analysis by Munshi.³ “In fact, the MRD negative high-risk [patients] did nearly as well as the MRD negative standard risk patients,” San Miguel said.

Other points that were discussed:

• The ODAC vote, although unanimous, is not a final FDA approval; it was also noted that the question before ODAC was for a composite end point, “MRD-negative CR.” Landgren emphasized that during the EVIDENCE study, the FDA was “very picky” that MRD and the CR measurement take place within the same 3-month window.
• Dorie noted that the ODAC vote does not recommend use of MRD negativity as a full surrogate, as it is recommended for accelerated approval. If long-term findings showed that PFS or overall survival (OS) results did not align with findings based on MRD negative CR, FDA would have to decide what to do about the approval.
• Dorie emphasized that while Landgren and the I2TEAMM each made presentations before ODAC, the FDA did its own analysis, and “all indicated a higher level of correlation.”
• In response to questions, panelists said the use of MRD negative CRD for accelerated approval was not limited to new therapies and could conceivably be used for accelerated approval of existing therapies in earlier lines of care.
• There were several questions whether European regulators will follow suit. San Miguel credited Dorie with trying to advance the matter in early 2020, but the pandemic sidelined the effort. Recent conversations have been “very positive,” San Miguel said. “I think we are in the right direction now, at this point in time with the European Commission.”

Moving the Field Forward

Carl Ola Landgren, MD, PhD | Image credit: Sylvester Comprehensive Cancer Center

On the day of the ODAC hearing, both Landgren’s group and a consortium led by Durie, I2TEAMM, presented ODAC with data collected over more than a decade in support of their request. During the discussion, Landgren said once the teams started collaborating, they discovered FDA had asked the I2TEAMM to provided MRD negativity measurements at 9 months, plus or minus 3 months, and the EVIDENCE team at 12 months, plus or minus 3 months, which Landgren found to be “very smart.”

“If you check multiple things, it’s better,” he said.

In the early years, Landgren said, the 2 groups were competing to some degree, but as the projects reached conclusion, “we worked closely with each other to align everything when we went to ODAC, to make sure we have one, single voice. To me, this is how group science works in the modern era—where you share with each other.”

The process helped correct statistical flaws that could have undermined the FDA presentation, he said. “To me, the most important message to everyone here today, is that we really have to work for the greater good. It's not about writing a paper or being famous. It's really to move the field forward.”

References

1. Yu Z, Xie L, Zhang J, Lin H, Niu T. The evolution of minimal residual disease: key insights based on a bibliometric visualization analysis from 2002 to 2022. Front Oncol. 2023;18:13: 1186198. doi: 10.3389/fonc.2023.1186198.
2. Landgren O, Prior TJ, Masterson T, et al. EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma. Blood. 2024;144(4):359-367. https://doi.org/10.1182/blood.2024024371
3. Munshi NC, Avet-Loiseau H, Anderson KC, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988-5999. doi: 10.1182/bloodadvances.2020002827.