FDA’s oncology advisory committee to consider MRD as a multiple myeloma endpoint

Intro to multiple myeloma

• Cancers of the blood and bone marrow can affect production and function of white blood cells, red blood cells, and platelets, all produced by hematopoietic stem cells. These stem cells generate billions of new cells each day and are remarkably able to self-renew, an ability that most of the cells they produce (e.g., immune cells and other blood cell types) lack. When this production process goes awry, the specific diagnosis of disease or condition depends on where the malfunction in cell proliferation occurs, and what the impact is on downstream processes.
• In myelomas, B cells, a type of immune cell, overproduce plasma cells, which crowd out other types of blood cells in the bone marrow. Different subtypes of myeloma are labeled and staged according to the prevalence and histology of the plasma cells and the proteins they produce.
• When abnormal plasma cells build up in multiple locations in the bone marrow, the disease is called multiple myeloma (MM). This type of hematological malignancy affects fewer than 50,000 people in the U.S., is more common with increasing age and in males, African Americans, and those with a family history, among other risks. Treatment for this cancer may be lifelong, with patient and disease characteristics guiding the course of treatment. Patients frequently receive up to four therapies at once and go through multiple prolonged courses of treatment to keep recurrence and progression at bay. Between 2012 and 2018, the five-year relative survival rate for patients with MM was 57%.

Current treatment options

• There are several types of products approved to treat multiple myeloma, and patients are typically prescribed a cocktail of 2-4 products. Commonly combined treatment options include antineoplastics (chemotherapies), radiation therapy, corticosteroids, immunomodulators, proteasome inhibitors, and monoclonal antibodies. Hematopoietic stem cell transplantation (HSCT) is another mainstay of MM treatment, though not all patients are eligible for this option. Over time, as more and more of these products have been approved, the ever-growing list of potential combinations has also grown. The specific combination that is recommended is informed by factors such as whether the patient is newly diagnosed, is preparing to undergo autologous HSCT, or has already undergone one or more treatments without an adequate or durable treatment response.
• More recently, CAR T cell therapies have been approved to treat advanced multiple myeloma. First, Celgene’s Abecma (idecabtagene vicleucel; ide-cel) received approval to treat relapsed or refractory disease (RRMM) “after four or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody,” according to the March 2021 approval letter. Janssen’s Carvykti (ciltacabtagene autoleucel, or cilta-cell) then received approval in February 2022 for treatment of adult patients with RRMM and the same treatment history as that required for treatment with ide-cel. However, the process of preparing and delivering these therapies takes time. Especially in the setting of a clinical trial, the logistics of CAR T cell delivery can mean that the entire process can span 8-12 weeks, with patients needing to undergo a treatment washout period from standard-of-care (SOC) therapy at two points: 1) After initial screening and before apheresis to harvest their T cells, 2) Before CAR T cell infusion. In the interval, most patients (up to 80%) will require bridging therapy to stave off their myeloma, which is typically an aggressive disease.

Minimal residual disease (MRD) as an oncology biomarker— and an endpoint

• Minimal residual disease (MRD) is described in FDA’s 2020 guidance on the use of MRD for hematologic malignancies as the detection of malignancies at low levels by measuring cell characteristics such as genetic mutations, cell surface markers, or specific DNA gene rearrangements. As was outlined by the FDA in the guidance, there are several technologies capable of measuring MRD, including multiparametric flow cytometry (MPFC), next-generation sequencing (NGS), quantitative reverse transcription polymerase chain reaction (RT-qPCR) of specific gene fusions, and allele specific oligonucleotide polymerase chain reaction (ASO-PCR).
• MRD’s acceptability as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker is highly dependent upon its specific context of use. While the FDA generally considers MRD to be a “ general measure” of tumor burden, the agency’s opinion on whether MRD is acceptable for regulatory use depends on the disease it is used to assess. For instance, when FDA issued the MRD guidance in 2020, the list of disease-specific considerations called MRD “one of the most significant prognostic factors” in acute lymphoblastic leukemia, regardless of a host of disease and patient factors. In contrast, that guidance also stated that “the molecular heterogeneity of AML [acute myeloid leukemia] poses substantial challenges to the use of MRD as a biomarker.”
• Challenges in using MRD: While each method is able to detect the presence of malignancies at a lower level than conventional morphologic methods, which have a threshold limit of one tumor cell per 100 cells, the Agency also noted that there is a high likelihood for “discrepant results” when comparing MRD measurements due to potential variation in techniques and tools from one laboratory to the next.
• The use of MRD in multiple myeloma: Regarding the use of minimal residual disease in MM, the guidance stated that “significant improvements in clinical outcomes of MM have spurred interest in the use of MRD as a potential surrogate endpoint to expedite drug development.” At that point, MRD had been used most often to evaluate the persistence of multiple myeloma via the examination of bone marrow using multiparametric flow cytometry (MPFC) and next-generation sequencing (NGS) methods.
• However, a major limitation noted by the guidance was that MRD has mostly been used in the context of newly diagnosed MM patients in the post-transplant setting. As a result, the guidance stated that “The relationship between MRD and clinical benefit and the test performance characteristics should be demonstrated in each disease setting (e.g., relapsed refractory, newly diagnosed, nontransplant eligible, smoldering MM) to validate MRD as a surrogate endpoint in MM.”
• During a panel at the American Society for Clinical Oncology (ASCO) annual meeting last June, R. ANGELO DE CLARO, Associate Director for Global Clinical Sciences at FDA’s Oncology Center of Excellence (OCD) and Division Director at Division of Hematologic Malignancies I, spoke broadly about the use of MRD as an endpoint. In response to a comment from industry that the only validated endpoints the FDA seems currently willing to consider as surrogate endpoints are overall response rate and progression-free survival; De Claro responded, “You’re right, there are various earlier endpoints to consider; there’s MRD negativity, or even CtDNA [circulating tumor DNA] -based endpoints.” The FDA’s ask of sponsors, he said, is to “provide us the data to support that these endpoints will be reasonably likely to predict clinical benefit.” The ideal scenario is to have a clinical trial that prospectively evaluates these endpoints, he said, providing a data package the FDA can use to evaluate such alternative endpoints.

What’s new?

• This week, the FDA announced that its Oncologic Drugs Advisory Committee (ODAC) will meet in April to weigh in on the “the use of minimal residual disease (MRD) as an endpoint in multiple myeloma clinical trials, including considerations regarding timing of assessment, patient populations, and trial design for future studies that intend to use MRD to support accelerated approval of a new product or a new indication.” The meeting will take place on April 12, 2024, 9 a.m. to 4 p.m. Eastern Time.

What’s next?

• What will be discussed? While the announcement does not provide further information about whether the discussion will focus on specific products or trials, MRD has been more frequently used as a secondary endpoint in trials to evaluate various combinations of “conventional” MM products, and in trials to investigate the efficacy of CAR T cell products to treat multiple myeloma as well. To provide a sense of how quickly the treatment landscape in MM is evolving, MRD is even now being used as a secondary endpoint in trials to investigate the use of products in patients with relapsed or refractory multiple myeloma following treatment with a CAR T cell product. In light of these developments, this new meeting announcement suggests that FDA is ready to reconsider the use of MRD as a primary efficacy endpoint in patients with multiple myeloma.
• The ODAC just met two weeks ago to discuss two CAR T cell products for the treatment of MM. However, despite the use of MRD as an endpoint that was measured and evaluated for both of these treatments, the biomarker wasn’t a primary endpoint and did not receive much mention during the meeting. [Read the full analysis of the advisory committee meeting here]
• Other potential uses of MRD to improve patient outcomes: In recent years, researchers have also been investigating the use of MRD to predict patients’ magnitude and durability of response to treatments. For instance, just last month, a new article was released that demonstrated MRD status could be used to identify patients with B-cell acute lymphoblastic leukemia at high risk for adverse outcomes and/or relapse within one year of CAR T-cell infusion. Moreover, the results from the MASTER trial, described as “the first published clinical trial in patients with newly diagnosed multiple myeloma to use prospective adaptation of treatment duration—including the possibility of treatment cessation—based on reaching MRD-negative status,” are especially significant on this front. The second iteration of the trial, now underway, is expected to build further on these results by using MRD to guide treatment selection for patients with multiple myeloma.
• Of note, the announcement states that “FDA and invited participants may attend the meeting at FDA White Oak Campus” without mention of any committee members attending remotely. The use of the permissive or conditional term “may” aligns with some of the discussion about a “new and improved” ODAC heard from RICHARD PAZDUR, the director of FDA’s Oncology Center of Excellence (OCE), just last week. He described the importance of in-person meetings for “spontaneity and an active exchange of ideas.” Another concept that has been frequently discussed in regard to potential advisory committee reforms is whether a disease-specific expert should be invited to advisory committee meetings, especially when it comes to the discussion of products to treat rare diseases. Such an expert spoke at the ODAC meeting that reviewed the two CAR-T products earlier this month, where Memorial Sloan Kettering Cancer Center’s SHAM MAILANKODY gave an overview of the treatment landscape. While it’s too soon to tell whether an expert on multiple myeloma will be invited to the upcoming meeting, it’s something AgencyIQ will be keeping an eye out for.

Featuring previous research by Kari Oakes.

To contact the author of this item, please email Rachel Coe ( [email protected]).
To contact the editor of this item, please email Kari Oakes ( [email protected]) .

Key documents

Oncologic Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments-Use of Minimal Residual Disease as an Endpoint in Multiple Myeloma Clinical Trials