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FDA's ODAC Votes 12 To 0 That MRD Is A Viable End Point In Myeloma Trials

The Oncologic Drugs Advisory Committee determined that minimal residual disease could serve as an accelerated approval end point in multiple myeloma clinical trials.

CAR T-cell therapy in multiple myeloma: © Kasloom - stock.Adobe.Com

In a 12 to 0 vote, the FDA's Oncologic Drugs Advisory Committee (ODAC) decided that evidence supported that minimal residual disease (MRD) could be used as an accelerated approval end point in clinical trials of multiple myeloma.

"I think the sets a precedence of actually moving the field forward, not only for the patients to get the drug earlier, but can we stop therapy based on MRD? If the duration of MRD is longer with better treatments, it kind of opens up a whole other way of even maybe treating patients where you don't have this continuously, where you can get treatment gaps like you do in solid tumors," said Ranjana H. Advani, MD, ODAC member and Saul Rosenberg Professor of Lymphoma, Division of Oncology, Stanford University School of Medicine.

Establishing MRD as an End Point in Multiple Myeloma Trials

Nicole Gormley, MD, associate director of oncology end point development for the FDA's Oncology Center of Excellence and director of the Division of Hematologic Malignancies II, presented guidance on how clinical end points were established for regulatory decisions.

"Approval is based on demonstration of clinical benefit or an effect on an established surrogate accelerated approval is intended for products that treat serious or life-threatening illnesses, taking into account the condition and availability of alternative treatment options. It should provide a meaningful benefit," Gormley said."In order for a biomarker to be a true surrogate for a long-term outcome of interest, it should be in the causal pathway between treatment of the disease and the true clinical end point of interest."

Gormley noted that most oncology accelerated approvals are based on intermediate clinical end points, including overall response rate (ORR), progression-free survival (PFS), and event-free survival. However, Gormley noted that it is "rare that there are true surrogates in oncology."

According to Gormley, considerations for how novel end points can be developed in oncology is important, which can include relying on meta-analysis data, including patient-level data from multiple clinical trials to evaluate individual- and trial-level surrogacy.

However, Gormley noted, "There are caveats regarding the use of a surrogate endpoint, even those that are fully clinically validated." These caveats include that the surrogate may not be appropriate for subpopulations or future trial populations if there are significant differences between the meta-analysis and new trial populations. Further, the therapeutic modalities may have a substantially different mechanism of action than those of the therapeutics included in the meta-analysis.

Bindu Kanapuru, MD, associate director of therapeutic review in the Division of Hematologic Malignancies II, presented additional regulatory considerations. These included assay considerations, like ensuring that the assays used had adequate performance, were appropriately validated for the context of use, and used standardized procedures of sample collection and processing. Kanapuru also highlighted the importance of confirmatory trials to verify clinical benefit and expedited withdrawal for drugs that do not verify benefit from the market.

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman - stock.Adobe.Com

Applicants' Perspectives

Representatives of 2 meta-analyses evaluating MRD as a surrogate for PFS and overall survival (OS) were present at the ODAC meeting. C. Ola Landgren, MD, PhD, presented background on the EVIDENCE meta-analysis.

Landgren began with an overview of the MRD initiative in myeloma, noting its beginnings in 2009 with an interagency collaboration with the FDA, National Cancer Institute, and National Heart, Lung, and Blood Institute to establish MRD as a regulatory end point. In 2021, Landgren noted that the FDA approved the initiative's statistical analysis plan for this evaluation.

"We do not yet have an established curative treatment [for multiple myeloma]. The most effective treatments are in the first line with our current end points, progression-free survival and overall survival. For patients with newly diagnosed multiple myeloma, we're taking a long time to mature. New effective therapies are unavailable to patients for more than 10 years while waiting for studies to mature," said Landgren, professor of medicine, chief of the Division of Myeloma, and director of the Sylvester Myeloma Institute at the Sylvester Comprehensive Cancer Center, University of Miami.

Based on PFS results in clinical trials, following an average of 2 years for adequate patient recruitment, comparative studies may now require over 8 years to show a statistically significant effect of a new therapy. Landgren also added that 15% to 35% of patients are lost at each line of multiple myeloma therapy and that establishing effective frontline therapies is a primary goal of multiple myeloma treatment.

While ORR has been used as an intermediate end point in myeloma studies, Landgren noted that it is not a good intermediate end point among the newly diagnosed population, as the assessment for ORR only requires a 50% reduction in disease.

"To accelerate the availability of new and effective treatments for patients with multiple myeloma, an objective and reliably measured early end point that is reasonably likely to predict long-term outcomes and clinical benefit is urgently needed," Landgren said.

Landgren noted that in January 2020, the FDA published guidance on 2 potential uses of MRD in drug development: as a validated surrogate end point for traditional approval, or as a surrogate end point reasonably likely to predict clinical benefit for accelerated approval. The strength of evidence required for a surrogate end point was based on biological plausibility of the relationship, demonstration of the prognostic value of the surrogate end point for the clinical outcome, and evidence from clinical trials that treatment effects on the surrogate end point correspond to effects on the long-term clinical outcome.

"MRD fulfills all these criteria in multiple myeloma," Landgren said.

Sean Devlin, PhD, associate professor of biostatistics and associate attending biostatistician at Memorial Sloan Kettering Cancer Center, presented data, methodology, and results of the EVIDENCE meta-analysis. The analysis included data from 16 phase 2 or 3 randomized clinical trials in patients with newly diagnosed transplant-eligible or -ineligible multiple myeloma. The investigators of EVIDENCE also established a sensitivity cutoff for MRD assays of 10-5 or better.

At an individual level, MRD and PFSand MRD and OS were strongly associated according to a Copula global odds ratio with a 95% confidence interval. Devlin and Landgren summarized that the results supported the consideration of MRD as an early clinical end point reasonably likely to predict clinical benefit in multiple myeloma that may be used to support accelerated approval.

The second industry presentation was from the International Independent Team for Endpoint Approval of Myeloma Minimal Residual Disease (I2TEAMM). Brian G. M. Durie, MD, Cedars-Sinai Comprehensive Cancer Center, presented the advantages of MRD as an early end point. These include earlier readouts of 9 to 12 months, timely approvals of life-saving therapies and combinations, and major positive impacts for patients.

"In myeloma, MRD negativity is the new complete remission," said Bruno Paiva, PhD, director of flow cytometry in the Department of Hematology and Immunology at the University of Navarra, Spain, and a member of I2TEAMM.

Qian Shi, PhD, professor of biostatistics and oncology at Mayo Clinic, presented data and results from I2TEAMM's meta-analysis. The findings similarly showed a high individual-level correlation between MRD and PFS/OS. The 9- and 12-month MRD negativity rate at 10-5 sensitivity threshold reasonably likely predicted clinical benefit of PFS and OS among patients with newly diagnosed transplant-eligible and -ineligible and relapsed/refractory multiple myeloma.

FDA's Perspective

Rachel Ershler, MD, MHS, clinical reviewer for the Division of Hematologic Malignancies II, and Jing Zhang, PhD, statistical reviewer for the Division of Biometrics IX, presented the FDA's considerations on the discussion. Ershler and Zhang noted that the FDA agreed with the general approaches and interpretation of the results.

Zhang confirmed that in the I2TEAMM and University of Miami analyses, there was a strong individual-level association for PFS and OS, but trial-level associations were weak to moderate in disease subpopulations for PFS and were generally weaker for OS.

Ershler explained that a strong trial-level association could become a validated surrogate end point and support regular approval; however, very few oncology end points have met this standard, and most end points that support accelerated approval have not been assessed for trial-level surrogacy or have weak trial-level associations.

Zhang also presented strengths and weaknesses of the meta-analyses. Strengths included the broad experience across multiple settings and randomized trials, high sensitivity of assays used, and stringent analysis methods that had been discussed with the FDA. However, the heterogeneity in trial designs, variations in MRD assays used, and unknown impact of disease setting were identified as limitations.

ODAC's Decision

The first discussion question posed to the ODAC was to the adequacy of the available data to support the used of MRD as an accelerated approval end point in multiple myeloma.

"When you look at the data, especially the patient-level data, I think that's clear that it meets the criteria for accelerated approval. I think that this is 1 of the most prognostic tests that we've seen in the disease," said Christopher Lieu, MD, ODAC member and associate professor of medicine at the University of Colorado Cancer Center.

"In terms of the biologic significance…there certainly is the biologic correlation that if you get that low with your MRD, you're probably going to have a longer [response]. Responders do better," Thomas Martin, MD, ODAC member and associate chief of the Division of Hematology/Oncology at the University of California San Francisco.

The second discussion topic posed was whether the available data supports the use of MRD as an endpoint in different myeloma disease settings, and the third discussion topic was about the acceptability of time points for MRD assessment. The voting question asked if the evidence supported the use of MRD as an accelerated approval end point in multiple myeloma clinical trials.

"There is great harm in not acting," said Christopher Hourigan, DM, DPhil, temporary ODAC member and director of the Virginia Tech Fralin Biomedical Research Institute Cancer Research Center.

REFERENCE: Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 12, 2024. Accessed April 12, 2024. Https://tinyurl.Com/2rexatkp

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Tracking A Mystery In Non-Secretory Myeloma

There is no difference in treatment for non-secretory multiple myeloma and multiple myeloma, an expert told CURE®.

Patients with non-secretory myeloma, a disease affecting a relatively small number of individuals, can face obstacles including difficulties in receiving a diagnosis, a scarcity of available clinical trials and a lack of connection with fellow patients.

About 98% of people with multiple myeloma have proteins in their blood that can be measured and followed over time, according to Dr. Sascha A. Tuchman, a hematologist and medical oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill.

When doctors do blood tests for multiple myeloma, because the myeloma cells stay in the bone marrow, the tests can't typically show the actual myeloma cells, Tuchman notes.

"However, in most cases, multiple myeloma conve­niently makes those immunoglobulin proteins that circulate in the blood," he says. "We can measure those proteins and that enables us to track the disease. As levels go up or down, that typically tells us the myeloma in the person is growing or shrinking."

However, that's not the case for everyone with multiple myeloma, as 1% to 2% of patients with myeloma don't secrete any proteins that can be measured in blood or urine.

"Non-secretory myeloma is not necessarily a separate disease," explains Dr. Nisha Joseph, a hema­tologist and medical oncologist at the Winship Cancer Institute at Emory University in Atlanta, Georgia. "It presents differently in that when we are evaluating these patients either at diagnosis or relapse, we notice that they don't secrete this abnormal paraprotein or monoclonal protein in either their blood or urine, which is an important part of our diagnostic workups." (Paraprotein and monoclonal protein are other terms for immunoglobulin secreted by myeloma.)

According to Joseph, the definition of non-secretory myeloma is that the patient has a negative serum immunofixation (a test for specific proteins in the blood), negative urine immunofixation (a test for abnormal proteins in urine) and normal serum free light chain assay (a blood test for proteins made by plasma cells).

"These are three of the tests we use to detect the abnormal protein that myeloma cells secrete," she says. "It is essentially a surrogate marker for how much myeloma there is in the body and, usually, the bone marrow."

'Something is Wrong.'

It's been nearly 20 years since Vicki Jones was diagnosed with multiple myeloma, a cancer of the plasma cells. Much of her past two decades have revolved around monthly blood tests to monitor levels of a protein — in her case, immunoglobulin A lambda (IgA) — secreted into her blood by myeloma cells.

Non-secretory myeloma is rare and may become a lonely journey, but Vicki Jones found comfort in a support group for patients like her.

Photo Credits: Elona Shea

"For 17 years, IgA was a completely reliable marker," Jones says. "We tested it every month and knew exactly whether chemo­therapy was working. I had a stem cell transplant in 2007 and was on many different chemotherapy types after that. I was never in a complete remission."

Then, something changed. Jones, 71, of Spokane, Washington, says she was taking a three-drug combination to control the myeloma. She took Darzalex (dara­tumumab), a monoclonal antibody that blocks proteins fueling myeloma cell growth, as well as a corticosteroid drug called Revlimid (lenalidomide) and an immunosuppressant called dexamethasone.

Jones says her IgA levels had been consistent for several years. With her doctor's blessing, she stopped her medication to get a COVID-19 vaccine. About a month later, her blood test showed her IgA levels had dropped. In fact, her numbers had improved so much that her doctor told her she could take a break from the drugs.

The next month's regular blood test showed her IgA numbers had dropped again, this time to a level that was better than they ever had been, Jones says.

"That's when I said, 'That's not the way things go for me,'" she says. "'Miracles do happen, but I don't think this is one. Something is wrong.'"

A bone marrow biopsy confirmed her instinct. "I had relapsed big time," she says. "I had 80% myeloma cells in my bone marrow, which is huge. That number had always been about 15% at the most through the years."

To continue monitoring, Vicki Jones undergoes bone marrow biopsies every four months since she received her diagnosis of non-secretory multiple myeloma.

Photo Credits: Elona Shea

Her myeloma had become non-secretory myeloma, a rare condition in which myeloma cells don't secrete or produce proteins. "I felt like I had been diagnosed all over again," Jones adds. "On the outside, I was totally calm. But on the inside, I was scared to death."

Plasma cells located in the bone marrow under normal circumstances help a person's immune system by making proteins called immunoglobulins (antibodies) that bind germs and viruses and kill them. But when plasma cells become cancerous, they grow too much, invade spaces they're not supposed to be in and secrete abnormally high levels of one clone of antibody protein but at the expense of the normal diversity of antibodies made by the collective immune system. That's multiple myeloma.

Myeloma can cause a shortage of different blood cell types and brittle bones that break easily. Myeloma can also cause problems with the kidneys, such as kidney failure, when the kidneys stop working entirely due to the toxic effects of the high clonal antibody load.

Typically, myeloma cells live in the bone marrow and don't circulate in the blood, but myeloma secretes immunoglobulin proteins into blood, after which the proteins are cleared through the kidneys and excreted into urine. Hematologist oncologists rely on these proteins as markers of myeloma activity to determine if myeloma is stable, improving or worsening.

Non-secretors present a diagnostic challenge, according to Tuchman. He notes that hematologist oncologists may suspect myeloma if a person has low blood counts or high blood calcium levels. Doctors may also detect holes in the bones (bone lesions) when someone has an X-ray or other imaging test.

"Those findings often prompt bone marrow biopsy, which leads to a diag­nosis," he says.

Jones estimates that she has had at least 20 bone marrow biopsies since being diagnosed with multiple myeloma — four of which have been since she became a non-secretor. "It's been pretty much every four months," she says, noting that she also has regular PET scans.

Doctors don't treat patients with non-secretory myeloma any differ­ently than they treat those who have myeloma that secretes proteins.

"Everything is exactly the same," says Dr. Shaji Kumar, a hematolo­gist and internist at Mayo Clinic in Rochester, Minnesota. "Other than the difference in biology in terms of the secretion of the protein itself, we don't really think the disease behaves differently when comparing the non-secretory type versus the secretory type."

Most patients with multiple myeloma receive a combination of chemotherapy or targeted therapy drugs, along with a steroid. Some patients also have a bone marrow or stem cell transplant. However, multiple myeloma isn't curable. That's why monitoring the disease and its response to treatment is so critical. Patients with myeloma often relapse after some time in remission.

"Once the disease comes back, we try to use different combinations of drugs and mix and match them to make sure we have drugs that patients haven't seen before," Kumar notes. "We also look at side effects they have had with previous therapy, the logistics of administration and whether somebody can come to the clinic once or twice a week to get infusions or (whether) they prefer oral therapies. All those considerations go into making that decision."

Monitoring patients for relapse is systematic for most individuals with myeloma, as they have intermittent blood and urine tests — but that's not possible for non-secretors.

"We cannot monitor their blood tests month after month," Joseph says. "There (are) no set guidelines on frequency, but we rely on serial bone marrow biopsies and PET scans, MRIs or some kind of definitive imaging.

Limited Data and Bouts of Frustration

Some patients with myeloma participate in clinical trials of multiple myeloma drugs, giving them access to new therapies. But that's not typically an option for those with non-secretory myeloma, as the condition is so uncommon.

"There's just not a lot of data on this, because non-secretory myeloma is a relatively rare phenomenon," Tuchman says. "Most studies exclude non-secretory myeloma."

That's because, according to Tuchman, the standard systems for assessments of response on clinical studies, such as published response criteria by groups such as the International Myeloma Working Group (IMWG), are based on tracking the immuno­globulin protein patterns. Patients start a new treatment, myeloma cells die and make less protein, blood and urine immunoglobulin levels hopefully drop, and that tells clinical researchers, physicians and patients that the treatment is working.

In people with non-secretory myeloma, "it's impossible to measure response by the standard, protein-based systems, and use those patients' experience to learn what you're trying to learn from the study," he says.

Tuchman notes that large multi-institutional registry studies include databases that can be analyzed to provide some insight into the experiences of individuals with non-secretory myeloma. There's also much to be learned from the patients themselves.

The HealthTree Foundation, which works to help patients with blood cancers learn about their disease, has started a support community specifically for individuals with non-secretory myeloma. Jones, who serves as a coach for HealthTree and co-leader of its non-secretory myeloma group, has been involved with the group since it began.

"It lets us compare notes and talk to one another and see [whether] things are consistent," she notes. "Once I found other [patients] who were also non-secretors, it was just so comforting.

"We've had doctors come and talk to our group, and we've been encouraging them to use us. We're telling them, 'Hey, we are something you've never seen before; we are a very large group of non-secretors. I think that should be pretty useful to researchers. Here's your study right here — just ask us."

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