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Research Efforts Are Underway for AL Amyloidosis
Volume 1
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Birtamimab Under Investigation in Mayo Stage IV AL Amyloidosis


Morie A. Gertz, MD, discusses the limitations of the current Mayo Stage IV amyloidosis treatment landscape, the rationale for investigating birtamimab in this population, and the importance of raising awareness for the AFFIRM-AL trial.

Morie A. Gertz, MD

Morie A. Gertz, MD

The monoclonal antibody birtamimab may improve survival and quality of life (QOL) outcomes in a subset of patients with light chain (AL) amyloidosis, according to Morie A. Gertz, MD.

The ongoing phase 3 AFFIRM-AL trial (NCT04973137) is investigating the efficacy and safety of birtamimab vs placebo plus standard-of-care (SOC) chemotherapy in previously untreated patients with Mayo Stage IV AL amyloidosis. The primary objective of this study is time to all-cause mortality, and additional objectives include six-minute walk distance and Physical Component Summary score.1

Previously, the phase 3 VITAL trial (NCT02312206) evaluated the agent vs placebo plus SOC in patients with newly diagnosed, treatment-naïve AL amyloidosis, who were stratified by Mayo stage. A futility analysis determined no significant differences in time to all-cause mortality between birtamimab and placebo, and this trial was terminated early. However, post hoc analyses demonstrated a potential benefit of birtamimab in patients with Mayo Stage IV disease, whose median overall survival (OS) was not reached in the birtamimab arm vs 8.3 months in the placebo arm.2

“This was a post hoc analysis, so it was only useful for hypothesis generation, but it certainly provides an excellent justification for initiating a phase 3 trial in patients with Mayo Stage IV disease and investigating birtamimab plus chemotherapy compared with placebo plus chemotherapy limited to patients with Mayo Stage IV disease,” Gertz said in an interview with OncLive®.

In the interview, Gertz, the chair of General Internal Medicine at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, discussed the limitations of the current Mayo Stage IV amyloidosis treatment landscape, the rationale for investigating birtamimab in this population, and the importance of raising awareness for the AFFIRM-AL trial.

OncLive: What unmet needs and treatment challenges exist with regard to the current SOC for patients with Mayo Stage IV amyloidosis?

Gertz: Patients with advanced cardiac amyloidosis are often delayed diagnosis and present with advanced heart failure with significant damage to their heart. When the heart is severely impaired, even with highly effective chemotherapy against the amyloid-producing plasma cells, stopping amyloid production does nothing to help the heart heal, and these patients continue to have a high mortality [rate]. Even with advances in chemotherapy, the fraction of patients that die within 6 months of diagnosis has not improved in 50 years.

What are the classification criteria for Mayo Stage IV amyloidosis?

There are several different staging systems, [including the] Mayo system and the European system. In the Mayo staging system, stage IVB means a patient meets all 3 of the following criteria: their N-terminal pro-brain natriuretic peptide [NT-proBNP] is [at least] 1800 ng/mL, their high-sensitivity troponin T [threshold] is greater than 40 ng/L, and the difference between their involved and uninvolved free light chain is [at least 18 mg/dL].

The European staging system is also highly effective. [Patients with] European stage IIIB cardiac amyloid disease have an NT-proBNP greater than 8500 ng/L. All these [stages] predict shorter survival with amyloidosis.

One agent under investigation in this population is birtamimab. What is this agent’s unique mechanism of action?

For over 50 years, the only treatment we’ve had available for AL amyloidosis is anti–plasma cell chemotherapy, which has moved from melphalan to cyclophosphamide to bortezomib [Velcade] and now daratumumab [Darzalex], where available. All these chemotherapy treatments are highly effective in the destruction of plasma cells, but they don’t do anything for resident amyloid in the tissue.

Birtamimab is a monoclonal antibody directed against a cryptic epitope on the fully formed amyloid fibril, as well as soluble toxic light chain intermediates, but has no effect at all on the fully formed immunoglobulin light chain. The antibody, once it binds to amyloid, activates macrophages, and can result in proteolysis, or engulfment and destruction of the amyloid fibril. We’re exploring anti–plasma cell chemotherapy to stop [amyloid] production and an anti-amyloid antibody, a depleter, to remove existing amyloid deposits in vivo.

Birtamimab was previously investigated in the phase 3 VITAL study in patients with AL amyloidosis. Although this was a negative trial, a post hoc analysis showed positive findings in patients with stage IV disease. What findings from this trial led to the initiation of the ongoing phase 3 AFFIRM-AL trial?

The VITAL trial, which looked at chemotherapy plus birtamimab compared with chemotherapy plus placebo, was terminated because of an interim futility analysis. The problem here was the inclusion of too many patients destined to do well, which would have required a decade of follow-up and probably 5 times as many patients.

However, when a post hoc analysis was done for patients at the highest risk of early mortality, patients with Mayo Stage IV disease, those who received birtamimab had twice the survival percentage at 9 months, with a hazard ratio of 0.413. They also had an improved QOL by looking at the SF-36 questionnaire and had an improved six-minute walk distance. All those [measures] achieved statistical significance.

What are the key goals of the AFFIRM-AL trial?

Based on what we know about the natural history of Mayo Stage IV disease, the AFFIRM-AL study is designed to produce a significant increase in OS at 9 months, meaning a reduction in all-cause mortality. In addition, we are [using] QOL measures and the six-minute walk test as both functional and patient-reported outcome measures of benefit.

Since this trial is limited to patients with Mayo Stage IV disease, what enrollment challenges exist?

We have 2 major barriers. One, with the introduction of daratumumab, certainly in the United States, patients are initiating therapy before they become aware that we have this exciting trial available to them. This trial is limited to treatment-naïve patients. If a patient is being seen in the community with Mayo Stage IV cardiac amyloidosis, it is imperative that they be referred so they can potentially enroll [in AFFIRM-AL] and benefit from an anti-amyloid, depleting molecule.

The second [challenge] is that [advanced AL amyloidosis] represents only [44%] of the total amyloid population. As physicians become more aware of this diagnosis, [patients are] being diagnosed earlier, [and Mayo Stage IV disease] may [comprise] less than [23%] of all amyloid patients in 2023.

What other agents are in development for patients with amyloidosis?

Caelum Biosciences is also investigating an amyloid-depleting molecule called CAEL-101. They currently have trials available for patients with Mayo Stage IIIA disease with an NT-proBNP greater than 800 pg/mL and patients with European stage IIIB disease. The former is a randomized, exploratory, single-arm trial.

Attralus has an agent that binds to amyloid that has been shown to be useful in imaging. It is also being investigated as a depleter. We’re excited about the landscape to try and remove amyloid deposits in vivo.

What is your main message for colleagues regarding the ongoing investigation of birtamimab in patients with Mayo Stage IV AL amyloidosis?

To bring birtamimab to the general amyloid population, it’s important that we complete accrual to [the AFFIRM-AL trial]. It’s imperative for [providers] who see patients with Mayo Stage IV cardiac amyloidosis to refer them immediately before treatment is initiated so we can enroll them and they can potentially benefit from amyloid-depleting antibodies.


  1. A study to evaluate the efficacy and safety of birtamimab in Mayo Stage IV patients with AL amyloidosis (AFFIRM-AL). Updated March 6, 2023. Accessed May 18, 2023.
  2. Gertz MA, Cohen AD, Comenzo RL, et al. Results of the phase 3 VITAL study of NEOD001 (birtamimab) plus standard of care in patients with light chain (AL) amyloidosis suggest survival benefit for Mayo Stage IV patients. Blood. 2019;134(supplement_1):3166. doi:10.1182/blood-2019-124482

Funding supported by Prothena. Content independently developed by OncLive.

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