Findings from an analysis of treatment patterns for patients with systemic amyloid light chain (AL) amyloidosis have demonstrated that several unmet needs exist, including timely diagnosis and limited survival outcomes for patients with advanced disease.

 Although the disease is rare, investigators have made efforts to categorize AL amyloidosis through prognostic staging and risk stratification.

AL amyloidosis shares characteristics with multiple myeloma, and patients with bone marrow plasma cells of 10% or less may receive a diagnosis of the disease.

 For staging purposes, cardiac characteristics play a prominent role in not only determining prognosis but the available treatments a patient is eligible to receive. Biomarkers include serum levels of cardiac troponin T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP).

“There are several different staging systems, [including the] Mayo system [

] and the European system,” Morie A. Gertz, MD, chair of general internal medicine at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, said in an interview with 

. “[For example,] in the Mayo staging system, stage IV means a patient meets all 3 of the following criteria: their NT-proBNP [level] is [at least] 1800 pg/mL, their high-sensitivity cTnT [threshold] is greater, 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 [level] greater than 8500 pg/L. All these [stages] predict shorter survival with amyloidosis.”

Vaishali Sanchorawala, MD, expanded on the staging system, underscoring the importance of finding a diagnosis for patients as soon as possible. “Unmet needs in advanced cardiac AL amyloidosis are early diagnosis and the [prompt] recognition of red flag symptoms,” Sanchorawala, director of the Autologous Stem Cell Transplantation Program at Boston Medical Center in Massachusetts, said in an interview. “The most important [symptom] is the reversal of organ dysfunction that is related to amyloid deposition, because this [affects] the survival as well as quality of life for patients with AL amyloidosis. The staging system has evolved in the past several decades, and the Mayo 2012 staging system incorporates not only the cardiac biomarkers, but it also incorporates the markers of plasma cell dyscrasia…. This staging system can risk-stratify patients into 4 different stages, with stage IV being patients with advanced disease with a median overall survival of less than 6 months.” Using the Mayo staging system, approximately 23% of patients with AL amyloidosis have stage IV disease.

Results of a post hoc analysis from the phase 3 VITAL study (NCT02312206) show that patients with advanced AL amyloidosis experienced a survival benefit with the monoclonal antibody birtamimab (formerly NEOD001).

 “The VITAL trial, which looked at chemotherapy plus birtamimab compared with chemotherapy plus placebo, was terminated because of an interim futility analysis,” Gertz said. “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 an HR of 0.413. They also had an improved quality of life by looking at the SF-36 [36-Item Short Form Survey] questionnaire and had an improved 6-minute walk distance. All those [measures] achieved statistical significance.”

Findings from the VITAL study were presented at the 63rd American Society of Hematology Annual Meeting and Exhibition. They specifically showed that among 38 patients who were assigned to birtamimab, 74% were alive at 9 months vs 49% for those assigned to placebo (n = 39; HR, 0.413; 95% CI, 0.191-0.895; 

“I present [birtamimab] to patients as an amyloid-busting agent,” Sanchorawala said. “It is a humanized IgG1 monoclonal antibody that selectively binds both λ and κ isoforms of soluble light chains…. This particular agent binds to the epitope and leads to removal of the amyloid deposits and the soluble aggregates via phagocytosis.”

Because these findings were assessed in the post hoc manner, a confirmatory phase 3 global study has been initiated, known as the AFFIRM-AL trial (NCT04973137). Investigators will evaluate patients with Mayo stage IV AL amyloidosis treated with birtamimab 24 mg/kg every 28 days in combination with standard-of-care chemotherapy of a bortezomib (Velcade)-containing regimen chemotherapy vs placebo and chemotherapy.

“The key inclusion criteria are newly diagnosed, treatment-naïve, AL amyloidosis with cardiac involvement, which require stage IV [classification] by Mayo 2012 staging system,” Sanchorawala explained. Of note, Sanchorawala said that patients cannot receive bortezomib or daratumumab (Darzalex) in the community setting because it would make them ineligible for enrollment.

The primary end point of the AFFIRM-AL trial is time to all-cause mortality. Secondary end points include change from baseline to month 9 in the 6-minute walk test distance and physical component summary scores of the SF-36 version 2. The 36-item quality-of-life (QOL) questionnaire is self-administered and measures health on functional status, well-being, and overall evaluation of health.

In the VITAL study analysis, there was a statistically significant advantage of birtamimab with a difference of 4.65 points (

=.046) in SF-36 physical component score change from baseline at month 9. Furthermore, birtamimab was associated with a 36.37-m improvement in the 6-minute walking test compared with placebo (

In terms of safety, birtamimab was well tolerated in the overall population (n = 130 in each arm) and in patients with Mayo stage IV disease. Among those with stage IV disease treatment-related adverse effects (TRAEs) were more common in the experimental arm (n = 38; 31.6%) than the placebo arm (n = 39; 25.6%); however, grade 3 or higher TRAEs were more common in the placebo arm (2.6% vs 10.3%). Incidence of serious TRAEs was 2.6% in both arms. There were no grade 5 TRAEs in either arm.

The 4 most common treatment-emergent AEs (TEAEs) were peripheral edema (55.3% vs 48.7%), constipation (42.1% vs 33.3%), nausea (42.1% vs 30.8%), and dyspnea (42.1% vs 30.8%) in the experimental vs placebo arms, respectively.

 Infusion-associated TEAEs were experienced by 3 patients, with 1 patient in the experimental arm reporting dyspnea, 1 patient reporting chest discomfort, and 1 patient reporting hypoxia concurring with an infusion-related reaction. TRAEs led to drug discontinuation in 7.9% of those in the birtamimab arm vs 5.1% of those in the placebo arm.

“[VITAL] was a post hoc analysis, [but] when you have such a strong signal, then you want to further clarify the benefits of a treatment and the value of a treatment. If the [results from the AFFIRM-AL] study prove to be positive, that will be a smaller solution in the [management] of AL amyloidosis,” Efstathios Kastritis, MD, associate professor at the National and Kapodistrian University of Athens in Greece, said in an interview with 

. “We urgently need something more for the treatment of patients with advanced cardiac disease, [and] we know that we can [manage] the plasma cell clone that causes the losses; however, we are still in desperate need [of] treatments that can improve organ function and reduce mortality. This is something that we need as vividly as this is an unmet need it if this is a positive study [result], I think it will be a huge advance in the [management] of this disease. Unfortunately, many patients at the time of diagnosis have already developed end-stage or advanced-stage [disease] or have dysfunction either of the heart or the kidneys…. This is something that we want to avoid in all these patients. What we need today is a treatment that will help us in addition to the hematologic responses that we can achieve to help improve the depth of organ responses and increase the rates of organ responses, and the rapidity with which we had seen this are the responses.”

Sanchorawala added that knowledge of clinical trials is paramount because treatments given in the community setting may have the unintended consequence of prohibiting patients from enrollment. “The takeaway message for the community physician is that there are many clinical trials that are ongoing [for patients with AL amyloidosis],” she said. “Please refer them to the centers of excellence where these clinical trials are being done. By giving treatment to patients in the community setting, you are denying them access to these important clinical trials. Second, patients with advanced cardiac involvement from AL amyloidosis have poor median overall survival and poor QOL. Please refer them for these clinical trials, which are testing amyloid-busting agent or antiamyloid fibril agents. These trials are crucial in advancing science and improving survival as well as improving QOL of patients.”

Palladini G, Schönland S, Merlini G, et al. The management of light chain (AL) amyloidosis in Europe: clinical characteristics, treatment patterns, and efficacy outcomes between 2004 and 2018. 

. 2023;13(1):19. doi:10.1038/s41408-023-00789-8

Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. 

. 2012;30(9):989-995. doi:10.1200/JCO.2011.38.5724

Baker KR. Light chain amyloidosis: epidemiology, staging, and prognostication. 

. 2022;18(2):27-35. doi:10.14797/mdcvj.1070

A study to evaluate the efficacy and safety of birtamimab in Mayo stage IV patients with AL amyloidosis (AFFIRM-AL). ClinicalTrials.gov. Updated March 6, 2023. Accessed July 17, 2023. https://clinicaltrials.gov/ct2/show/NCT04973137

Gertz MA, Cohen AD, Comenzo RL, et al. Birtamimab plus standard of care in light chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. 

. Published online June 27, 2023. doi:10.1182/blood.2022019406

Funding supported by Prothena. Content independently developed by 

Articles

Findings from an analysis of treatment patterns for patients with systemic amyloid light chain amyloidosis have demonstrated that several unmet needs exist, including timely diagnosis and limited survival outcomes for patients with advanced disease.

Birtamimab Pushes the Needle in AL Amyloidosis

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.

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.

“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 

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.

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

: 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.

A study to evaluate the efficacy and safety of birtamimab in Mayo Stage IV patients with AL amyloidosis (AFFIRM-AL). ClinicalTrials.gov. Updated March 6, 2023. Accessed May 18, 2023. 

https://clinicaltrials.gov/ct2/show/NCT04973137

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. 

. 2019;134(supplement_1):3166. doi:10.1182/blood-2019-124482

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.

Birtamimab Under Investigation in Mayo Stage IV AL Amyloidosis

Morie A. Gertz, MD, chair, General Internal Medicine, Mayo Clinic Comprehensive Cancer Center, discusses the rationale for the phase 3 AFFIRM-AL trial (NCT04973137) in patients with amyloid light chain (AL) amyloidosis and elaborates on the challenges that may arise when enrolling patients to this trial.

Dr Gertz on the Objectives of the AFFIRM-AL Trial

The ongoing AFFIRM-AL trial is evaluating the efficacy and safety of birtamimab in patients with Mayo Stage IV AL amyloidosis. The primary end point of this trial is time to all-cause mortality.

Patients will be randomized 2:1 to receive either intravenous birtamimab at 24 mg/kg or placebo every 28 days. All patients will also receive standard-of-care chemotherapy.

The goal of the AFFIRM-AL trial is to elicit a significant overall survival benefit at 9 months, thus reducing all-cause mortality, Gertz says. Additional study objectives include functional and patient-reported quality of life measures, including six-minute walk test distance and Physical Component Summary score, Gertz notes.

Dr Gertz on Enrollment Challenges for AFFIRM-AL

This multicenter, global trial aims to enroll approximately 150 patients at least 18 years of age with newly diagnosed, treatment-naïve Mayo Stage IV disease with cardiac involvement. One barrier to patient enrollment in AFFIRM-AL is the availability of daratumumab (Darzalex) as a treatment option in this population, Gertz says. AFFIRM-AL is limited to treatment-naïve patients, but if patients are unaware of this trial opportunity, for example, those receiving treatment in a community setting, they may begin daratumumab treatment and thus become ineligible for enrollment in AFFIRM-AL, Gertz explains. Prior to initiating daratumumab treatment, patients with previously untreated Mayo Stage IV AL amyloidosis should be referred to a center participating in AFFIRM-AL so they can potentially enroll in this trial and receive birtamimab, Gertz emphasizes.

Another enrollment barrier is the relatively small patient population that is eligible for AFFIRM-AL, as 23% of the total population of patients with amyloid disease have advanced AL amyloidosis, Gertz notes. Increased awareness of AL amyloidosis has resulted in many patients being diagnosed with this disease at earlier stages, which has further decreased the number of patients who are potentially eligible for this trial, Gertz concludes.

Videos

Morie A. Gertz, MD, discusses the rationale for the phase 3 AFFIRM-AL trial in patients with amyloid light chain amyloidosis and elaborates on the challenges that may arise when enrolling patients to this trial.

Dr Gertz on the Investigation of Birtamimab in Mayo Stage IV AL Amyloidosis

Efstathios Kastritis, MD, Division of Clinical Therapeutics, University of Athens School of Medicine, discusses the background of birtamimab (formerly NEOD001) and the rationale for investigating the agent in combination with standard-of-care chemotherapy in newly diagnosed patients with Mayo Stage IV amyloid light chain (AL) amyloidosis in the phase 3 AFFIRM-AL trial (NCT04973137).

Birtamimab is a monoclonal antibody designed to specifically and selectively target and clear the amyloid that accumulates and results in organ dysfunction and failure in patients with AL amyloidosis. 

Birtamimab was previously investigated in the phase 3 VITAL study (NCT02312206) in patients with newly diagnosed AL amyloidosis. The study was terminated due to futility when the monoclonal antibody plus standard of care did not demonstrate a statistically significant difference in time to all-cause mortality or time to cardiac hospitalization vs placebo in the overall population.

 showed that birtamimab elicited a significant survival benefit compared with placebo in newly diagnosed patients with Mayo Stage IV AL amyloidosis, Kastritis continues. The 9-month overall survival rate was 74% in patients with Mayo Stage IV AL amyloidosis treated with birtamimab, compared with 49% for patients treated with placebo.

Although these data were promising, the findings for patients with Mayo Stage IV AL amyloidosis were from a post-hoc analysis, and a prospective trial is needed to further investigate the efficacy signal in this patient population, Kastritis adds. The ongoing AFFIRM-AL trial is evaluating birtamimab in combination with chemotherapy vs chemotherapy alone in patients with Mayo Stage IV AL amyloidosis.

Efstathios Kastritis, MD, discusses the background of birtamimab and the rationale for investigating the agent in combination with standard-of-care chemotherapy in newly diagnosed patients with Mayo Stage IV amyloid light chain amyloidosis in the phase 3 AFFIRM-AL trial.


Research Efforts Are Underway for AL Amyloidosis | Supplements and Featured Publications

Birtamimab Pushes the Needle in AL Amyloidosis

Birtamimab Under Investigation in Mayo Stage IV AL Amyloidosis

Dr Gertz on the Investigation of Birtamimab in Mayo Stage IV AL Amyloidosis

Dr Kastritis on the Investigation of Birtamimab in Mayo Stage IV AL Amyloidosis