Birtamimab Pushes the Needle in AL Amyloidosis

Morie A. Gertz, MD

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.¹ Although the disease is rare, investigators have made efforts to categorize AL amyloidosis through prognostic staging and risk stratification.^1,2

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.³ 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).^2,3

“There are several different staging systems, [including the] Mayo system [Table²] 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 OncologyLive. “[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.”

Table. Mayo AL Amyloidosis Staging Criteria²

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.²

Birtamimab May Address Unmet Need

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).⁴ “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; P = .021).⁴

“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.⁵

Figure. AFFIRM-AL Trial Design⁴

“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.⁴

In the VITAL study analysis, there was a statistically significant advantage of birtamimab with a difference of 4.65 points (P=.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 (P = .022).⁵

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.⁵

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.⁵ 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 OncologyLive. “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.”

References

1. 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. Blood Cancer J. 2023;13(1):19. doi:10.1038/s41408-023-00789-8
2. 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. J Clin Oncol. 2012;30(9):989-995. doi:10.1200/JCO.2011.38.5724
3. Baker KR. Light chain amyloidosis: epidemiology, staging, and prognostication. Methodist Debakey Cardiovasc J. 2022;18(2):27-35. doi:10.14797/mdcvj.1070
4. 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
5. 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. Blood. Published online June 27, 2023. doi:10.1182/blood.2022019406

Funding supported by Prothena. Content independently developed by OncLive.