Moving the Therapeutic Needle in Immunoglobulin Light Chain and TTR Cardiac Amyloidosis

Abstract

As recently as 10 years ago patients with New York heart stage IV cardiac amyloidosis had a median survival of less than 6 months. The development of anti-amyloid therapeutics and improved heart failure management has dramatically improved outcomes for these patients.

A major gap in improving outcomes remains delay in diagnosis. In light chain amyloidosis, hematologists are monitoring patients with MGUS and smoldering myeloma for the development of CRAB (hypercalcemia, renal insufficiency, anemia, bone disease). If a patient develops progressive fatigue, dyspnea, lower extremity edema, or atrial fibrillation the existence of light chain amyloidosis may be overlooked. From a cardiologist perspective patients with cardiac symptoms and a thickened ventricle by echocardiography may be diagnosed as hypertensive cardiomyopathy even when voltage criteria on the EKG are not seen. Patients may be told they have hypertrophic obstructive cardiomyopathy in the absence of diagnostic screening for cardiac amyloidosis. Cardiac amyloidosis is increasingly recognized as a cause of heart failure with preserved ejection fraction (HFpEF). Overlooking the diagnosis of cardiac amyloidosis is a classic example of confirmation bias.

When cardiac amyloidosis is suspected by echocardiography, endomyocardial biopsy is generally unnecessary. For immunoglobulin light chain amyloidosis, amyloid deposits can be confirmed in the bone marrow, subcutaneous fat, or lip biopsy. For TTR cardiac amyloidosis (formerly designated senile cardiac amyloidosis) technetium pyrophosphate imaging in North America and technetium 3,3-diphosphono-1,2-propanodicarboxylic acid (99m TcDPD) or technetium hydroxymethylene diphosphonate (99mTcHMDP) in Europe confirm the diagnosis without a biopsy. When amyloid deposits are found in tissue, typing of the deposits is necessary to ensure the type of amyloid is accurately determined with immunoglobulin light chain amyloid and TTR amyloid being the most common. Approximately 20%–25% of patients with TTR cardiac amyloidosis also have a monoclonal gammopathy. Assuming that a patient with echocardiographic features of cardiac amyloidosis and an M protein has immunoglobulin light chain amyloidosis is incorrect. There is too much risk of the far more common TTR cardiac amyloidosis occurring in the presence of an incidental MGUS. Although immunohistochemistry is used because of widespread availability and low-cost, the gold standard is laser capture mass spectroscopic analysis of the amyloid peptides and has shown greater sensitivity and specificity then immunohistochemistry. Immunohistochemistry is particularly inaccurate in light chain amyloidosis because protein misfolding buries the epitopes identified by commercially purchased antisera. Accurate classification will prevent the administration of systemic chemotherapy to patients with TTR cardiac amyloidosis where chemotherapy treatment would have no value. Although rare, whenever TTR amyloidosis is diagnosed sequencing of the TTR gene is mandatory to recognize the rare subset of patients with autosomal dominant inherited TTR amyloidosis. This gene sequencing can be done on a saliva sample and two companies offer this at no charge to patients in the US and Canada. In black Americans, a genetic mutation for TTR amyloid is present in 3%–4% leading to late onset cardiomyopathy. Once a patient with mutant ATTR amyloidosis is identified screening of all first-degree family members becomes an important consideration. Even in patients with known inherited ATTR amyloidosis, a positive family history is obtained in only half.

Refinement in cardiac magnetic resonance imaging is useful both in the recognition of cardiac amyloidosis as well as assessing prognosis and as a serial measure of response to intervention. Late gadolinium enhancement on the MRI is considered quite specific for amyloidosis. The development of extracellular volume mapping in characterizing cardiac amyloid has been found to be independently associated with mortality and changes in the extracellular volume over time helps define cardiac response [1]. Studies of the use of PET imaging to identify amyloid deposits are underway.

The importance of an accurate diagnosis and classification is relevant because highly effective therapies have been developed for cardiac amyloidosis. There are currently two approved agents for the treatment of TTR cardiac amyloidosis. Both of these stabilize the tetrameric form of TTR preventing it from dissociating into monomers and misfolding into amyloid. These two agents, tafamidis and the recently approved acoramidis have been shown to improve survival, quality of life, and physical performance as measured by the 6 min walk test. Rise in the NT proBNP level is statistically lower than the placebo group. The use of a stabilizer also raises the level of TTR in the blood presumably because it prevents the tetramer [2] from dissociating into amyloid. These agents are oral, have a very low toxicity profile and there is no required monitoring of therapy.

The introduction of daratumumab in the treatment of immunoglobulin light chain amyloidosis has had a profound impact when compared with chemotherapeutic anti plasma cell regimens with a bortezomib backbone. Hematologic response rates are tripled, 59% versus 19% at 20 months, by the addition of daratumumab. More importantly cardiac organ responses are doubled, 57% versus 28% at 12 months which resulted in significantly longer median survival of 61 months. This trial excluded patients with an NT proBNP greater than 8500 pg/mL. The relative contribution of this quadruplets individual components therefore are unclear in this inherently poor prognosis group. One third of these patients die within 3 months of diagnosis [3]. There is also the suggestion that bortezomib may have significant cardiotoxicity in this poor prognosis group [4]. Even in patients with advanced heart failure that were not eligible for the andromeda trial, clear cut improvements when compared with the standard of care are realized. In stage III B cardiac amyloidosis, the median overall survival in the daratumumab group was not reached after a median follow-up of 14.5 months and in the bortezomib based group was 6.6 months. Overall, hematologic response at 6 months was better in the daratumumab group 59% versus 37%. Cardiac response at 6 months was 46% with daratumumab, 21% without [5]. Daratumumab, bortezomib, cyclophosphamide, dexamethasone is the standard of care for all patients with immunoglobulin light chain cardiac amyloidosis even in advanced stage.

In light chain amyloidosis, progress has not been limited to chemotherapy alone; 40%–50% of patients with AL amyloidosis have plasma cells that express t(11;14). Venetoclax in patients with this translocation and advanced cardiac involvement had an overall response rate of 100%, of which 78% were complete responses. Cardiac organ responses were seen in 2/3. Venetoclax was discontinued in 2/3 of patients at a median of 15 months. There were patients that benefited with demonstrated BCL 2 expression on plasma cells without a detected t(11;14) [6].

Targeted immunotherapy is being reported as effective in AL amyloidosis. Belantamab mafadotin a BCMA directed drug antibody conjugate achieves a best hematologic response rate of 71%, VGPR or better in 58%; 68% had keratopathy but it improved in all patients. Only one patient required treatment cessation due to ocular toxicity. There were no treatment related deaths [7]. Registration trials are underway with the bispecific anti BCMA antibody teclistamab with case series reporting responses as early as 14 days, a median time to best hematologic response of 1 month and a VGPR or better response in 88%. There was no grade 3 or 4 cytokine release syndrome. There was one grade 3 ICANS. Severe infections were seen in 35%, suggesting the standard schedule of administration once the patient has achieved a hematologic response should be reduced [8].

The safety and efficacy of BCMA directed car T therapy has also been reported. Based on small case series-suggesting benefit from car T therapy, a trial of NXC-201 has been activated for amyloidosis (NCT06097832) [9]. However, the Israeli group recently reported cardiac decompensation in two patients and have reported late cardiac deaths suggesting special precautions for the prevention of cytokine release syndrome in patients with significant systolic dysfunction are warranted [10].

Supportive care in cardiac amyloidosis is also being redefined. In an analysis of 784 cardiac amyloidosis patients, the use of beta-blockers were independently associated with an increased risk of sudden death in multivariable analysis. The use of beta-blockers for rate control in sinus rhythm or atrial fibrillation is to be discouraged. In practice, clinical deterioration of patients is commonly observed with the initiation of beta blocking drugs. In a case series, 41% of cardiac amyloid patients were on a beta-blocker and 25% of patients with AL cardiac amyloidosis received this drug class. In the multivariable analysis the hazard ratio for sudden death using beta-blockers was 7.06, p = 0.01 [11]. The frequency of sudden death at 3 years in patients treated with beta-blockers was 25%.

SGLT2 inhibitors have demonstrated benefit in heart failure patients. In a case, series of amyloid light chain cardiomyopathy these agents were associated with significantly greater reductions in loop diuretic dosage and reduction in the cardiac biomarker NT proBNP at 3, 6, and 12-month time points. The two most commonly prescribed agents in this class include empagliflozin (Jardiance) and dapafliflozin (Farxiga) both orally administered. Volume depletion symptoms complicated the use of these agents [12].

What does the future hold in the management of advanced cardiac amyloidosis? In TTR cardiac amyloidosis gene silencing therapies that prevent production of TTR mRNA with resultant 90% reduction in the amyloid precursor protein have been completed and have met their trial end points [13]. Vutrisiran is administered subcutaneously once every 12 weeks and interferes with hepatic synthesis of TTR. Administration over 36 months led to a lower risk of death from any cause compared to placebo. There was less decline in the 6 min walk test and less of a decline in the Kansas City cardiomyopathy questionnaire score [14]. Antibodies against TTR, so called amyloid depleters, are currently actively being tested [15]. The mode of action consists of removal of amyloid accumulations by activating phagocytic immune cells.

In cardiac AL amyloidosis 2 large studies in Mayo class IV cardiac amyloidosis combining anti amyloid antibody with standard of care chemotherapy in treatment naive patients have been activated, with 1 having completed accrual, anselamimab, and 1 still actively accruing, birtamimab using survival as the primary endpoint. The potential for amyloid dissolving antibodies in light chain amyloidosis is exciting [16]. Recently discovered selective small molecule kinetic stabilizers of amyloid immunoglobulin light chains have been described. The goal is to prevent immunoglobulin light chains from misfolding into amyloid fibrils thus blocking the process of fibril deposition [17].

The rapid developments of highly effective therapies for all forms of cardiac amyloidosis makes it important for hematologists to keep this diagnosis in mind in all patients they see and evaluate with a monoclonal gammopathy. For cardiologists unexplained heart failure, that is, no ischemic or valvular etiology detected, should lead to studies looking for cardiac wall infiltration. Both cardiologists and hematologists need to be familiar with the use of the immunoglobulin free light chain assay for screening as well as the cardiac biomarkers troponin and NT proBNP. Most nuclear medicine departments have available technetium pyrophosphate, 99m Tc-DPD or 99mHDMP imaging to confirm the presence of TTR cardiac amyloidosis [18].