Multiple myeloma and cardiac amyloidosis

Introduction

Multiple myeloma (MM) and immunoglobulin light chain amyloidosis are plasma cell disorders. Both are characterized by increased clonal plasma cells in the bone marrow and detectable monoclonal proteins in the serum and/or urine. After lymphoma, myeloma is the second most common hematologic malignancy, comprising 1.8% of all malignancies. Immunoglobulin light chain (AL) amyloidosis is about one-fifth as common as MM, and approximately 10% to 15% of patients with myeloma will have AL amyloidosis. Both are diseases of the elderly, with median ages at diagnosis of approximately 70 years. ^, Men are 1.6 times more likely to develop MM, and African-Americans are twice as likely to develop MM than whites.

Diagnosis and differential diagnosis

As shown in the Central Illustration, clinical manifestations are dissimilar for the two diseases. In myeloma, the defining symptoms and signs are anemia, bone pain (or asymptomatic lesions), hypercalcemia, renal dysfunction, and high levels of serum monoclonal proteins (most commonly found on serum protein electrophoresis), and bone marrow plasma cells. When present, fatigue is a function of anemia, renal failure, or hypercalcemia. Occasionally, significant abnormalities are incidentally found even before patients are symptomatic. One must distinguish MM from its truly asymptomatic form (smoldering myeloma) and from its precancerous form (monoclonal gammopathy of undetermined significance).

The diagnosis of AL amyloidosis is often more challenging than that of MM. Fatigue and edema are the most common presenting symptoms. Fatigue often relates to heart failure with preserved ejection fraction (HFpEF) and edema to either cardiomyopathy and/or nephrotic syndrome. The cardiomyopathy of AL amyloidosis is frequently overlooked in part owing to the preserved ejection fraction, and there are significant delays before a diagnosis is made. Patients may have hepatomegaly with a cholestatic picture, a small fiber peripheral neuropathy, autonomic dysfunction, signs of microvascular involvement (periorbital purpura, jaw claudication), early satiety, or changes in their bowel patterns. The diagnosis is made by a tissue biopsy with (sub-) typing of the amyloid to prove that it is indeed AL amyloidosis rather than another form of inherited or acquired amyloidosis ( Table 51.1 ). Elevated serum immunoglobulin free light chains and/or the presence of a monoclonal protein by immunofixation are supportive of a diagnosis of AL amyloidosis, but not definitive. The differential diagnosis for AL amyloidosis includes monoclonal gammopathy of undetermined significance, MM, and other types of amyloidosis, especially wild type transthyretin (ATTR _wt ) amyloidosis. The diagnosis of acquired form of transthyretin (ATTR) amyloidosis can be made with a positive 99m-technetium pyrophosphate (PYP) or 99m-technetium (99mTc) and 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan in the ABSENCE of a monoclonal protein by immunofixation or by serum immunoglobulin free light chain assay ( Fig. 51.1 ). Cardiac imaging with echocardiography and magnetic resonance imaging can help support a diagnosis of AL amyloidosis, but neither is diagnostic nor can either distinguish AL from ATTR. This holds true also for echo strain imaging, although apical sparring on the bull’s eye view of global longitudinal strain (“cherry on top” appearance) should prompt further investigation into amyloidosis (sensitivity 96%, specificity 88% in patients without coronary artery disease). Increased left ventricular wall thickness, septal hypertrophy with granular sparking myocardium, and pericardial and pleural effusions are other echocardiographic features of amyloidosis. Lack of R-wave progression in the precordial leads (pseudoinfarction pattern) and low voltage are the classic electrocardiographic features, but have low sensitivity. A QTc greater than 440 ms and a Sokolow-Lyon index equal to or less than 1.5 mV have a sensitivity of 85% and a specificity of 100% for cardiac amyloidosis, mainly the AL subtype. The diagnosis of AL always requires a Congo red positive tissue biopsy that has been typed to be composed of immunoglobulins.

Prognosis

For patients with MM, staging is not directly related to tumor burden, but rather the genetics of the tumor (i.e., plasma cells), which is most commonly determined by f luorescent in situ hybridization (FISH). Certain cytogenetics, such as deletion 17p, translocation t(4;14), and t(14;20), are considered high-risk features. These bone marrow plasma cell abnormalities, along with serum albumin, serum beta-2 microglobulin, and lactate dehydrogenase (LDH) are the components of the Revised International Staging System (R-ISS), and patients are placed into three groups with discrete outcomes ( Table 51.2 ). The relative risk of death between each of the stages is approximately 3, yielding approximate 5-year overall survival rates of 80%, 60%, and 40%, respectively.

The greatest risk of death for patients with AL amyloidosis is during the first 6 to 12 months after diagnosis. It is during this period that approximately 30% of patients die. After the first year, the slope of the survival curves, especially for those with stage III disease, becomes less steep. Overall, for patients with AL amyloidosis, 6-year survival rates are 85%, 45%, 30%, and less than 10% for patients with stage I, II, IIIa and IIIb, respectively. Among those patients who achieve a deep hematologic response (a very good partial response or better), more than 80% of them are alive at 6 years. Staging for patients with AL amyloidosis is done using serum troponin, N-terminal pro-brain natriuretic peptide (NT-proBNP), and immunoglobulin free light chain ( Tables 51.3 and 51.4 ).

Treatment and side effects

Many of the drugs to treat these two conditions are the same as are the side effects but typically more severe in AL amyloidosis. Over the course of 15 years, nine drugs have been approved for MM, several of which are shown in Central Illustration. Other drugs used to treat myeloma not shown in the Central Illustration include pomalidomide (another immune modulatory drug [IMiD]), ixazomib (another proteasome inhibitor), daratumumab (an antibody directed at CD38), elotuzumab (an antibody directed at SLAMF7), and panobinostat (a histone deacetylase inhibitor). Additional promising drugs for the treatment of myeloma are in clinical trials (discussed below). Although there are no US Food and Drug Administration (FDA) approved drugs for the treatment of AL amyloidosis, many myeloma drugs are employed to treat this otherwise progressive and lethal disease. Such pharmacologic advances have resulted in approximately a doubling of overall survival for both MM and AL amyloidosis in the past two decades. ^{, ,}

Among patients with MM, treatment strategies are aligned with age (and functional status) and cytogenetic risk more so than tumor burden or R-ISS stage. The general MM treatment plan is induction (typically the first 4 months of therapy), followed by consolidation (ASCT in those eligible or continuation of induction for non-ASCT candidates), and maintenance (most often lenalidomide, but in certain cases bortezomib, ixazomib, or carfilzomib).

The general strategy to treat AL amyloidosis is based on the extent of cardiac involvement (dysfunction) followed in part by tumor burden as measured by serum free light chains. The distinction between amyloid with and without myeloma is in part semantics because so much of the prognosis is dependent on cardiac involvement. Early death relates predominantly to the severity of cardiac impairment (Central Illustration). That said, clonal burden has an impact on both presentation and long-term outcomes. A patient with AL amyloidosis who has fewer than 10% bone marrow plasma cells at diagnosis is (1) less likely to have cardiac involvement, (2) more likely to have a very deep response to chemotherapy, that is a complete response; and (3) very likely to expect a median overall survival of greater than 10 to 15 years assuming they survive the first year after diagnosis. In contrast, those patients with AL amyloidosis with more than 10% to 20% bone marrow plasma cells, whether or not they have classic myeloma bone lesions or classic myeloma kidney, are (1) more likely to have cardiac involvement, (2) less likely to have a deep response to chemotherapy, and (3) in general have shorter long- term survival, even if they survive past the first year. ^,

Toxicity of therapy

Each of the different chemotherapeutic agents used to kill bone marrow plasma cells have their own cardiac toxicities, but a few additional general principles need to be considered as well. Virtually all chemotherapy is myelosuppressive, which increases a patient’s risk of sepsis syndrome and all the cytokine-mediated toxicities that accompany it. Practically every regimen incorporates corticosteroids into the treatment plan—most often as a potent killer of plasma cells, but also sometimes as a knee-jerk antiemetic. The fluid retention that accompanies high-doses of weekly—and even sometimes daily—corticosteroids can aggravate hypertension, diastolic dysfunction, and systolic dysfunction, resulting in congestive heart failure (CHF). In addition, chronic steroid use can result in reduced adrenal reserve or frank adrenal insufficiency, resulting in cardiovascular collapse when stressed. The use of beta-blockers in patients with myeloma has been associated with a better overall survival in a retrospective study. In contrast, beta-blockers and calcium channel blockers (anything that slows the heart rate) can precipitate worsening functional status and even CHF among patients with AL amyloidosis.