Management of AL amyloidosis in 2020

A 65-year-old man with a history of hypertension developed worsening exertional dyspnea over the course of 6 months. During the previous 6 months he had progressively reduced and eventually discontinued his angiotensin-converting enzyme inhibitors because of “resolution” of hypertension. His cardiologist suspected amyloid heart involvement based on an echocardiography and recommended cardiac magnetic resonance (CMR) imaging, which showed late gadolinium enhancement. ^99mTc-hydroxymethylene-diphosphonate scintigraphy revealed cardiac uptake. A diagnosis of transthyretin (ATTR) amyloidosis was presumed. The patient was referred to a medical geneticist to rule out hereditary amyloidoses and to a hematologist to rule out light chain (AL) amyloidosis. Genetic testing for hereditary ATTR amyloidosis was negative. Immunofixation revealed κ Bence Jones protein. The patient was then referred to our center for amyloid typing and presented with New York Heart Association class III (NYHA class III) heart failure and postural hypotension. The κ-free light chain (FLC) concentration was 206 mg/L (ratio [FLCR], 10.3, and differential FLC [dFLC], 186 mg/L); bone marrow plasma cell (PC) infiltrate was 12% without chromosomal abnormalities; blood count, calcium, and liver function test results were normal; estimated glomerular filtration rate (eGFR) was 48 mL/min; proteinuria was 2.8 g per 24 hours, predominantly albumin; N-terminal pronatriuretic peptide type-B (NT-proBNP) was 10 625 ng/L (upper reference limit [url], 227 ng/L); and cardiac troponin I (cTnI) was 124 ng/L (url, 44 ng/L). A computed tomographic (CT) scan showed no bone lesions. Abdominal fat aspirate showed amyloid deposits typed as AL κ by immunoelectron microscopy (IEM). A diagnosis of AL amyloidosis with cardiac (stage IIIb) and renal (stage II) involvement was established. The patient received attenuated treatment with cyclophosphamide, bortezomib, and dexamethasone in subintensive care. Treatment was associated with fluid retention. Nevertheless, he received the second cycle as an outpatient. After 2 cycles, very good partial response (VGPR) was reached (dFLC, 11 mg/L; FLCR, 2.1; and persistence of κ Bence Jones protein), with improvement of markers of cardiac (NT-proBNP, 7225 ng/L) and renal (proteinuria, 1.7 g per 24 hours) involvement. Two more cycles were administered that were accompanied by fluid retention but did not improve hematologic (dFLC, 9 mg/L; FLCR, 2.0; and persistence of κ Bence Jones protein) and organ (NT-proBNP, 6792 ng/L; proteinuria, 1.5 g per 24 hours) response. Heart failure improved (NYHA class II), and treatment was discontinued based on the patient’s preference. Follow-up testing was scheduled every 3 months. After 15 months, markers of organ involvement were stable (NT-proBNP, 7471 ng/L, proteinuria, 1.4 g per 24 hours), but FLC increased (dFLC, 98 mg/L; FLCR, 5.9). The patient was treated with daratumumab, bortezomib, and dexamethasone. After 1 week, VGPR was reestablished (dFLC, 8 mg/L; FLCR, 1.8; and persistence of κ Bence Jones protein), and after 4 months, complete response (CR) was attained (dFLC, 3 mg/L; FLCR. 1.2; and negative serum and urine immunofixation) with cardiac response (NT-proBNP, 2809 ng/L). Twelve months later, CR had been maintained, and minimal residual disease (MRD) was not detectable by next-generation flow cytometry.

In systemic AL amyloidosis a PC clone, or, less frequently, a lymphoplasmacytic or marginal zone lymphoma, produces a toxic LC that causes organ dysfunction and damage and forms amyloid fibrils in tissues. In contrast, localized deposition of LCs causes nodules to develop in the skin and in the respiratory, urinary, and gastrointestinal tracts, with local symptoms and a benign course that usually is managed with local treatment.¹  In systemic AL amyloidosis, the PC clone is usually small (median infiltrate, 10%), and presents t(11;14) and gain 1(q21) in ∼50% and 20% of clones, respectively, whereas high-risk aberrations are uncommon.^2,3  Patients whose PC clones harbor t(11;14) have a worse outcome with bortezomib and immunomodulatory drugs (IMiDs), whereas gain 1(q21) is associated with poorer results with oral melphalan.^3-5 

Heart involvement is the major determinant of survival. Preclinical models and clinical observation of rapid cardiac improvement after a decline in LC concentration disclosed a direct cardiotoxic effect of the circulating precursor.^6,7  The severity of organ involvement is assessed with biomarkers combined in accurate staging systems (Table 1).^8-12  Survival also depends on hematologic response (HR), because LCs are the agents directly causing organ dysfunction. If the disease is not treated promptly and effectively, organ dysfunction progresses and eventually leads to death. Recent trials of immunotherapies targeting the amyloid deposits (the anti-fibril antibody NEOD001 and the combination of the amyloid P component [which targets small-molecule miridesap], and dezamizumab) failed. Only one anti-amyloid fibril antibody CAEL-101 is still under evaluation (www.clinicaltrials.gov #NCT04304144). Current treatments target the underlying clone and are aimed at suppressing the production of LCs to restore organ function and extend survival. Advanced organ involvement, particularly cardiac, is associated with early death and causes extreme frailty limiting the delivery of effective therapy. In recent years, advancements in biomarker-based risk stratification and monitoring of response and novel anti-PC agents has improved outcomes. Early and correct diagnosis is the prerequisite to beneficial use of these tools.

The clinical presentation of AL amyloidosis depends on organ involvement, and it is protean and deceitful. Symptoms are often misinterpreted and recognized late. When they appear, organ involvement is often irreversible. However, cardiac and renal amyloidosis can be detected by NT-proBNP and albuminuria before overt heart failure and nephrotic syndrome arise. Moreover, a monoclonal component can be found at least 4 years before diagnosis.¹³  Therefore, hematologists can intercept, diagnose, and treat patients during the presymptomatic stage, by including biomarkers of organ involvement in the monitoring panel of subjects with monoclonal gammopathy of undetermined significance (MGUS).¹⁴  Recent findings suggest that CMR can detect very early cardiac involvement¹⁵ ; hence, CMR may be used as a confirmatory test in subjects with MGUS in whom elevated NT-proBNP is found. However, the cost effectiveness of this approach is unknown. A diagnostic flowchart for AL amyloidosis is reported in Figure 1.

A tissue biopsy is always necessary to establish the diagnosis of AL amyloidosis. Notably, other types of systemic amyloidosis can have clinical presentations that overlap that of AL amyloidosis (Table 2). Of these, wild-type transthyretin (ATTRwt) amyloidosis, is the most common. Effective treatments are now available for wild-type and hereditary ATTR amyloidosis, but correct amyloid typing is mandatory. The other, rarer types should not be disregarded. In contrast to AL amyloidosis, the diagnosis of ATTRwt amyloidosis requires tissue typing only in patients in whom a monoclonal component is detected. In the absence of a monoclonal component, a nonbiopsy diagnosis of ATTRwt amyloidosis is possible based on cardiac uptake of bisphosphonate scintigraphy tracers.¹⁶  Patients with cardiac AL amyloidosis usually have no or modest uptake; however, patients may have intense uptake. Moreover, one-fourth to one-third of patients with ATTRwt have a monoclonal component. AL amyloidosis is by far the most rapidly progressing type of cardiac amyloidosis and is the one that benefits most from early initiation of effective therapy. Thus, the first step in the diagnostic workup of cardiac amyloidosis should be searching for monoclonal components. In the present clinical case, a substantial diagnostic delay resulted from deferred testing for PC dyscrasia.

Once the diagnosis of AL amyloidosis is established, the characteristics of the underlying clone and the extent and severity of organ involvement should be studied (Figure 1). This information is essential for designing the therapeutic strategy.

Treatment should be risk adapted, considering the severity of organ involvement, characteristics of the clone, and comorbidities and seeking to deliver the most rapid and effective therapy patients can safely tolerate. Delicate up-front therapy can sometimes trigger early improvement of organ dysfunction, allowing for subsequent, more aggressive treatment. Early and profound reductions of the amyloid LC are associated with the greatest chance of organ improvement, and prolongation of progression-free (PFS) and overall (OS) survival.^17-19  Changes in biomarkers can be used to assess response to therapy according to validated criteria (Table 3).^12,17,20,21  The optimal end point of therapy is still a matter of debate. Achievement of organ response can indicate that the amyloid LC level has fallen below the concentration needed to sustain organ dysfunction. Organ response can parallel HR, as it did in the patient described herein, but it is sometimes delayed. For this reason, assessment of treatment efficacy and a decision to shift to rescue regimens should be based on early HR assessment (3 months after autologous stem cell transplantation [ASCT], 1 to 2 months after nontransplantation therapies). Achievement of organ response and profound clonal response should be the long-term goal of therapy. Individual frailty, age, bone marrow PC infiltration, residual organ dysfunction, and treatment tolerability should be considered to decide whether CR should be pursued. Novel definitions of deep HR are being investigated.^18,19  The relatively low sensitivity and imprecision of available FLC assays demand novel technologies, such as mass spectrometry (MS)–based detection of monoclonal components²²  and assessment of MRD²³  that await validation in AL amyloidosis.

Accurate risk stratification is crucial in designing the treatment strategy (Figure 2). Approximately 20% of patients with newly diagnosed disease are candidates for ASCT, and more can become eligible after effective up-front therapy. Moreover, pretransplantation induction therapy independently improves PFS.²⁴  In a large series, 84% of patients attained HR after ASCT (VGPR, 33%; CR, 39%),²⁵  and the CR rate can increase to ∼60% (∼40% MRD⁻) with posttransplantation bortezomib-based treatment.²⁶  OS of patients who reach CR with ASCT is >50% at 15 years.²⁷ 

Most patients with AL amyloidosis are not eligible for ASCT. Oral melphalan + dexamethasone (MDex) has been a standard of care for many years in these subjects. Currently, bortezomib is the backbone of up-front treatment regimens and is combined with MDex (BMDex) or with cyclophosphamide and dexamethasone (CyBorD). A phase 3 trial in intermediate-risk patients (#NCT01277016) showed that BMDex induces a significantly higher HR rate (81% vs 57%; CR, 23% vs 20%; VGPR 42% vs 20%) than MDex, with prolonged OS.²⁸  Cardiac and renal responses were observed in 38% and 44% of cases with BMDex and in 28% and 43% of cases with MDex, respectively.²⁸  In a large, unselected, retrospective series, overall HR rate in response to CyBorD was 65% (CR, 25%; VGPR, 24%), with cardiac response in 33% of patients and renal response in 15%.¹⁸  A phase 3 trial comparing CyBorD with CyBorD+subcutaneous daratumumab has been completed (#NCT03201965). The uncontrolled safety assessment performed in a portion of the study showed a remarkable 96% overall HR rate.²⁹  The randomized trial preliminary results indicate that addition of daratumumab results in significantly higher hematologic (92% vs 77%; CR/VGPR, 79% vs 42%), cardiac (42% vs 22%), and renal (54% vs 27%) response rates across cardiac and renal stages and independent of t(11;14) and prolonged PFS.³⁰ 

Approximately 20% of patients have advanced (stage IIIb) cardiac involvement at diagnosis. Treatment of these patients remains an unmet need. However, if a profound response is reached within 1 month, OS can improve, even in these subjects.³¹  Ideally, these patients need a very rapidly acting, safe regimen. The safety profile and rapidity of action of subcutaneous daratumumab make this agent appealing in this setting, and a phase 2 trial is under way (#NCT04131309). Supportive therapy is vital to sustaining organ function while chemotherapy is delivered (Figure 3).

Patients who do not attain satisfactory response should be shifted to second-line treatment as early as possible. So far, there is no evidence to support maintenance therapy in responders, who should be closely followed. However, there is no consensus on when treatment should be started at relapse. We lack validated hematologic progression criteria, and the definition of PFS varies in different studies. Organ progression criteria predict shorter patient and renal survival and such progression should not be awaited before starting rescue therapy.^12,17  In general, organ progression is preceded by FLC increases, which can be small and should not be disregarded.³²  Other factors to be considered are FLC level and severity of organ involvement at diagnosis, as well as the quality of response to previous treatment.

The mainstay of rescue therapy is IMiDs that can overcome resistance to alkylating agents and proteasome inhibitors, with an OS benefit in responders. In a pooled analysis of patients enrolled in 2 phase 2 clinical trials of lenalidomide and 1 of pomalidomide, 39% of patients achieved VGPR or CR.³³  In a real-world European study of pomalidomide, overall HR rate was 44% (CR, 3%; VGPR, 23%).³⁴  Treatment with IMiDs interferes with cardiac response assessment, being associated with NT-proBNP increase, and worsening renal failure can be observed in patients with proteinuria. A phase 3 study compared the oral proteasome inhibitor ixazomib with physician’s best choice (lenalidomide in 57% of patients) in relapsed/refractory AL amyloidosis.³⁵  The study failed to meet its primary end point, an improvement in overall HR rate (53% vs 51%), but CR rate was higher (26% vs 18%) and PFS longer in ixazomib-treated patients. Ixazomib can be safely combined with lenalidomide and dexamethasone in an all-oral regimen.³⁶ 

Non-IMiD–based rescue has recently been evaluated. A phase 2 study reported a 57% HR rate (CR 11%) with bendamustine+dexamethasone.³⁷  In the past few months, 2 phase 2 trials and numerous retrospective series have addressed the efficacy of daratumumab-based regimens in relapsed/refractory disease. Sanchorawala et al observed a remarkable 90% response rate (CR 41%) in a phase 2 single-agent trial of daratumumab.³⁸  Cardiac and renal response rates were also high (50% and 67%, respectively).³⁸  In a European trial, 55% of patients responded to daratumumab (CR 8%), with lower cardiac (25%) and renal (31%) response rates.³⁹  Notably, in this trial, >50% of patients had not achieved VGPR or better with previous lines of therapy.³⁹  Close monitoring revealed that most HRs occurred after the first daratumumab infusion.^38,39  The largest retrospective study included 168 patients treated with daratumumab alone or combined with bortezomib.⁴⁰  There was no significant difference in outcome with the 2 regimens, and overall HR rate was ∼65% (CR/VGPR ∼50%).⁴⁰  Interestingly, shorter PFS was observed in patients with nephrotic syndrome.⁴⁰  Combination of daratumumab with IMiDs is particularly interesting in relapsed/refractory disease, and several clinical trials are under way.

Despite late recognition of symptoms and delayed referral to a specialized center, the patient described herein benefited from sequential treatment with powerful and rapidly acting regimens guided by biomarker-based risk stratification and monitoring. General practitioners, cardiologists, and nephrologists should be able to recognize symptoms early and to suggest appropriate testing (first, search for a monoclonal component) that can direct patients to the diagnostic pathways of AL or non-AL amyloidosis. Hematologists are in the unique position of recognizing and treating presymptomatic patients. Common pitfalls in the management of patients with AL amyloidosis are reported in Figure 4.

After many years without positive controlled studies, in the past few months, 3 phase 3 trials have been published.^28,30,35  Daratumumab combined with bortezomib emerged as a new standard of care. Yet, therapeutic innovation left old questions unanswered and opened new ones. A standard of care for high-risk patients is lacking, and the role of maintenance must be clarified, as well as the positioning of ASCT in the new scenario. A validated definition of hematologic progression would be useful in patient care and in the design of future trials. Further advancements in anti-PC therapy is likely to be based on depth of response, and validation of MS-based detection of monoclonal components and of MRD assessment is warranted to establish optimal goals of therapy. Newer anti-PC approaches, including CAR-T cells and antibody drug conjugates are being considered. Exploration of additional treatment targets, such as interference with LC toxicity by LC stabilizers or doxycycline, which may also target amyloid deposits and is currently undergoing testing in a randomized trial (#NCT03474458), should not be abandoned.

Contribution: G.P., P.M., and G.M. wrote the manuscript.

Conflict-of-interest disclosure: G.P. has received honoraria and serves on the advisory board of Janssen-Cilag and has received travel grants from Celgene. P.M. has received honoraria as a speaker for Pfizer and Janssen-Cilag and travel support from Celgene. G.M. reports no competing financial interests. Off-label drug use: None disclosed.

Correspondence: Giovanni Palladini, Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy; e-mail: giovanni.palladini@unipv.it.