Early diagnosis and management of AL amyloidosis: An underdiagnosed multiorgan disease
19 Jun 2024
byProf. Morie Gertz, Mayo Clinic, Minnesota, US
Light-chain (AL) amyloidosis is a progressive, underdiagnosed disease with multiorgan involvement, most notably of the heart, kidneys, and liver. Nearly half of the patients consult ≥4 physicians before receiving correct diagnosis. At the Hong Kong Society of Haematology Annual Scientific Meeting (HKSH ASM) 2024, Professor Morie Gertz of the Mayo Clinic, Minnesota, US, shared insights into establishing an early and accurate diagnosis and discussed the ANDROMEDA trial, which led to the first US FDA–approved treatment – daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd).
AL amyloidosis: Hidden in plain sight
AL amyloidosis is characterized by misfolded monoclonal immunoglobulin light chains (either Kappa or lambda) that aggregate and deposit in vital organs as amyloid fibrils. [Chem Commun (Camb) 2018;54:10664-10674]
The incidence ratio of AL amyloidosis to multiple myeloma (MM) is approximately 1:5. “If you see 20 MM cases per year, you should expect to see four cases of AL amyloidosis,” said Gertz. [Blood Cancer J 2018;8:44]
Nearly half (49 percent) of patients with AL amyloidosis consult ≥4 physicians before receiving correct diagnosis. Apart from haematologists or oncologists, the condition is most commonly seen by cardiologists and nephrologists, as most patients have cardiac (71 percent) or renal (58 percent) involvement. However, cardiologists and nephrologists provide correct diagnosis far less frequently than haematologists or oncologists – in 19 and 23 percent of patients, respectively, compared with 34 percent. [Blood Cancer J 2018;8:44; Adv Ther 2015;32:920-928]
Overall, one-fifth of patients spend >2 years before receiving AL amyloidosis diagnosis. [Adv Ther 2015;32:920- 928]“There is a serious diagnostic gap here,” pointed out Gertz. “Delayed diagnosis remains a major obstacle to initiating effective therapy before progression to end-stage organ failure.”
Diagnostic work-up
Diagnosing AL amyloidosis can be challenging because the initial symptoms (eg, fatigue, peripheral oedema, weight loss, exertional dyspnoea) are often nonspecific. “Physical signs such as tongue enlargement and periorbital purpura are highly specific but lack sensitivity, as these are only found in 15 percent of AL amyloidosis patients,” noted Gertz. [Adv Ther 2015;32:920-928; J Natl Compr Canc Netw 2023;21:83- 90; Blood Cancer J 2018;8:44]
Clues to diagnosis include symptoms that reflect the organs involved, such as heart failure with preserved ejection fraction (HFpEF), proteinuria, nondiabetic neuropathy, and unexplained hepatomegaly, or diarrhoea. (Figure 1) [Am J Hematol 2020;95:848- 860]
“Neglecting the possibility of AL amyloidosis in patients with smoldering myeloma or monoclonal gammopathy of undetermined significance [MGUS] remains a major error in diagnosis, as these patients can develop progressive amyloid organ failure and never develop MM,” added Gertz. As illustrated in the case report in this article, the presence of unexplained fatigue, oedema, weight loss, or paresthesias in patients diagnosed with MGUS or smoldering myeloma should raise clinical suspicion of AL amyloidosis. (Figure 1)
Appropriate screening tests for suspected AL amyloidosis include serum or urine immunofixation and immunoglobulin free light chain (FLC) assay, and a pyrophosphate (Pyp) scan for patients with cardiac symptoms. (Figure 1)
If the serologic workup is positive, clinicians should obtain tissue for Congo red staining. Positive amyloid staining by Congo red in any tissues (eg, fat aspirate, bone marrow, or organ biopsy) is required for diagnosis, followed by amyloid typing (ie, confirmation of the amyloid protein composition) with mass spectroscopy. (Figure 1) “Mass spectroscopy is superior to immunohistochemistry and is the gold standard for amyloid typing,” pointed out Gertz.
D-VCd: The first US FDA–approved treatment
“D-VCd is the only US FDA–approved treatment and the only rigorously studied treatment for AL amyloidosis. Melphalan, dexamethasone and bortezomib [as combination therapy] are not approved by US FDA for this indication,” emphasized Gertz. [Blood 2022;140:2317-2322; Darzalex Daspro US Prescribing Information]
The FDA approval of D-VCd was based on the phase III, multicentre, randomized, open-label, active-controlled ANDROMEDA trial in 388 patients with newly diagnosed AL amyloidosis. Patients were randomized 1:1 to receive six cycles of either VCd alone (control group; n=193), or subcutaneous daratumumab plus VCd followed by single-agent daratumumab Q4W for up to 24 cycles (D-VCd group; n=195). [N Engl J Med 2021;385:46-58; Blood 2021;138:159-162]
The primary endpoint was haematologic complete response (CR), which was defined as an involved FLC level less than the upper limit of normal range with negative serum and urine immunofixation, in the intention-to-treat population. As the treatment goal of AL amyloidosis is organ function preservation or improvement, organ response in patients with measurable organ involvement was one of the secondary endpoints. [Adv Ther 2015;32:920-928; N Engl J Med 2021;385:46-58; Hematol Transfus Cell Ther 2021;43:S1-S546]
Haematologic CR rates were significantly higher with D-VCd vs VCd at both 6 months (53 vs 18 percent; odds ratio [OR], 5.1; 95 percent confidence interval [CI], 3.2–8.2; p<0.001) and 12 months (59 vs 19 percent; OR, 5.9; 95 percent CI, 3.7–9.4; p<0.0001). “By adding daratumumab to VCd, haematologic CR rate was tripled to nearly 60 percent,” highlighted Gertz.
Both cardiac and renal response rates were significantly higher with D-VCd vs VCd at 6 months. “Of note, D-VCd doubled rates of organ response at 12 months [cardiac response: 57 vs 28 percent; OR, 3.5; 95 percent CI, 2.0–6.2; p<0.0001] [renal response: 57 vs 27 percent; OR, 4.1; 95 percent CI, 2.3–7.3; p<0.0001],” pointed out Gertz. (Figure 2)
D-VCd supported by international guidelines
Rapid and deep haematological response to treatment is often followed by organ response and, subsequently, a possibility of improved OS. Based on positive results of ANDROMEDA, UK’s National Institute for Health and Care Excellence (NICE) 2024 Guidance recommends D-VCd for adult patients with newly diagnosed systemic AL amyloidosis. [JCO Oncol Pract 2023;19:265- 275; NICE Technology appraisal guidance TA959, 27 March 2024]
The Mayo Consensus on AL amyloidosis: Diagnosis, treatment, and prognosis (mSMART) treatment guideline recommends D-VCd as induction therapy before autologous stem cell transplant (ASCT) for transplant-eligible patients and as first-line treatment for transplant-ineligible patients with newly diagnosed AL amyloidosis. (Figure 3) [mSMART treatment guideline, April 2023]
