Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group

Figures & data

Table 1. Updated criteria for organ response and progression in AL amyloidosis [108–110].

Organ	Response	Progression
Heart	NT-proBNP response (>30% and > 300ng/L decrease in patients with baseline NT-proBNP ≥ 650 ng/L) OR NYHA class response (≥2 class decrease in subjects with baseline NYHA class 3 or 4)	NT-proBNP progression (>30% and > 300 ng/L increase)* OR cTn progression (≥33% increase) OR Ejection fraction (EF) progression (≥10% decrease in EF)
Kidney	30% decrease of 24-hr urine protein or drop below 0.5 g/day (urine protein must be > 0.5 g/day pretreatment). Estimated glomerular filtration rate must not worsen by 25% over baseline.	25% worsening of estimated glomerular filtration rate
Liver	50% decrease in abnormal alkaline phosphatase value Decrease in liver size radiographically at least 2 cm	50% increase of alkaline phosphatase above the lowest value
Peripheral nervous system	Improvement in electromyogram nerve conduction velocity (rare)	Progressive neuropathy by electromyography or nerve conduction velocity
Definitions for Haematologic response in AL amyloidosis
Response categories	Definitions
Complete response	Both criteria must be met: Absence of amyloidogenic light chains (either free and/or as part of a complete immunoglobulin) defined by negative immunofixation electrophoresis of both serum and urine Either a FLC ratio within the reference range or the uninvolved FLC concentration is greater than involved FLC concentration with or without an abnormal FLC ratio
Very good partial response	dFLC concentration < 40 mg/L
Partial response	dFLC decrease > 50% compared to baseline
No response	All other patients

NT-proBNP: N-terminal pro-Brain Natriuretic Peptide; NYHA: New York Heart Classification; FLC: free light chain ratio; dFLC: difference between the involved and uninvolved light chains; cTn: cardiac troponin T; EF: ejection fraction.

Table 2. Levels of evidence.

Level of evidence	Grade of recommendation	Basis
Ia	A	Evidence obtained from meta-analysis of randomised controlled trials
Ib	A	Evidence obtained from at least one randomised controlled trial
IIa	B	Evidence obtained from at least one well-designed, non-randomised study, including phase II trials and case-control studies
IIb	B	Evidence obtained from at least one other type of well-designed, quasi-experimental study, i.e. studies without planned intervention, including observational studies
III	B	Evidence obtained from well-designed, non-experimental descriptive studies. Evidence obtained from meta-analysis or randomised controlled trials or phase II studies which is published only in abstract form
IV	C	Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Table 3. Recommendations for non-transplant treatment of AL amyloidosis.

Status	Patient		Risk assessment	Recommended treatments
				First choice	Alternative
Newly diagnosed	Patients without significant neuropathy		Cardiac stage I–IIIa	Dara-CyBorD^A	CyBorD^BVMDex^A
			Cardiac stage IIIb	Dose modified Dara-CyBorD^CSingle agent daratumumab^C	Dose modified CyBorD^BOr VMDex^B
	Patients with significant neuropathy		All stages*	Single agent daratumumab^CLenalidomide-Dexamethasone^B	MelDex^BCarfilzomib-Dex^CVenetoclax^C
Relapsed	Proteasome inhibitor Naïve or prolonged response to 1^st line PI		All stages*	CyBorD/VMDex^BIxazomib-Dex^A	Dara-V(C)D^C
	ProteasomeInhibitorExposed	Daratumumab Naïve	All stages*	Single agent daratumumab^BDara-V(C)D ^C	Dara-RD^BIsatuximab^C
		IMiD Naïve	All stages*	Lenalidomide-Dexamethasone (±cyclophosphamide)^B	IRD^B
		Lenalidomide refractory	All stages*	Pomalidomide-Dexamethasone^B	Bendamustine^B
		t(11;14)	All stages*	Venetoclax^C	Venetoclax-Bortezomib-Dexamethasone^CMelDex^C
IgM related AL (With lymphoid component in the marrow)			All stages*	Rituximab-Bendamustine^CASCT ^C	Rituximab-bort-Dex^CRituximab-Cyclo-Dex^CCyBorD^CIbrutinib (±Ritux)^C

Dara: Daratumumab; CyBorD: cyclophosphamide-bortezomib-Dexamethasone; VMDex: bortezomib – melphalan-dexamethasone; VCD: bortezomib -cyclophosphamide-dexamethasone; VD: bortezomib -dexamethasone; Ritux: Rituximab; MelDex: oral melphalan dexamethasone; IRD: Ixazomib-lenalidomide-Dexamethasone; Dex: dexamethasone.

Stages: defined as per the European update of Mayo 2004 staging system.

*Dose modification and adjustments mandatory in patients with advanced end organ damage (cardiac or other).

^A,B,CLevels of available evidence for the recommendation.