Management of relapsed/refractory AL amyloidosis

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Abstract

Frontline therapy for systemic amyloid light chain (AL) amyloidosis has evolved significantly with the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone, which has significantly improved rates of both hematologic and organ responses. Despite these advances, many patients eventually relapse, and there remains no established standard salvage regimen or optimal timing. In this review, we examine optimal timing of salvage regimens and currently available therapeutic options after daratumumab failure, including next-generation proteosome inhibitors or immunomodulatory drugs, autologous stem cell transplant, BCL-2 inhibitors, and emerging immunotherapeutic agents such as chimeric antigen receptor T-cell therapy and bispecific antibodies.

Introduction

Systemic immunoglobulin amyloid light chain (AL) amyloidosis is associated with a plasma cell clone, less frequently a lymphoplasmacytic or marginal zone lymphoma clone, causing deposits of misfolded light chain amyloid fibrils in various organs and tissues, most frequently the heart and kidneys. Current treatment strategy focuses on rapid, deep suppression of amyloidogenic free light chain (FLC) production by targeting plasma cells.

Plasma cell–directed therapies have formed the foundation of AL amyloidosis for decades, with a standard-of-care up-front therapy only recently being established. The phase 3 ANDROMEDA study demonstrated that the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (D-VCD) was associated with higher frequencies of hematologic complete response (CR; 53%) and survival free from major organ deterioration, hematologic progression, or death (HR 0.58; 95% confidence interval, 0.36-0.93; P = .02) compared to VCD in newly diagnosed AL amyloidosis.¹ Survival results after a 5-year analysis shows that addition of daratumumab to VCD reduces the relative risk of death by 38% compared to VCD alone, despite crossover in >70% of VCD patients.² These data have led to D-VCD being the standard-of-care first-line therapy for AL amyloidosis.

One-fourth of patients will not achieve deep response (very good partial response [VGPR] or better) with D-VCD induction, and others will eventually progress.¹ With the incorporation of daratumumab into first-line regimens, data guiding the optimal management of relapsed or refractory AL amyloidosis remain limited, and no universally accepted treatment standard has been established, reflecting the paucity of prospective randomized trials. Several novel therapeutic options have demonstrated efficacy, including newer-generation proteasome inhibitors (PIs) and immunomodulatory agents (immunomodulatory drugs [IMiDs]). Venetoclax has demonstrated particularly high efficacy in patients with t(11;14). Immune effector cell–based strategies, such as bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapies, are under investigation after success in multiple myeloma. Retreatment with bortezomib- or daratumumab-containing regimens may be considered in patients with prior durable response and tolerated therapy well. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) remains a feasible salvage option in selected individuals.³

In this review, we summarize response and progression criteria, the optimal timing of salvage regimens, and available management strategies for relapsed/refractory AL amyloidosis.

Assessment of response and progression

Evaluation of both hematologic and organ responses (ORs) is essential during and after treatment, with consideration for early intervention when initial response is insufficient. Hematologic response (HR) criteria, developed by the International Symposium on Amyloid and Amyloidosis (Table 1), rely mainly on changes in the difference between involved and uninvolved serum FLCs (dFLC) and is typically assessed ∼3 months (AL amyloidosis complete response [aCR], VGPR, PR, and not reached [NR]). Early HR strongly correlates with survival.⁴

Table 1.

Updated HR criteria

Response categories	2005 criteria	2012 criteria
CR (aCR)	Both criteria must be met •Serum and urine negative for a monoclonal protein by immunofixation •FLC ratio normal	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 an FLC ratio within the reference range or an uninvolved FLC concentration greater than the involved FLC concentration, with or without an abnormal FLC ratio5 (due to severe immunoparesis from effective therapies)
VGPR	Not reported	dFLC concentration <40 mg/L
PR	•If serum M component >0.5 g/dL, a 50% reduction •If light chain in the urine with a visible peak and >100 mg/d and 50% reduction •If FLC >10 mg/dL (100 mg/L) and 50% reduction	dFLC decrease >50% compared to baseline
Stable/no response	No CR, no PR, no progression	All other patients
Progression	From CR, any detectable monoclonal protein or abnormal FLC ratio (involved FLC must double); from PR or stable response, 50% increase in serum M protein to >0.5 g/dL or 50% increase in urine M protein to >200 mg/d, with a visible peak required; or, involved FLC increase of 50% to >10 mg/dL (100 mg/L).

Adapted from Milani and Cibeira.⁶

M component, monoclonal component.

Low dFLC (<50 mg/L) is an independent predictor of improved overall and renal survival,⁷ and in patients with baseline dFLC of 20 to 50 mg/L, achieving a low-dFLC PR (reduction in dFLC after therapy of <10 mg/L) confers superior overall and renal survival.⁸ Accordingly, patients with baseline dFLC >20 mg/L should continue to undergo HR assessment, despite previously being considered nonevaluable in clinical trials.

OR reflects suppression of amyloidogenic light chains below levels that cause organ dysfunction. These criteria are summarized in Table 2, with particular emphasis on N-terminal pro–brain natriuretic peptide (NT-proBNP; or BNP) levels. A reduction >30% and ≥300 ng/L (or ≥50 ng/L for BNP) is linked with improved overall survival (OS).⁴ NT-proBNP is increasingly used as a surrogate end point for pivotal trials but is nonspecific and influenced by cardiac or renal disease, atrial fibrillation, medications, activation of the sympathetic and renin-angiotensin-aldosterone system, requiring contextual interpretation.⁹ A proposed grading system for depth of OR has been associated with improved survival.10, 11, 12 Importantly, ORs tend to occur later than HRs, meaning early HR assessments are crucial for guiding treatment decisions and determining the need for rescue therapies.¹³ Notably, lack of OR despite hematologic CR does not automatically warrant salvage therapy.

Table 2.

OR criteria

Organ criteria	Response	Progression
Heart	NT-proBNP response (>30% and >300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L) or NYHA class response (≥2 class decrease in patients with baseline NYHA class 3 or 4)	NT-proBNP increase (>30% and >300 ng/L; not precipitated by infection, elevated creatinine, or arrhythmia), or cTn increase ≥33%, or EF decrease ≥10%
Heart (graded responses)	CarCR, nadir NT-proBNP ≤350 ng/L or BNP ≤80 ng/L CarVGPR, 60% reduction in NT-proBNP/BNP from baseline level not meeting CarCR CarPR, 31%-60% reduction in NT-proBNP/BNP from baseline level not meeting CarCR CarNR, ≤30% reduction in NT-proBNP/BNP from baseline level
Renal	Decrease in proteinuria by ≥30% or <0.5 g/24 h without renal progression	≥25% decrease in eGFR
Renal (graded responses)	Kidney CR, ≤200 mg/d proteinuria Kidney VGPR, ≥60% reduction in proteinuria Kidney PR, 30%-60% reduction in proteinuria No response, ≤30% reduction in proteinuria
Liver	50% decrease in abnormal alkaline phosphatase value Decrease in liver size radiographically at least 2 cm	50% increase in alkaline phosphatase above the lowest value
Peripheral nervous system	Improvement in nerve conduction study/EMG parameter	Progressive neuropathy by EMG or nerve conduction studies

CarCR, Cardiac Complete response; CarPR, Cardiac Partial response; CarVGPR, Cardiac Very Good Partial Response; cTn, cardiac troponin; EF, ejection fraction; eGFR, estimated Glomerular Filtration Rate; EMG, electromyography; NYHA, New York Heart Association.

Assessment of minimal residual disease (MRD) is becoming an important tool for prognostication, especially in patients achieving a VGPR or deeper response. Studies using next-generation flow cytometry have shown that MRD negativity is linked to higher rates of renal and cardiac response.³³ A recent meta-analysis supports these findings, demonstrating that patients with undetectable MRD experience better ORs and longer progression-free survival (PFS), although effects on OS remain unclear.⁴¹ In addition, MRD assessment using mass spectrometry–based FLC assays has been associated with increased cardiac response and improved OS.⁴²

Criteria for hematologic and organ progression (Tables 1 and 2), established by the International Society of Amyloidosis,⁴³ are consensus based, have not been formally validated, and are rarely used in clinical trials; consequently, time to next therapy is often reported in clinical trials. Cardiac and renal progression, as currently defined, are associated with worse survival and higher risk of dialysis, reinforcing the need for intervention before overt organ progression occurs.^4,44

Timing of salvage regimens

Determining the appropriate timing for altering therapy in patients with suboptimal response remains a challenge. Current consensus suggests that achieving at least a VGPR early in the treatment course, ideally within the first month, is important for maximizing the likelihood of organ improvement, particularly in patients with advanced cardiac involvement (stage IIIb; NT-proBNP >8500 ng/L or BNP >700 ng/L).45, 46, 47 Patients who fail to show any HR by 2 months or who do not reach VGPR by 4 months should be considered treatment refractory and evaluated for alternative or rescue therapy.⁴⁸

In patients achieving a VGPR, additional therapy to deepen response toward CR may be appropriate in selected cases, particularly with absent OR or organ progression, whereas observation is reasonable when ORs are improving or toxicity is a concern. Management of patients in hematologic CR with ongoing or progressive organ dysfunction remains particularly challenging and may reflect irreversible organ damage or continued low-level amyloidogenic light chain production despite conventional CR.⁴⁹ In this setting, MRD assessment may identify residual clonal disease and inform consideration of alternative therapy to achieve MRD negativity, although these strategies are based on expert opinion and lack prospective validation.

When to restart treatment at clonal relapse remains controversial. One approach supports early intervention to prevent organ progression; another cautions against premature therapy in frail patients without organ deterioration.^50,51 There are no prospective data to clearly answer this question. The Boston University Group reported the outcomes of 82 post-ASCT complete responders who had recurrent detectable clonal disease.⁵² Only 16% relapsed without accompanied organ progression, and these patients did not require treatment over a median follow-up of 6.53 years, suggesting delayed treatment may be safe in selected cases. Measurements of FLC were limited, and as such, the extent of clonal relapse could not be accurately quantified. In a larger nontransplant cohort of 259 patients,⁵³ Palladini et al showed that high involved/uninvolved FLC ratio predicted earlier need for second-line therapy and proposed the concept of “high-risk dFLC progression,” defined as a dFLC of ≥20 mg/L, a level >20% of baseline value and a >50% increase from the value reached at best response. “High-risk dFLC progression” preceded cardiac progression by a median of 6 months in 85% of cases and was associated with a significantly shorter survival after second-line therapy initiation. The multivariate analysis was, however, underpowered to clarify the interaction between high-risk dFLC progression and baseline characteristics (such as extent of response) and baseline cardiac function.⁵¹

Although international opinion remains divided and objective guidelines are unavailable, therapy may be considered for Pallidini-defined “high-risk dFLC-progressor,” especially in those with significant cardiac or autonomic involvement or when dFLC rises to ≥50% of the diagnostic level, although the latter is opinion based. Baseline organ involvement at diagnosis and persistent or residual organ dysfunction should guide the timing of salvage therapy. Treatment decisions should be individualized, accounting for patient fitness, frailty, and extent of end-organ damage.

Salvage regimens

There is no established standard-of-care therapy for relapsed AL amyloidosis, particularly after D-VCD. Given frontline D-VCD was approved by the US Food and Drug Administration in 2021, some patients remain daratumumab and/or bortezomib naïve at relapse and should be considered for regimens incorporating these agents. Retreatment may be appropriate in patients who remain sensitive, especially those with coexisting myeloma.

Treatment choice at relapse should be guided by the depth and duration of initial response and, when possible, the use of drug classes not previously exposed.⁵⁴ Optimal choice of salvage therapy should carefully integrate patient-, disease-, and treatment-related factors (Figure 1). For example, avoiding carfilzomib in cardiac amyloidosis due to cardiotoxicity, while favoring venetoclax in patients with t(11;14). A range of therapeutic options in relapsed/refractory disease are summarized in a risk-adapted framework (Figure 2), largely based on expert consensus given limited data. Major studies of PIs, anti-CD38 monoclonal antibodies and IMiDs are summarized in Table 3.

Figure 1.

Factors affecting treatment choice in R/R amyloidosis. NYHA, New York Heart Association; R/R, relapsed/refractory; WHO, World Health Organization.

Figure 2.

Therapeutic approach for relapsed/refractory AL amyloidosis. Abs, Antibodies; CrCI, Creatinine Clearance.

Table 3.

Major studies of PIs, anti-CD38 monoclonal antibodies, and IMiDs in relapse/refractory AL amyloidosis

Author	Intervention	Study design	n	HR (CR), %	OR, %	OS
Kastritis et al14	Bortezomib/dexamethasone	Retrospective, multicentre	94	72 (25)	29	1-y, 76%
Reece et al15	Bortezomib	Prospective, phase 2	70	69 (29)	29	1-y, 94%
Bomsztyk et al16	DVD	Prospective, observational	116	70 (36)	NRp	1-y, 83.7%
Dispenzieri et al17	Ixazomib/dexamethasone	Prospective, phase 3	168	53 (26)	36	Median, NR
Cohen et al18	Ixazomib-Len-Dex	Retrospective	40	65 (25)	9	Median, 29.1 mo
Roussel et al19	Daratumumab	Phase 2	40	55 (15)	33	2-y, 74%
Sanchorawala et al20	Daratumumab	Phase 2	20	90 (41)	50	Median, NR
Kimmich et al21	DVD	Retrospective	106	64 (8)	22	Median, 25.6 mo
Szalat et al22	Daratumumab	Retrospective	107	93 (44)	39	1-y, 95% 2-y, 83% 3-y, 70%
Parker et al23	Isatuximab	Phase 2	35	77 (6)	53	2-y, 85%
Kumar et al24	CRD	Phase 2	35	60 (11)	31	Median, 37.8 mo
Kastritis et al25	RcD	Phase 1/2	37	55 (8)	22	Median, 17 mo
Mahmood et al26	Len-Dex	Retrospective, single centre	84	61 (20)	16	2-y, 74%
Kastritis et al27	Len-Dex	Retrospective	55	51 (5.5)	16	Median, 25 mo
Basset et al28	Len-Dex	Retrospective	260	31 (5)	NRp	Median, 32 mo
Dispenzieri et al29	Pomalidomide/dexamethasone	Phase 2	33	48 (3)	15	Median, 28 mo
Sanchorawala et al30	Pomalidomide/dexamethasone	Phase 1/2	27	44 (30)	Renal 7.1%	NR
Palladini et al31	Pomalidomide/dexamethasone	Phase 2	28	68 (4)	Renal 17%	Median, 26 mo
Milani et al32	Pomalidomide/dexamethasone	Retrospective	153	44 (3)	11	Median, 29 mo

CRD, cyclophosphamide, lenalidomide and weekly dexamethasone; Len-Dex, lenalidomide and dexamethasone; NRp, not reported; RcD, lenalidomide, low-dose cyclophosphamide, and pulse dexamethasone.

Although this review focuses on plasma cell–directed therapies, optimal supportive care is fundamental, particularly in cardiac and renal amyloidosis. Early interventions aimed at controlling fluid overload, hypotension, and malnutrition should be instituted early. Readers are referred to International Society of Amyloidosis consensus guidelines for detailed supportive care recommendations.⁵⁵

PI

Bortezomib

Bortezomib has long been a cornerstone of therapy for AL amyloidosis in both frontline and relapsed settings. Its high efficacy is attributed to the heightened susceptibility of clonal plasma cells to proteosome inhibition.⁵⁶ In D-VCD, bortezomib exposure is limited to 6 cycles; therefore, retreatment with bortezomib-containing regimen may be appropriate in bortezomib-sensitive patients who relapse after a prolonged treatment-free interval.

Although most evidence supports its frontline use, single-agent bortezomib has demonstrated activity in relapse or refractory disease.^14,15 Twice-weekly dosing may induce faster responses but increases toxicity, particularly neuropathy.¹⁵ In a study by Venner et al, VCD achieved significantly higher CR rates when used up front compared with at relapse (65% vs 21.7%; P = .03).⁵⁷

Bomsztyk et al evaluated second-line daratumumab-bortezomib-dexamethasone (DVD) in bortezomib-exposed patients, reporting CR/VGPR rates of 70%, comparable to frontline D-VCD.¹⁶ Median event-free survival (EFS) was shorter when DVD was used for inadequate first-line response vs relapse (18 vs 34 months; P = .002). Despite reduced efficacy in those with inadequate response, 50% will still achieve a CR/VGPR, likely reflecting the added benefit of daratumumab. Although prospective data on bortezomib retreatment after D-VCD are limited, bortezomib rechallenge remains reasonable in selected nonrefractory patients without ongoing toxicity who previously achieved durable response, particularly when at least 6 to 12 months have elapsed since the last exposure, based on expert opinion.

Ixazomib

Ixazomib, an oral second-generation PI, offers reduced neurotoxicity compared to bortezomib. In the phase 3 TOURMALINE-AL1 trial, ixazomib-dexamethasone was compared with physicians’ choice (typically lenalidomide-dexamethasone) in relapsed AL amyloidosis. The study was terminated early after interim analysis predicted failure to meet its primary end point of improved HR; however, ixazomib-dexamethasone prolonged time to organ deterioration, PFS, and time to subsequent therapy.¹⁷ Ixazomib is also well tolerated in combination with lenalidomide and dexamethasone, achieving CR and VGPR rates of 25.6% and 20.5%, respectively, and a median PFS of 17 months.¹⁸ Overall, weekly oral ixazomib appears to be an active, convenient, and well-tolerated option for relapsed/refractory AL amyloidosis, with minimal neuropathy.

Carfilzomib

There are limited data on the use of carfilzomib in AL amyloidosis, with only small studies demonstrating efficacy but with significant safety concerns, predominantly in patients with cardiac involvement. In a phase 1/2 trial by Cohen et al involving 28 patients with relapsed/refractory Mayo cardiac stage I or II disease, the maximum tolerated dose was 20/36 mg/m² given biweekly.⁵⁸ Although the HR rate of 63% is comparable to other therapies for relapsed/refractory disease, CR was low at 11%. Up to 71% experienced grade 3/4 toxicity, predominantly cardiac or pulmonary, and 40% met criteria for cardiac progression based on NT-proBNP elevation. Similarly, the UK National Amyloidosis Centre phase 1 study identified that 45 mg/m² weekly as safe, achieving a 60% HR rate.⁵⁹ Given the potential for significant cardiac and renal adverse events, current guidelines recommend reserving carfilzomib for patients who cannot tolerate other therapies, with careful monitoring and preference for once-weekly dosing when used.⁵⁴ In carefully selected patients with minimal or no cardiac involvement, carfilzomib may still be considered.

Anti-CD38 monoclonal antibodies

Daratumumab

Before frontline approval, daratumumab demonstrated high HR rates in relapsed/refractory AL amyloidosis across several prospective and retrospective studies.19, 20, 21, 22^,60,61 In a phase 2 trial of 40 relapsed/refractory patients, daratumumab monotherapy demonstrated overall HR rate of 55% (VGPR or better, 47.5%) and 25% OR among those with cardiac involvement, with responses typically within 1 cycle and no unexpected adverse events.¹⁹ Sanchorawala et al reported higher hematologic overall response of 86%, with cardiac and renal responses in 25% and 31%, respectively, and a median PFS of 2 years.²⁰ Retrospective analyses confirmed high HR rates (64%-93%), with encouraging ORs and survival.^21,22,60,61

Data on daratumumab-based regimens after D-VCD failure are limited. Zanwar et al showed only 10% CR in 28 patients, with a median EFS of 8.3 months, although the sample size was small.⁶² Rechallenge with daratumumab may be appropriate if relapse occurs after a significant treatment-free interval.⁶³

Single-agent daratumumab appears comparably effective to combination regimens, with no significant difference in efficacy or toxicity between daratumumab/dexamethasone and DVD.²¹ Trials assessing combinations with ixazomib (newly diagnosed; NCT03283917) and with venetoclax (newly diagnosed; NCT06629818) are ongoing. The NCT04895917 trial evaluating combinations with pomalidomide was terminated early due to low patient accrual.

No trials have specifically evaluated daratumumab maintenance after D-VCD. The ANDROMEDA study was not designed to answer this question because all patients enrolled in the D-VCD arm received single-agent daratumumab maintenance. Nevertheless, Boston University Group reported that patients receiving >12 cycles of monotherapy daratumumab had significantly longer major organ deterioration PFS (30 vs 13 months; P = .0018) and OS (NR vs 15 months; P > .0001), suggesting there may be a role for daratumumab maintenance.²² However, data on safety and cost effectiveness of ongoing maintenance are unknown. In patients who achieve a deep response, some clinicians may consider discontinuing daratumumab after 12 months, particularly if concerned regarding cumulative toxicity, immunosuppression, or frailty.

Isatuximab

In a phase 2 trial of isatuximab monotherapy in previously treated AL amyloidosis, 35 patients achieved an overall HR rate of 77.1%, including 6% CR and 51% VGPR.²³ Estimated 24-month response durability and OS were 81% and 85%, respectively, with renal and cardiac responses in 50% and 56%, respectively. Adverse events were high at 26%, commonly leading to discontinuation. In a separate phase 2 study of isatuximab, pomalidomide, and dexamethasone (IsaPd), VGPR or better was achieved in 38.5% by day 8, with an overall HR rate of 85%.⁶⁴ ORs are yet to be reported. Pomalidomide dose adjustments were common due to grade ≥3 neutropenia and infections. Overall, IsaPd demonstrated effective and rapid responses.

iMiDs

iMiDs showing activity in relapsed patients with AL amyloidosis include thalidomide, lenalidomide, and pomalidomide.⁶⁵ Evidence mainly consists of phase 2 studies and retrospective series. Due to significant neurotoxicity, thalidomide can no longer be considered as an optimal agent for treatment of relapsed AL amyloidosis. All IMiDs may worsen renal function and increase NT-proBNP, confounding cardiac response assessments.

Lenalidomide

Lenalidomide has shown variable efficacy in AL amyloidosis, with early monotherapy producing limited responses. Initial studies that applied dosing of 25 mg daily alongside dexamethasone achieved HRs but were associated with substantial hematologic, renal, and dermatologic toxicities.^66,67 Subsequently, a daily lenalidomide dose of 15 mg was established as the maximum tolerated dose yielding HR rates of 31% to 61% in combination with dexamethasone, although CR rates were uncommon.24, 25, 26, 27, 28^,66, 67, 68

Combination regimens have further improved clonal response rates. HR rates of ∼60% have been reported when combined with cyclophosphamide and dexamethasone, although CR rates have remained disappointingly low.^24,25 There is preliminary evidence that lenalidomide should be continued after achievement of maximal response in a maintenance fashion to improve ORs.²⁶ Daratumumab, lenalidomide and dexamethasone (Dara-Rd) shows efficacy in both frontline and relapsed settings, although prior daratumumab exposure data are lacking.69, 70, 71

Lenalidomide does not appear to induce or exacerbate neuropathy in most patients with AL amyloidosis, thus can be considered for patients with amyloid neuropathy.

Pomalidomide

In relapsed/refractory AL amyloidosis, this third-generation IMiD plus dexamethasone achieves HR rates of 44% to 68%, with low CR rates.29, 30, 31, 32 In a European cohort (n = 153), the overall response rate (ORR) was 44%, with a median PFS of 18 months and cardiac and renal responses of 11% and 20%, respectively.³² Most participants received 4 mg daily, whereas dose reductions were implemented in some cases due to frailty, comorbidities, or cytopenias. Only 3 patients in this cohort previously received daratumumab combinations. Despite limited data and no direct head-to-head comparison trials, pomalidomide appears to have the best response and side effect profile compared to lenalidomide and thalidomide. Early data suggest combining pomalidomide with anti-CD38 antibodies, isatuximab⁶⁴ or daratumumab,⁷² significantly enhances responses, with ongoing trials (NCT04895917 and NCT04270175) showing encouraging preliminary results.

Venetoclax

Venetoclax has shown activity in multiple myeloma with t(11;14), despite negative results in prospective trials in unselected myeloma populations. Given the t(11;14) is present in ∼50% of patients with AL amyloidosis, venetoclax is perfectly positioned as a therapeutic agent. Retrospective studies report HRs of 67% to 90%, with encouraging ORs.34, 35, 36, 37^,40 Table 4 Unsurprisingly, higher HR and OR have been observed among patients harboring t(11;14).^38,39 In a large multicenter cohort of 43 patients, HR and OR rates were 68% and 38%, respectively, with a median PFS of 31 months.³⁴ Similarly, patients with t(11;14) had higher rates of HR and OR as well as longer PFS.

Table 4.

Major studies of venetoclax in AL amyloidosis

Author	Intervention	Study design	n	HR (CR), %	OR, %	Median OS, mo	t(13,33) positive, %
Premkumar et al34	Venetoclax	Retro, multicentre	43	68 (34)	38	NR	68
Pasquer et al35	Venetoclax	Retro, single centre	10	67 (30)	57	10.5	70
Lebel et al36	Venetoclax	Retro, multicentre	26	88 (35)	NRp	33	88
Roussel et al37	Venetoclax	Retro, multicentre	51	90 (61)	NRp	NRp	94
Rieger et al38	Venetoclax	Retro, multicentre	9	100 (77)	67	NRp	100
Dima et al39	Venetoclax	Retro, multicentre	31	97 (65)	Cardiac 74%, renal 46%	NRp	100
Theodorakakou et al40	Venetoclax	Prospective, single centre	23	76 (41)	23	NR	91

NRp, not reported; Retro, retrospective.

Venetoclax-based therapy has shown high efficacy in daratumumab-refractory t(11;14) AL amyloidosis.^38,39 Dima et al achieved high overall hematologic ORR of 97%, with 65% CRs and rapid responses (median time, 2 months).³⁹ Rieger et al evaluated a small cohort of patients (n = 9) with advanced cardiac involvement (at least Mayo stage III), in which venetoclax achieved a 100% HR, with cardiac and renal responses in 6 of 9 patients and 3 of 5 patients, respectively.³⁸ Venetoclax discontinuation occurred in 6 patients after a median of 15 months due to toxicity or disease progression. Similarly, BCL-2 inhibitor therapies (venetoclax or lisaftoclax) achieved 50% CR rates in 6 patients after D-VCD, with a median EFS of 34.9 months, exceeding outcomes with daratumumab-based salvage regimens.⁶²

Prospective data confirm substantial activity (ORR, 76%; CR, 41%) but highlight significant infectious toxicity, including grade 5 events, leading to treatment discontinuation in 17%.⁴⁰ Venetoclax is typically effective at 200 to 400 mg daily, with careful attention to drug interactions and infection prophylaxis.

Overall, venetoclax represents one of the most promising targeted approaches for t(11;14) AL amyloidosis, yielding deep and durable responses even after daratumumab failure; however, preventive measures are essential to mitigate infection risk. Prospective trials are needed to confirm these findings and clarify the role, dosing, and combination strategies for this agent, particularly in advanced cardiac disease.

Stem cell transplantation

ASCT

Although the only randomized trial comparing HDM with ASCT vs melphalan-dexamethasone in newly diagnosed AL amyloidosis showed high treatment-related mortality (TRM; 24%) and superior OS with chemotherapy (56.9 vs 22.2 months; P = .04), HDM/ASCT remains an effective treatment option for carefully selected individuals. Contemporary data have shown improvements in TRM through refined patient selection and improved supportive care.73, 74, 75, 76, 77 The Mayo Clinic reported a retrospective study of 672 patients showing improved HR (84%), markedly reduced TRM (2.4%), and improved OS (median, NR) since 2012.⁷⁶ Similar outcomes were reported by the Boston University Group with substantial reductions in early mortality.⁷⁸ The CIBMTR registry, encompassing 1536 patients across the United States and Canada (1995-2012), found that both high- and low-volume transplant centers achieved lower TRM over time, although day-100 TRM remained higher in low-volume centers (7% vs 3%; P = .01).⁷⁹ Cardiac involvement was the strongest predictor of poor outcomes, whereas melphalan dose of <180 mg/m² negatively affected PFS. Although selection criteria for HDM/ASCT may vary between institutions, commonly used eligibility and exclusion criteria are listed in Table 5. Only 20% to 30% of newly diagnosed patients meet eligibility criteria for HDM/ASCT.⁸⁰ When strict eligibility cardiac biomarker-based selection criteria were applied, the Mayo Clinic group showed that TRM dropped to 1.1%.⁷³

Table 5.

Commonly used eligibility criteria and definite exclusions for ASCT

Clinical factors Age <70 y NYHA class I-II ECOG performance status ≤ 2 Systolic blood pressure ≥90 mm Hg Oxygen saturation >95% on room air

Organ function cTnT <0.06 μg/L or cTnI <0.1 μg/L NT-proBNP <5000 ng/L Creatinine clearance >50 mL/min Direct bilirubin <2 mg/dL Left ventricular ejection fraction ≥40% DLCO >50%

Definite exclusions Symptomatic and/or medically refractory ventricular and atrial arrythmias Symptomatic and/or medically refractory pleural effusions Uncompensated heart failure Orthostatic hypotension refractory to medical therapy Factor X deficiency with factor X level of <25% or/and evidence of active bleeding Extensive GI involvement with evidence of active GI bleeding or risk of bleeding

cTnI, Troponin I; cTnT, Troponin T; GI, Gastrointestinal; NYHA, New York Heart Association.

Adapted from EHA-ISA working group guidelines.⁸⁰

Use of up-front HDM/ASCT has declined given the availability of D-VCD.⁸¹ It remains uncertain whether D-VCD can fully replace autologous transplantation, because the ANDROMEDA trial enrolled transplant-ineligible patients. However, HDM/ASCT remains an important salvage option for patients with suboptimal response, relapsed disease, and in patients with immunoglobulin M amyloidosis or high bone marrow plasma cell burden (myeloma phenotype). A retrospective cohort study from the Pavia group showed the feasibility of reserving HDM-ASCT as a rescue therapy for patients with suboptimal response to VCD induction.⁸² Patients who had partial OR or better at the end of treatment had a similar 5-year OS and durability of response, irrespective of whether they underwent transplant.⁸² Zanwar et al reported that ASCT after daratumumab exposure was effective in 8 patients, achieving an HR in 87%, including CR in 75%, with a median PFS of 36.3 months.⁶² Muchtar et al evaluated safety and outcomes of second ASCT in 26 patients with relapsed/refractory AL amyloidosis, with a median interval of 7.2 years, and found VGPR of better in 87%, with a median PFS and OS of 39 and 88 months, respectively.⁸³ Collectively, these findings support HDM/ASCT as an effective and durable therapy for appropriately selected patients in the relapse/refractory setting. Decisions to pursue HDM/ASCT should balance TRM risk, side effects, and patient or caregiver burden against toxicity profiles and durability of response associated with emerging novel therapies.

Novel therapies on the horizon

BCMA-directed therapies

Belantamab mafodotin

The role of belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) expressed on plasma cell surface, in AL amyloidosis remains under investigation, with limited published data. In a retrospective study of 31 patients, including those with chronic kidney disease, the hematologic ORR was 71% (CR/VGPR, 58%), despite multiple prior therapies; keratopathy occurred in 73%, causing 1 treatment discontinuation.⁸⁴ The European Myeloma Network phase 2 trial (EMN27) reported 51% overall HR, 31% VGPR or better, and 11% cardiac responses at 3 months, but ocular toxicity was common.⁸⁵ These results suggest that belantamab mafodotin has meaningful activity in heavily pretreated patients, including those with advanced cardiac disease, although ocular toxicity remains a major limitation. Combination strategies and extended dosing intervals warrant exploration to improve tolerability while maintaining efficacy.

T-cell engagers

CAR T-cell therapy and bispecific T-cell engagers, highly active in myeloma, also show promise in AL amyloidosis. Considering the lack of cardiac reserve in patients with AL amyloidosis with cardiac involvement, safety has become a significant concern, particularly regarding cytokine release syndrome (CRS) and neurotoxicity. In a phase 1a/b trial of anti-BCMA CART NXC201 (formerly HBI0101), 16 heavily pretreated patients with AL amyloidosis were treated, including 88% who were triple refractory and 5 patients with Mayo stage III cardiac involvement.⁸⁶ Grade 3 CRS occurred in 3 patients but was manageable; no Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were reported. Hematologic CR occurred in 75%, with 62% OR, although the median OS was short at only 10.1 months, largely due to cardiac deaths despite initial responses. Phase 1/2 dose-escalation and dose-expansion study of NXC-201 is ongoing and suggest promising, safe induction of rapid and deep HRs.⁸⁷ Similarly, commercial BCMA-directed CAR T-cell therapy (idecabtagene vicleucel and ciltacabtagene autoleucel) achieved VGPR/CR in all evaluable patients (5/5) with acceptable safety (no grade ≥3 CRS or ICANS).⁸⁸ BCMA-directed CAR T-cell therapy were found to produce remarkably rapid, deep, and meaningful responses, but advanced cardiac involvement is a major cause of mortality, even in patients achieving rapid response. Larger prospective trials are needed to refine patient selection and confirm these early promising results. Additional BCMA-directed and dual-target BCMA/CD19 CAR T-cell therapies are under development and currently recruiting (NCT06983951 and NCT07081646).

Data on BCMA-targeting bispecific antibodies are emerging. Elranatamab achieved 100% overall and 67% complete HR in 9 patients, with rapid (median, 9 days) and deep light chain suppression within the first treatment cycle.⁸⁹ Teclistamab has demonstrated comparable efficacy in early reports.90, 91, 92, 93 In the largest retrospective cohort (n = 17), 88% achieved VGPR or better and 29% OR, with only mild CRS (53%; all grade 1) and rare discontinuation due to ICANS and infection.⁹² Etentamig, a second-generation bispecific antibody with bivalent BCMA domain and reduced CD3 affinity, has shown low incidence of CRS and no ICANS in a phase 1/2 dose-escalation study (NCT06158854).⁹⁴ BCMA-targeting bispecific antibodies have shown to induce deep responses in patients with multirefractory AL amyloidosis, but further larger and prospective studies are required. Ongoing phase 2 studies are evaluating teclistamab (NCT06935162 and NCT06649695) and linvoseltamab is under investigation in a phase 1/2 study (NCT06292780).

Antifibril antibodies

Organ dysfunction is a major cause of morbidity and mortality in patients with AL amyloidosis. Recently monoclonal antibodies have been developed that bind on to amyloid fibril precursors in the circulation or to fibrils deposited in organs and lead to removal of toxic amyloid aggregates, but early clinical results have been disappointing. A phase 3 trial of birtamimab plus standard of care was terminated early due to futility, leading to discontinuation of its development.⁹⁵ CAEL-101 (anselamimab) showed improved cardiac and renal responses, but cardiac responses trended down around 2-year follow-up,⁹⁶ whereas long-term follow-up has shown sustained safety and tolerability for >10 years.⁹⁷ Efficacy and safety of CAEL-101 in combination with Cyclophosphomide, bortezomib and dexamethasone (CyBorD) vs placebo combined with CyBorD are being evaluated in newly diagnosed patients with AL amyloidosis with Mayo stages IIIb (NCT04504825) and IIIa (NCT04512235). Although the primary end point was not met, a clinically meaningful improvement in all-cause mortality and cardiovascular hospitalization was observed in a prespecified subgroup; full results are pending publication. Safety and tolerability of AT-02, an antibody-peptide fusion protein with broad reactivity against multiple amyloid types, is currently being evaluated in a phase 2 study (NCT05951049), with initial data suggesting potential improvement in renal responses among patients who achieve an HR.⁹⁸

Conclusions

The approval of D-VCD has revolutionized first-line therapy for AL amyloidosis but underscored the absence of a standard approach for relapsed/refractory disease after quadruplet therapy. The role of ASCT in this setting remains unclear. Establishing validated definitions of hematologic progression and relapse is essential to guide management and trial design. Larger prospective studies are required to evaluate novel anti–plasma cell therapies, including T-cell engagers, antibody-drug conjugates, and antifibril antibodies.

Conflict-of-interest disclosure: M.G. reports personal fees from Ionis/Akcea; honoraria from Alnylam, AstraZeneca, Medscape, Dava Oncology, and Alexion; personal fees from Sanofi and Janssen; personal fees for data safety monitoring board from AbbVie and Arcellx; and fees from Johnson & Johnson. The remaining authors declare no competing financial interests.