Autologous Stem Cell Transplantation in AL Amyloidosis: Muddy Waters

Abstract

Immunoglobulin light chain (AL) amyloidosis is a malignant plasma cell dyscrasia causing multi-organ morbidity. High dose melphalan and autologous stem cell transplantation (ASCT) is a preferred consolidation approach and is safe with improved patient selection criteria. With the advent of bortezomib and daratumumab based induction therapy, nearly all patients can achieve deep hematological responses but follow up for daratumumab based induction is short. Consequently, the traditional approach of induction followed by ASCT is called into question. Given the multi-organ involvement of AL, endpoints beyond depth of response and hematological progression free survival (PFS) are important. Major organ dysfunction PFS (MOD-PFS) adds to PFS and is a composite endpoint of PFS, renal and cardiac organ progression, and overall survival. It is currently unknown which consolidative approach (ASCT or non-ASCT) will generate improved outcomes across the MOD-PFS spectrum a question the recently opened S2213 trial will attempt to answer.

INTRODUCTION

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell dyscrasia characterized by the production of immunoglobulin free light chains (FLC) that deposit as amyloid fibrils in various tissues. These amyloidogenic free light chain proteins are misfolded as β-pleated sheets (instead of conforming to the α-helical configuration) that can deposit and interfere with various organ functions including but not limited to the heart, kidney, neurological system, liver, and soft tissue.¹ Early diagnosis and initiation of treatment remain key challenges with 37% of patients diagnosed over a year from the onset of symptoms and a median of three physician visits before a diagnosis is established.² Like other plasma cell dyscrasias, AL amyloidosis is considered incurable. However, outcomes including progression free survival (PFS), overall survival (OS), and organ responses have dramatically improved over the past decade. For those patients achieving a complete hematological response (CR)³ and particularly amongst those achieving a normal/low involved FLC (iFLC) levels, long term outcomes are excellent with a median hematological PFS of around 69 months and 5-year OS of around 90%.^{4, 5} AL amyloidosis patients can have ongoing morbid end organ damage even with a minute residual burden of iFLC-secreting clonal plasma cells. Due to this, the optimal treatment approach in AL amyloidosis with the eradication of even small amounts of clonal disease may be key to optimal long-term outcomes as demonstrated by reports showing that even minimal residual disease (MRD) can lead to inferior organ responses.⁶

While high dose chemotherapy and autologous stem cell transplantation (ASCT) remains a standard of care in early consolidative therapy among transplant-eligible patients, real-world data suggest that only 15–20% of AL amyloidosis patients are transplant eligible.⁷ The treatment landscape has evolved in recent years with the introduction of proteasome inhibitors, immunomodulators, CD38-targeted monoclonal antibodies, and more recently, BCL2-inhitors such as venetoclax and B-cell maturation antigen (BCMA)-directed therapies. The addition of daratumumab (dara) to standard induction therapy of cyclophosphamide, bortezomib, and dexamethasone (Dara-VCD) has generated deep responses with CR rates around 50% at 6 months offering newly diagnosed patients with stage I-IIIA amyloidosis a therapeutic option associated with excellent response and tolerability.⁸ Thus, the optimal consolidation approach in newly diagnosed AL patients following induction regimens that achieve such deep hematological responses is now as uncertain as ever.

In this article, we aim to review ASCT and non-ASCT approaches to consolidation therapy in newly diagnosed AL amyloidosis patients following induction therapy. We cover the history of ASCT in AL as well as candidacy for consolidative ASCT therapy. Importantly, given the multi-organ effect of this disease and two effective consolidative approaches, we will frame this discussion in the context of the various important clinical and patient-focused outcomes including hematological response and PFS, MRD, OS, organ responses, the new composite endpoint of modified progression free survival (MOD-PFS), as well as patient-related outcomes (PROs) and toxicity. We conclude by outlining the path forward and highlighting the recently opened randomized phase 3 Southwest Cancer Chemotherapy Study Group (SWOG) led intergroup trial S2213 attempting to definitively answer the question of the optimal consolidation approach in AL patients.

A History Lesson:

Oral Melphalan and Early Experience with High Dose Chemotherapy and Autologous Stem Cell Transplantation:

With recent advances in AL amyloidosis, it is important to reflect on the past as unlike in MM, the development of novel therapeutics and implementation into routine clinical care has been more methodical and slower moving due to early toxicity signals as well as the multi-organ pathological nature of the disease. As early as 1972, reports of responses to melphalan appeared in the literature⁹ and over the next decade plus, a variety of individual case reports and clinical trials would be published highlighting the potential role of cytotoxic therapy in controlling the malignant plasma cell burden driving amyloidogenic light chain production.^{10, 11} In 1991, the Mayo Clinic group reported on a large series of previously untreated AL amyloidosis patients who underwent therapy with melphalan and prednisone.¹² Although response rates were modest at only 18%, the median overall survival (OS) of responding patients was 89.4 months, which was a vast improvement over published OS at the time of only 13 months.¹³ Several randomized clinical trials that followed comparing melphalan and prednisone with or without colchicine to colchicine alone done at the Mayo Clinic and Boston University ^{14, 15} as well as the high response rates seen in an Italian study evaluating melphalan and dexamethasone ¹⁶ showed the promise of melphalan-based therapy. This quickly established oral melphalan as the standard of care in newly diagnosed AL amyloidosis patients.

The promise of oral melphalan therapy and lack of other therapeutic options led to the early investigation of high dose melphalan and ASCT starting in the 1990s into the early 2000s. While there was enthusiasm for ASCT-based approaches to treat all plasma cell dyscrasias during this time period, early reports noted the high toxicity of both allogeneic and ASCT approaches in this setting,^{17, 18} thus tempering expectations. Based on improved response rates noted in patients with recurrent or refractory MM, the Boston University group embarked on a planned assessment of the role of high dose melphalan and ASCT in newly diagnosed AL patients. In 1996, they reported the first cohort of patients with adequate follow up to assess treatment efficacy.¹⁹ This initial report as well as an expanded cohort published two years later ²⁰ showed the efficacy of high dose melphalan and ASCT. Twenty-five patients with a median follow up of 24 months were found to have a median OS not reached with 68% of patients still alive 2 years post-ASCT. Day 100 transplant related mortality (TRM) was 13% and a complete hematological response (CR) rate of 62% at 3 months post-transplant was seen. Following these positive reports from the Boston group, other groups followed shortly thereafter highlighting both the efficacy but also potential toxicity and importance of patient selection. Reports out of the Mayo Clinic Rochester,²¹ Toronto,²² the Intergroupe francophone du myélome (IFM),²³ and an early Center for International Blood and Marrow Transplant Research (CIBMTR) ²⁴ report highlighted the high TRM with the IFM group in particular noting a 43% 30-day TRM (Table 1). In an editorial to the CIBMTR report which showed a TRM of 18%, Dr Morie Gertz noted the study had 107 patents from 48 centers, thus most patients in the report received their care at centers with limited experience and that the 30-day mortality rate for ASCT in the Mayo Clinic program at the time was down to just 7.4%.²⁵

Table 1:

Early Experience with High Dose Melphalan and Autologous Stem Cell transplantation

	Number of Patients and Treatment Site	Treatment Prior to Transplant	Organs involved	Melphalan Dose	Transplant Related Mortality	Overall Survival	Hematological and Organ Response Rates	Predictors of Transplant Related Mortality
Comenzo et al; BLOOD 1998* 20	25; Boston University	No prior therapy: 18 Oral Mel: 7	Cardiac: 8 Renal: 7 Hepatic: 6 Neuropathic: 3 1–2 organs: 15 ≥3 organs: 10	200mg/m2: 22 <200mg/m2: 3	30-day: 0 100-day: 13% 1-year: 17%	Median: NR 2-year: 68%	CR: 62% Cardiac: 38% Renal: 64%	• 3 or more organs involved • Cardiac involvement • ECOG ≥3
Moreau et al; BJH 1998** 23	21; IFM Group	No prior therapy: 10 MP: 5 VAD: 6	Cardiac: 7 Renal: 17 Hepatic: 7 Neuropathic: 9 1 organ: 9 ≥ 2 organs: 12	200mg/m2: 11 140mg/m2: 7 140mg/m2 +12 Gy: 3	30-day: 43%	4-year OS: 57%	CR: 30% 10/12 surviving patients achieved organ response: • 3 cardiac responses • 4 renal responses	≥ 2 organs: 4-year OS 91.7% v 11.1%
Saba et al; BMT 1999*** 22	11; Toronto Hospital	No prior therapy: 6 Mel: 4 Cy: 1	Cardiac: 11 Renal: 6 Hepatic: 4 Neuropathic: 1 ≤ 2 organs: 4 • organs: 2 • organs: 2 • organs: 2	140mg/m2: 2 140mg/m2 +12 Gy: 4	100-day: 66%	33%	ORR: not reported Cardiac: 33% Renal: 0%	Unable to calculate due to small patient numbers
Gertz et al; BMT 2000# 21	20; Mayo Clinic Rochester	No prior therapy: 12 Mel: 3 Dex: 5	Cardiac: 12 Renal: 14 Hepatic: 10 Neuropathic: 2 1 organ: 10 2 organs: 7 3 organs: 3	200mg/m2: 4 140mg/m2 + 12 Gy: 16	Overall 20%	65% OS with median follow up 16 months	ORR: 40% Cardiac: 0% Renal: 50%	• Clinical CHF • TB > 3.0mg/dl • EF < 55% • Cr > 22.0 mg/dl • Interventricular septal thickness > 15mm • Age > 60 • >2 organs involved

ASCT: Autologous Stem Cell Transplantation

CHF: congestive heart failure

CR: complete hematological response

Cr: serum creatinin

Cy: cyclophosphamide

Dex: dexamethasone

ECOG: Eastern Cooperative Oncology Group Performance Status

EF: ejection fraction

Gy: gray

IDM: intermediate dose melphalan

IFM: Intergropue Francais du Myeloma

Mel: melphalan

MP: melphalan and prednisone

NR: not reached

ORR: overall hematological response rate

OS: overall survival

TB: total bilirubin

TRM: transplant related mortality

VAD: vincristine, doxorubicin, and dexamethasone

^*Transplant selection criteria not specified; criteria for melphalan dose reduction not specified

^**Transplant selection criteria for ASCT were not specified, and the number of patients with AL who could not proceed to ASCT was not known. Patients with secondary, familial, senile, localized amyloidosis, or overt symptomatic multiple myeloma were not included

^***Only 6 of the 11 patients proceeded to high dose melphalan and ASCT. All patients had cardiac involvement. Patients with secondary, localized, senile amyloidosis, or overt multiple myeloma were not included.

^#Patients with secondary, familial, or localized amyloidosis were excluded. Patients with AL whose disease was limited to only cutaneous involvement, purpura, or carpal tunnel syndrome were excluded. To ensure adequate ability to procure stem cells, patients could not have received >500 mg total lifetime dose of melphalan. Their ECOG must have been 0 to 2. Serum Cr concentration had to be < 2.5 mg/dl. The alkaline phosphatase concentration had to be <4 times the institutional upper limit of normal. Patients with overt multiple myeloma were excluded. 2 X 10⁶ CD34-positive cells/kg must have been collected. Patients with moderate to severe congestive heart failure were not eligible for this protocol.

Attention to Patient Selection and Transplant Center Experience:

With early efficacy signals and under the caution of potentially high TRM, further evaluations of ASCT in newly diagnosed AL were reported in the early 2000s leading up to the only randomized trial conducted by the IFM and published in 2007.²⁶ These reports would highlight the obligation of centers to perform careful patient selection and a regimented approach to transplant candidacy. Indeed, a timely review by Drs Comenzo and Gertz in 2002 would note the high average TRM and that in AL amyloidosis, unlike in MM, deaths were reported during stem cell mobilization and infusion; thus, these patients are disproportionately prone to adverse events.²⁷ Traditional selection criteria for ASCT alone are not enough for AL amyloidosis but single center clinical trials being done at the time utilized standard criteria for ASCT which led to unnecessarily high TRM. Early ASCT eligibility criteria were developed with age younger than 70 years, lack of significant cardiac involvement (ventricular septal thickness less than 15 mm, cardiac ejection fraction greater than 55%), adequate renal function (creatinine concentration less than 2 mg/dL), and adequate liver function (alkaline phosphatase value less than 3 times normal, and direct bilirubin value less than 2 mg/dL) cited. It was clear early on that multi-organ involvement (>2) and, particularly, cardiac involvement was driving TRM. When these criteria were applied to a retrospective cohort of 234 patients with AL amyloidosis at the Mayo Clinic (18% of all AL amyloidosis patients seen at the center), excellent long-term outcomes were seen with a median survival of 46 months ²⁷ suggesting that patients eligible for ASCT represent a highly selected population.

Table 2 outlines the “second wave” of reports highlighting the efficacy and improved toxicity of high dose chemotherapy and ASCT for newly diagnosed AL amyloidosis.^28–33 Although strict transplant eligibility criteria are not outlined in each of these reports, early patterns were emerging highlighting the risk of transplant in patients with renal insufficiency, cardiac involvement, multiple organ involvement (particularly those with ≥3 organs), hypotension, and poor performance status. In particular, the report out of Princess Margaret Hospital, Toronto showed that after additional eligibility criteria were implemented, TRM dropped from an unacceptably high 50% down to 20%.²⁹ Further, the relationship between dose intensity of melphalan directly leading to improved long-term outcomes ³¹ and lower doses leading to improved morbidity and TRM ³⁴ was established. Finally, in the first study incorporating a novel agent into ASCT, a phase 2 trial using risk-adapted melphalan and 9 months of post-SCT adjuvant thalidomide and dexamethasone for those not achieving strict CR ³³, an impressively low TRM was achieved at only 4% and a 2-year OS of 84%.

Table 2:

Improved outcomes following the initial experience with autologous stem cell transplantation

	Number of Patients and Treatment Site	Reported Transplant Eligibility	Treatment Prior to Transplant	Organs involved	Melphalan Dose (mg/m2)	Transplant Related Mortality	Overall Survival	Hematological and Organ Response Rates	Predictors of Transplant Related Mortality
Gertz et al; Am J Med 2002 28	66; Mayo Clinic Rochester	Minimum 2 X 106 CD34/Kg	43%: steroids 20%: cytoxic (mostly Mel)	Cardiac: 48% Renal: 68%	200: 74% ≤140: 26%	Overall: 14%	2-year: 70%	ORR: 50% Renal: 51% Cardiac: 19%	• Serum Cr level • Number organs involved
Mollee et al*; BMT 2004 29	26; Princess Margaret Hospital	Age ≤65 ECOG ≤3 No history of syncope VWT: ≤ 15mm Systolic BP ≥90 mmHg	27% with prior therapy (not specified)	Cardiac: 77% Renal: 73% 1 organ: 38% 2 organs: 23% ≥3 organs: 40%	200: 9 140: 11 140 +12 Gy: 2	100-day: 20%	Median: 5 years	ORR: 56% CR: 28% Cardiac: 40% Renal: 75%	ECOG • Normal alkaline phosphatase • Nephrotic syndrome • Absence of hypotension
Skinner et al; ACP 2004 30	312; Boston University Medical Center	Age ≤ 80 Compensated CHF EF ≥ 40% Lack of pleural effusion Systolic BP ≥ 90 mm Hg O2 sat ≥ 95% ECOG ≤2 (unless neuropathy)	NA	Cardiac: 43% Renal: 86% 1 organ: 20% 2 organs: 30% ≥3 organs: 50%	Risk adapted; 200: 56% ≤ 140: 44%	100-day: 13%	Median: 4.6 years	CR: 40% Cardiac: 21% Renal: 32%	Age • Worse performance status • Longer time from diagnosis to referral • Melphalan < 200mg/m2
Gertz et al BMT 2004 31	30; ECOG study at 12 transplant centers	BMPC > 30% ECOG 0-2 Cr ≤2 mg/dL EF ≥ 50% VWT: ≤ 15 mm PFT DLCO ≥50% PFT FVC ≥ 60% PFT FEV1 ≥ 55% Collect 6 X 108 mononuclear cells/kg or 5 X 106 CD34 cells/kg	NA	Cardiac: 25% Renal: 93% 2 organs: 26% ≥ 3 organs: 19%	200: 100%	Overall: 10%	Median: NR 2 year: 86%	ORR: 64%	NA
Goodman et al; BJH 2006 32	92; 32 centers within the UK	Per treating physician discretion --	VAD: 29%	Cardiac: 42% Renal: 76% 2 organs: 35% ≥ 3 organs: 26%	200: 60% ≤ 140: 20% Other: 20%	Overall: 23%	Median: 5.3 years	CR: 58% PR: 24% Cardiac: 22% Overall organ response rate: 48%	• Number of involved organs • Worse performance status • Cardiac involvement • Transplant time period
Cohen et al; BJH 2007** 33	45; MSKCC	BMPC > 30% ≤ 2 organs LVEF <45% DLCO <50% TB > 34.2 umol/l Symptomatic cardiac arrhythmias within 60 days Cardiac syncope NYHA ≥ 3 Restrictive cardiomyopathy MI within 6 months	No prior therapy	Cardiac: 24% Renal: 30% 1 organ: 69% 2 organs: 31%	Risk adapted; 200: 33% 140: 53% 100: 13%	Overall: 4.4%	2-year: 84%	CR: 36% ORR: 78% Cardiac: 36% Renal: 40% Overall organ response rate: 44%	• Number of organs involved

ASCT: Autologous Stem Cell Transplantation

BMPC: bone marrow plasma cells

BP: blood pressure

CR: complete hematological response

CHF: congestive heart failure

Cr: serum creatinin

Db: direct bilirubin

Dex: dexamethasone

DLCO: diffusing capacity of the lungs for carbon monoxide

ECOG: Eastern Cooperative Oncology Group Performance Status

EF: ejection fraction

FVC: forced vital capacity

FEV1: forced expiratory volume

IDM: intermediate dose melphalan

IFM: Intergropue Francais du Myeloma

LVEF: left ventricular ejection fraction

Mel: melphalan

MI: myocardial infarction

MP: melphalan and prednisone

MSKCC: Memorial Sloan-Kettering Cancer Center

NA: not available

NR: not reached

NYHA: New York Heart Association

O2 sat: oxygen saturation on room air

ORR: overall hematological response rate

PFT: pulmonary function test

PR: partial hematological response

RA: room air

sat: saturation

TB: total bilirubin

TRM: transplant related mortality

UK: United Kingdom

VAD: vincristine, doxorubicin, and dexamethasone

VWT: ventricular wall thickness

^*ASCT initially offered to all patients except those older than 65 years or ECOG performance status >3. Following initial review of outcomes, additional selection criteria were introduced, from January 1999 onwards patients with syncope, cardiac interventricular wall thickness >15mm and significant sustained hypotension (systolic blood pressure p90 mmHg) were also excluded. Minimum target CD34+ cell count was 2X10⁶ cells/kg. Patients with hereditary or localized AL were excluded, as were patients with underlying lymphoma or myeloma, including those with >20% bone marrow plasmacytosis.

^**Patients with persistent clonal plasma cell disease at 3 months post-SCT (defined as detectable clonal light chain in serum or urine by immunofixation, persistent increase in involved light chain-restricted plasma cells in bone marrow, or persistent increase in involved serum-free light chain (FLC) with abnormal kappa/lambda ratio) were treated with 9 months of adjuvant thal and dex (thal/dex) or dex alone (if they had a history of venous thromboembolic disease or neuropathy).

With the unprecedented responses and improved TRM noted above but also the understanding that patients who have received stem cell transplants for amyloid are highly selected, the U.S. Eastern Cooperative Oncology Group undertook a multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97). The goals were to demonstrate that small volume centers could achieve results comparable to those reported from centers that see large numbers of AL amyloidosis patients as well as gain knowledge about feasibility and toxicity for a future large-scale phase 3 trial. The results were promising with a median OS not reached (2-year OS of 86%), high hematological response rate of 64%, and a TRM of 10%.³¹

IFM 2007 and the emergence of a Geographical Approach to high dose chemotherapy and ASCT

In the early 2000s, many attributed the success of high dose chemotherapy and ASCT in newly diagnosed AL patients to patient selection. A report by Dispenzieri et al ³⁵ showed that amongst patients referred to and treated at the Mayo clinic between 1983 and 1997 that were eligible for ASCT (absence of clinical diagnosis of MM, age < 70 years, cardiac interventricular septal thickness < 15 mm, cardiac ejection fraction more than 55%, serum creatinine < 2mg/dL, and direct bilirubin < 2.0 mg/d) but did not undergo the procedure, they did relatively well with chemotherapy with a median survival of 42 months. However, shortly thereafter the same group published a case-control study demonstrating the superiority of ASCT as compared to the currently available therapies with a 4-year survival of 71% v 41%.³⁶ Thus, the need for a randomized trial was clear and despite the successes of the E4A97 trial³¹ and promising results reported in the phase 2 trial by Cohen et al,³³ the French would conduct the first randomized trial evaluating ASCT v non-ASCT treatment approach in newly diagnosed AL patients.

The IFM study enrolled 100 patients from January 2000 to January 2005 and randomized patients to received oral melphalan and dexamethasone monthly for up to 18 months or high dose chemotherapy with Melphalan at 200mg/m² and ASCT.²⁶ Limited inclusion criteria included age ≤ 70, less than or equal to 2 previous courses of therapy, no concurrent MM, and ECOG performance status 0–2. Cardiac involvement was not an eligibility criterion nor a stratification criterion. Melphalan dose was reduced to 140mg/m² if age ≥65, ejection fraction (EF) <30%, creatinine clearance (CrCl) < 30 ml/min, or severe liver disease (prothrombin index, <50%; total bilirubin or alkaline phosphatase level >5 times the normal level) was present. Eligibility also included a minimum cell dose of 2 X 10⁶ CD34/kg. The primary outcome was overall survival with a landmark analysis performed looking at those who survived at least 6 months to account for early toxic effects. After a median follow-up of 3 years, the estimated median overall survival was 22.2 months in the group assigned to ASCT and 56.9 months in the group assigned to receive melphalan plus dexamethasone (P=0.04) while there was no difference in the landmark analyses looking at those who survived 6 months (p=0.38). The study concluded that high dose melphalan was not superior but did note that a trial comparing the two where TRM would be significantly lower could impact results. The resulting publication²⁶ received several comments^37–41 with a clear dividing line being developed between European and North American practices. It is of note that immediately preceding enrollment onto this trial, the IFM group had published some of the highest TRM in the literature ²³ exceeding 40%. Comments from several key stakeholders in North America noted the problematic design highlighting several factors:

• Patients treated at non-experienced centers with a TRM on this study of 24% double that being reported from the US at the time in literature

• Enrollment of patients with 3 or more organ involvement (36%) and poor cardiac status thus favoring melphalan and dexamethasone

• Nearly a 1/3 of the patients receiving dose reduced melphalan at 140mg/m² despite recent data highlighting the inferiority of that approach³⁴

• Lack of true randomization with relevant stratification as no data on cardiac biomarkers were available or reported

• Lack of rigorous eligibility criteria that at the time were known to drive poor outcomes in ASCT patients

Observations from the United Kingdom at the time noted that in North America, TRM of 13% can be seen even in specialist centers and that chemotherapy without transplantation was favored in the UK where the median survival exceeded 60 months and TRM was less than 7% among 448 patients treated with such regimens.⁴² This preference holds even today as evidenced by the recently reported ALCHEMY study, an observational study of newly diagnosed AL patients treated with upfront bortezomib based regimens from 2010 to 2017, where <1% of newly diagnosed AL patients received up front ASCT. Thus, a clear divide was created in practice patterns internationally with many European specialist centers, favoring a non-transplant approach while the large US specialist centers continuing to regularly offer up front ASCT in eligible patients. In 2014, Venner et al ⁴³ published a UK experience of 90 patients who underwent ASCT between 2003 to 2012 representing all patients in the database at the UK National Amyloidosis Centre. They noted an improved TRM of 6.8% including patients who underwent ASCT in the up-front as well as relapsed setting highlighting improved TRM.⁴²

An Update on Transplant Related Mortality and the Impact of the 2015 CIBMTR Report: Patient Selection, Center Experience, and moving toward high risk patients

Following the IFM randomized clinical trial,²⁶ several North American centers published updated reports of their individual experience with ASCT in newly diagnosed AL patients.^{44, 45} These reports (Table 3) demonstrated some key developments:

Table 3:

Improved outcomes following the IFM 2007 Report

	Number of Patients and Treatment Site	Transplant Eligibility	Treatment Prior to Transplant	Organs involved	Melphalan Dose mg/m2	Transplant Related Mortality	Overall Survival	Hematological and Organ Response Rates	Predictors of Transplant Related Mortality
Sanchorawala et al; Blood 2015 44	624; Boston University	• EF >40% • No pleural effusions • No uncompensated HF or arrhythmia • O2 saturation ≥95% • DLCO ≥50% predicted • Supine BP > 90 mm Hg • SWOG performance status score ≤2 unless limited by peripheral neuropathy • Minimum 2 X 106 CD34 cells/kg	NA	NA	200: 55.6% ≤140: 44.4%	Day 100: Overall: 7.5% After 2005: 3.4%	Median: 7.63 years • NR for those in CR • Mel200 v ≤140:10.47 v 5.15 years (P=0.0001)	Hematological: CR: 40.3% Mel200 v ≤140: 44.9% v 33.8% (p=0.0091)	NA
Gertz et al; BMT 2011 45	157; Mayo Clinic Rochester	• Physiological age 70 years or younger (or ‘robust elderly’); • ECOG Performance score of ≤ 2 • Troponin T ≤ 0.06 ng/mL; • CrCl 30 mL/min (unless on chronic dialysis); • NYHA ≤ grade 2 • ≤ 2 organs • Minimum 2 X 106 CD34 cells/kg	NR	Cardiac: 50.3% Renal: 72.6% > 2 organs: 14%	200: 38.2% ≤140: 61.8%	Day 100: 3.8%	2-year OS: 82%	NR	Whole cohort multivariate analyses: • Presence of cardiac amyloid involvement by consensus criteria • Troponin T level
Jimenez-Zepeda et al; BJH 201346	78; Princess Margaret Cancer Center Toronto, ON	• ≤ 2 previous courses of chemotherapy • ECOG Performance score of ≤ 2 • EF ≥ 45% • No symptomatic cardiac arrhythmias • No history of cardiac syncope • NYHA ≤ grade 2 • No myocardial infarction within 6 months	• 76.9% of patients did not receive induction therapy	Cardiac: 47.4% Renal: 71.8% >2 organs: 20.5%	200: 24.4% 140: 56.4% 100: 19.2%	Day 100: 11.5%	After median follow up of 122 months; 76.9% of patients were still alive	Hematological: • CR: 50% Cardiac: 51% Renal: 60%	• BNP > 300 pg/mL • Troponin-I > 0.07 ng/mL
Landau et al; Leukemia 2013 47	40; Memorial Sloan-Kettering Cancer Center	• Serum bilirubin ≤ 2.0 mg/dl • DLCO ≥ 50% • LVEF ≥ 45% • NYHA ≤ grade 2 • No symptomatic cardiac arrhythmia or cardiac syncope • Plasma cells ≤ 30%	None	Cardiac: 65% Renal: 70%	200: 35% ≤140: 65%	Day 100: 10%	2-year OS: 82%	Hematological Day 100 CR: 27% Cardiac: 53% Renal: 52%	• BNP • Troponin-I
Parmer et al; BMT 2014 49	145; MD Anderson Cancer Center	NR	Any induction: 80% Bortezomib based: 32%	Cardiac: 25% Renal: 68% ≥ 2 organs: 33%	200: 87% ≤140: 3%	Day 100: 7.5%	5-year: 64% 10-year: 56%	Hematological: ORR: 75% CR: 18.6% PR: 56% Overall organ response: 39%	• age < 60 years • Induction therapy with novel agents

ASCT: Autologous Stem Cell Transplantation

BNP: B-Type Natriuretic Peptide

BP: blood pressure

CR: complete hematological response

Cr: serum creatinine

CrCl: creatinine clearance

Db: direct bilirubin

DLCO: diffusing capacity of the lungs for carbon monoxide

ECOG: Eastern Cooperative Oncology Group Performance Status

EF: ejection fraction

HF: heart failure

IV: interventricular

LVEF: left ventricular ejection fraction

Mel: melphalan

Mel200: melphalan at 200mg/m2

Mel≤140: melphalan at 140mg/m2 or 100mg/m2

NA: not available

NR: not reached

NTproBNP: N-terminal pro-brain natriuretic peptide

NYHA: New York Heart Association

ORR: overall hematological response rate

PR: partial hematological response

SWOG: Southwest Oncology Group

TRM: transplant related mortality

• A lack of strict transplant eligibility could still lead to an unacceptably high TRM ^{46, 47}

• When strict eligibility using cardiac biomarkers was applied, the Mayo Clinic group showed a TRM of just 1.1% for those transplanted later than 2009⁴⁸

It would become clear that depth of organ involvement, and in particular cardiac involvement, was the most critical factor driving early mortality as exemplified by a cohort of 24 stage III Mayo patients with both troponin level ≤ 0.06 ng/mL and NT-proBNP level ≤ 5000 pg/mL achieving a median survival of 66.1 months. In addition, for the first time the MD Anderson group showed the positive impact of pre-transplant induction therapy ⁴⁹ which would lead to a change in practice patterns of offering pre-transplant induction therapy that stabilizes and improves organ involvement allowing more patients to be eligible for ASCT and undergo the procedure with reduced morbidity and mortality.

Although earlier reports demonstrated the importance of transplant center experience, there was an appetite to demonstrate that if stringent eligibility criteria are applied, even less experienced centers can safely offer ASCT. The SWOG S0115 was only the second U.S. cooperative group study evaluating ASCT in AL amyloidosis.⁵⁰ Eligibility included previous non-transplant therapy but cumulative dose of melphalan less than 200 mg, performance of 2 or less, left ventricular ejection fraction (LVEF) of >45%, diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50%, and minimum collection yield of 7.0 X 10⁶ CD34 cells/kg. Patients underwent tandem ASCT with melphalan at 100mg/m2. The trial would enroll 93 eligible patients with either MM or AL amyloidosis at 17 SWOG sites. Of the 58 patients who underwent ASCT for AL amyloidosis, median number of organs involved was 2, 32% had cardiac involvement, and 20% of patients had end stage renal disease (ESRD). Despite no cardiac biomarkers as eligibility and patients undergoing tandem transplantation, TRM was only 6.9%. A subsequent European Society for Blood and Marrow Transplantation (EBMT) analyses looked at 1,314 patients from 259 centers who underwent ASCT from 1997 to 2010.⁵¹ They showed dramatically improved 1 year OS from 65% during the period of 1997–1999 to 91% during the period of 2009 to 2010. Not surprisingly, patient selection was the driving force and in addition to time-period, transplant experience predicted outcomes.

The EBMT report would never be published in a peer-reviewed journal, but in 2015, the CIBMTR experience describing the US and Canadian experience would result in a landmark publication.⁵² A large cohort of 1,536 patients with AL who underwent ASCT at 134 centers between 1995 and 2012 was evaluated. In the latest time-period that was studied (2007–2012), 38% of patients had cardiac and 76% renal involvement. There was an increase in pre-transplant induction therapy noted with 10% receiving bortezomib and 14% receiving immunomodulatory drug (IMID) based induction prior to transplant. The mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995–2000 to 3% and 5%, respectively, in 2007–2012. The 5-year OS also improved from 55% in 1995–2000 to 77% in 2007–2012. Like the EBMT report above, transplant center experience was found to impact outcomes with day 100 TRM of 7% vs 3% at centers performing less than or greater than four AL amyloidosis ASCT procedures per year (p=0.01). However, both high and low volume centers reported improved TRM over this time period (P<0.01). On multivariable analyses, cardiac involvement was the most significant risk factor of poor outcomes predicting early TRM, PFS, and OS and melphalan dose of less than 180mg/m2 was found to negatively impact relapse/progression. Of note, despite a similar proportion of patients with cardiac involvement, transplantation after 2007 was associated with lower early mortality and superior OS than the earlier time periods. Therefore, the improvements seen in early mortality were likely multifactorial, including not only better patient selection but also better supportive care.

Following the CIBMTR report, several single center experiences demonstrated these improved outcomes, led by the Boston University and Mayo Clinic groups but extending to other US centers as well as Europe. In 2021, the Boston University group reported their 40-year experience ⁵³ treating both transplant eligible and ineligible AL patients. Early mortality among ASCT-treated patients decreased from 10% to 6% to 2% in the following 3 eras: 1990–1999, 2000–2009, and 2010–2019. In non ASCT-treated patients, it decreased between eras 1 and 2 from 26% to 11%, then remained fixed at 11% thereafter. The Mayo Clinic group reported similar improvements.⁵⁴ When looking at three sequential time periods (cohort 1, 1996–2002; cohort 2, 2003–2009; cohort 3, 2010–2016), hematologic response was higher in cohort 3 (P = .002), median OS improved (75 months v 120 months v not reached; P=0.001), and importantly, TRM declined (14.5% v 8.6% v 2.4%; P=0.001). The importance of full dose melphalan at 200mg/m2 was noted with conditioning dose, Mayo stage 2012, and hematologic response predicting OS on multivariable analyses. In the most recent time period, 51% received pre-ASCT therapy with 38% receiving bortezomib based treatment. As alluded to above, although up front ASCT is offered infrequently in Europe, outcomes including early mortality were improving. Gutiérrez-García et al. ⁵⁵ reported their experience with ASCT for 66 patients at Hospital Clinic of Barcelona. In their most recent cohort, where they applied strict patient selection and avoided G-CSF mobilization, they reported 0 TRM and 3-year OS of 100%.

With improved supportive care, more strict patient selection, and ongoing transplant center experience, the ability to offer ASCT to high-risk patients would be re-evaluated. Outcomes were improving in these high-risk patients including patients with multiple organs involved, impaired renal function, cardiac involvement, induction failure, and the elderly (Table 4). These reports would demonstrate that advanced degree of cardiac involvement would continue to prove to be the Achilles heel of early mortality, organ involvement and age alone are not prohibitive, and patients with renal impairment can be safely transplanted although risk of renal progression and ESRD is important to recognize. The progression to ESRD is of concern for those patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/m².⁵⁶

Table 4:

Autologous Stem Cell Transplantation in High Risk Patients

	Number of Patients and Treatment Site	High Risk Category	Treatment Prior to Transplant	Organs involved and Staging	Melphalan Dose mg/m2	Transplant Related Mortality	Overall Survival	Hematological and Organ Response Rates	Predictors of Overall Survival, Morbidity, and TRM:
Induction Failure:
Wong et al; BMT 2017 94	12; single center UCSF	Less than VGPR to bortezomib based induction therapy	Bortezomib based induction; median 4 cycles (range 2–8)	2-organs: 50% Cardiac: 58% (six stage 2 and one stage 3) Renal: 58% Staging: NA	200: 33% 140: 58% 100: 8%	8% (1 patient at 2 months post ASCT, 70-year-old stage 2 cardiac and stage 2 renal disease, received MEL 100 mg/m2 improved hematologic response status from NR to PR)	Median: NR 1 early mortality at 2 months	Hematological: • CR: 42% • ≥ VGPR: 75% Renal: 29% Cardiac: 57%	NA
Multiple Organ Involvement
Al Saleh et al; BBMT 2017 95	75; single center Mayo Clinic Rochester	3 or more organs involved: • 3 organs: 75% • 4 organs: 21% • 5 organs: 4%	None: 51% Vel/IMID: 20%	Cardiac: 95% Renal: 84% Mayo 2012 stage • I: 19% • II: 34% • III: 35% • IV: 12%	200: 45% 140: 55%	16% (cardiac involvement not number or organs predicted TRM)	Median: 68 months	Hematological: • ORR: 75% • CR: 36% Renal: 29% Cardiac: 57%	Overall Survival: • Mayo 2012 (I-II v III-IV) • Mel200mg/m2 • NTproBNP >2000 • Hematological response
Impaired renal function:
Batalini et al; BBMT 2018 96	32; single center Boston University	ESRD on HD	Any induction: 53% Vel/IMID: 13%	Cardiac: 28% Renal: 100% ≥2 organs: 75% Staging: NA	200: 33% 70–140: 67%	8% -- 3 patients all due to infection; no cardiac/renal causes	Median: 5.8 years	Hematological: • ORR: 75% • CR: 70% Renal: 29% Cardiac: 57% Of note: 33% had kidney transplantation at a median of 2.4 years after ASCT and all in CR at the time	TRM was no different (8%) than the whole cohort of 629 patients (7.5%) treated with ASCT at the institution during this period
Sidiqi et al; BMT 2019 97	87; single center Mayo Clinic Rochester	IRF with eGFR < 45 ml/min; IFR group was compared to those with eGFR ≥45 ml/min (NRF)	Any induction: 53% Vel/IMID: 22%	Cardiac: 51% Renal: 89% ≥2 organs: 26% Mayo 2012 stage • I: 48% • II: 25% • III: 15% • IV: 12%	200: 30% 70-140: 70%	Whole cohort: 6.5%. IRF cohort: 14%	Median OS: • IRF: 118 months • NRF: 142 months p=0.07)	Hematological: • ORR: 88% • CR: 42% • ≥VGPR: 73 Renal: 29% Cardiac: 57%	6.7% required dialysis within 100 days of ASCT. Renal stage predicted dialysis • Stage I: 3% • Stage II: 10% • Stage III: 22% p < 0.000 Rates of HD at 100 days: higher in the IRF cohort (16% v 6%) p =0.0007 Renal stage did not predict for OS
Cardiac involvement
White et al; BMT 2018 98	20; single center Boston University	Advanced cardiac involvement defined as: • TnI > 0.1 ng/mL • BNP > 100 pg/mL Group that underwent ASCT compared to those with cardiac involvement not undergoing ASCT	None	Cardiac: 100%	200: 55% 140: 45%	5% (one death from sepsis and multi-organ failure)	Median OS • ASCT: NR • Non-ASCT: 1.8 years	NR	NR
Phull et al; BMT 2019 99	15; single center Boston University	Patients with active cardiac defibrillator support (including ICDs and wearable defibrillators) in place prior to ASCT	Any induction: 20%	Cardiac: 100% Renal: 60%	200: 31% 140: 69%	6.7% (1 patient had sudden death from PEA without ICD discharge or detectable arrhythmia)	Median OS: 48.8 months	Hematological: • ORR: 93% • CR: 33% • ≥VGPR: 60% Cardiac: 15%	NR
Elderly
Sidiqi et al; BBMT 2018 100	34; single center Mayo Clinic Rochester	Age ≥ 70	Any induction: 41% Vel/IMID: 22%	Cardiac: 47% Renal: 59% Mayo 2012 stage • I: 44% • II: 22% • III: 19% IV: 15%	200: 26% <200: 74%	3%	Median: 66 months	Hematological: • ORR: 75% • CR: 25%	NR

ASCT: Autologous Stem Cell Transplantation

BP: blood pressure

CR: complete hematological response

Cr: serum creatinin

Db: direct bilirubin

DLCO: diffusing capacity of the lungs for carbon monoxide

ECOG: Eastern Cooperative Oncology Group Performance Status

ESRD: end stage renal disease

EF: ejection fraction

eGFR: estimated glomerular filtration rate

HD: hemodialysis

HF: heart failure

ICD: implanted cardiac defibrillator

IMID: Immunomodulatory drug

IRF: impaired renal function

IV: interventricular

Mel: melphalan

Mel200: melphalan at 200mg/m2

Mel≤140: melphalan at 140mg/m2 or 100mg/m2

NA: not available

NR: not reached

NRF: normal renal function

NTproBNP: N-terminal pro-brain natriuretic peptide

NYHA: New York Hearth Assoication

OS: overall survival

PEA: pulseless electrical activity

TnI: troponin I

TRM: transplant related mortality

UCSF: University of California San Francisco

Vel: Velcade/Bortezomib

VGPR: very bood partial response

An infrequent but additional indication that has arisen in the current era is the role of ASCT in patients who undergo early solid organ transplantation. Highly selected patients with advanced amyloid organ dysfunction who get cardiac, or renal, or liver transplantation may benefit from a subsequent ASCT either as the first hematologic-directed treatment or as consolidation to obtain an MRD-negative CR. The National Amyloidosis Center showed that cardiac transplant patients who underwent subsequent ASCT had significantly longer overall survival.⁵⁷

Current Transplant Eligibility Criteria in AL amyloidosis:

The improvement seen in early mortality following high dose chemotherapy and ASCT is directly linked to the development of strict eligibility criteria in combination with improved mobilization techniques, dose adjusted melphalan, and improved supportive care. The Mayo Clinic and Boston University groups have led the field and have published their general eligibility criteria as has the International Society of Amyloidosis (ISA) and several other European groups (Table 5). Criteria are generally consistent across these different groups highlighted by depth of cardiac involvement, minimal decline in renal function (although chronic hemodialysis (HD) is permitted), adequate cardiopulmonary reserves and lack of persistent pleural effusions, lack of severe autonomic dysfunction, lack of uncompensated arrhythmias, and adequate stem cell yields. When these selection criteria are followed, early mortality is on par with MM patients, deep remission can be achieved, and long-term survival is excellent.

Table 5:

Transplant Eligibility Criteria

	Age	Cardiac Imaging	NYHA Class	Cardiac Biomarkers	Renal Function	Pulmonary Function	Blood Pressure	Performance Status	Stem Cell Yield (CD34/Kg)	Other Exclusion Criteria
ISA 63	<70	LVEF ≥ 40%	I or II	• NTproBNP: < 5,000 pg/mL • Troponin I: <0.1 ng/mL • Troponin T: <60 ng/L • Hs-Troponin T: <75 ng/mL	eGFR: >30 mL/min/m2 **	O2 sat: 95% DLCO > 50%	Supine systolic blood pressure > 90 mm Hg	ECOG ≤ 2 unless limited by peripheral neuropathy	NR	• Direct bilirubin ≥ 2 mg/dL • Uncompensated heart failure • Orthostatic hypotension refractory to medical therapy • Symptomatic arrhythmias • Persistent pleural effusions • Extensive GI involvement • Active bleeding • Factor X level < 25%
Mayo Clinic 48	<70	LVEF ≥ 40%	I or II	• NTproBNP: < 5,000 pg/mL • Troponin I: <0.1 ng/mL • Troponin T: <0.06 ng/mL • Hs-Troponin T: <75 ng/mL	CrCl > 30 mL/ min (unless on chronic HD)	DLCO > 50%	Supine systolic blood pressure > 90 mm Hg	ECOG ≤ 2	≥1.98 X 106	none
Boston University 101	NR	LVEF ≥ 45%	NR	NR	Chronic HD not excluded	DLCO > 50% O2 sat: 95%	Supine systolic blood pressure > 90 mm Hg	ECOG ≤ 2	≥2.5 X 106	• ≥3 organs involved • ≥ grade 2 peripheral neuropathy • Uncompensated CHF • Symptomatic arrhythmias • Syncope • Persistent pleural effusions
Amyloidosis Center Pavia Italy 102	<70	LVEF ≥ 45%	I or II	• NT-proBNP <5000 ng/L • Troponin T <60 ng/L	eGFR > 50 or on HD	DLCO > 50%	Supine systolic blood pressure > 100 mm Hg	ECOG ≤ 2	NR	Direct bilirubin ≥ 2 mg/dL
Tufts University 103	<75	LVEF ≥ 45%	I or II	NTproBNP: <8500	eGFR > 30 or on HD	DLCO > 40%	Supine systolic blood pressure > 90 mm Hg	ECOG ≤ 2	NR	• ≥3 organs involved • Symptomatic arrhythmias • Persistent pleural effusions
National Amyloidosis Centre, London 73	<70	NR	NR	NT-proBNP <5000 ng/L, Troponin <60 ng/L	Cr < 150 mmol/L	NR	NR	NR	NR	≥3 organs involved
Amyloidosis Center Heidelberg 104	<70	NR	I or II	NR	CrCl > 30 mL/ min (unless on chronic HD)	NR	Supine systolic blood pressure > 90 mm Hg	ECOG ≤ 2	NR	• Factor X level < 10% • Symptomatic pleural effusions

ASCT: autologous stem cell transp antation

CHF: congestive heart failure

Cr: creatinin

CrCl: creatinine clearance

DLCO: diffusing capacity of the lungs for carbon monoxide

ECOG: Eastern Cooperative Oncology Group Performance Status

eGFR: estimated glomerular filtration rate

ESRD: end stage renal disease

GI: gastrointestinal

HD: hemodialysis

ISA: international society of amyloidosis

LVEF: left ventricular ejection fraction

NR: not reported

NTproBNP: N-terminal pro-brain natriuretic peptide

NYHA: New York Hearth Association

O2 sat: oxygen saturation on room air

^*consider ≥70 if discussed at a multidisciplinary setting and evaluated for ASCT at a center of excellence

^**Patients on chronic and a stable schedule of dialysis for ESRD are eligible if other criteria are met

With the improvement in non-transplant therapies, the use of straight ASCT without induction therapy has fallen off favor. The use of induction treatment helps start plasma cell-directed therapy without delays and also helps better selection of patients who may declare transplant eligibility or ineligibility after starting therapy.⁵⁸ The use of induction treatment has been associated with improved outcomes regardless of plasma cell burden.⁵⁹ Many centers only consider patients who are eligible for full dose melphalan at 200 mg/m2. While retrospective reports point to superiority of full dose melphalan as compared to non-transplant therapies ^{49, 60, 61}, no such evidence exists for dose-reduced melphalan at 140mg/m2 or less. Indeed, several reports point to the inferiority of dose-reduced melphalan for ASCT. ^{59, 62} If considering dose reduced melphalan in patients at high risk or morbidity and mortality, several centers and groups have reported criteria for dose reductions. The ISA ⁶³ recommends dose reductions if age 66–69 years, cardiac stage II or III, or eGFR 30–50 mL/min/m². The Boston University group ⁶⁴ recommends dose reductions if left ventricular ejection fraction is 40–45%, poor functional status (ECOG performance score >2) or as evaluated by the 6-minute walk test and/or stair climb test, or stem cell collection yield 2.0–2.5 × 10⁶ CD34+ cells. A less cited approach come from the Japanese group out of Sapporo Medical University.⁶⁵ They reported successful outcomes including a TRM of 0% using melphalan 200 mg/m2 in patients who had a performance status of zero or one, 2 or less organs involved, a creatinine of 1.5 mg/dL or less, an ejection fraction greater than 50%, and BNP of 200 pg/mL or less, while all other patients received 140 mg/m2. Finally, The mSMART criteria from the Mayo Clinic group ⁶⁶ recommend dose reductions if CrCl < 30 utilizing melphalan 140mg/m2. The Mayo Clinic scoring system to determine risk and appropriate melphalan dosing used criteria to determine the dose included number of organs involved (soft tissue involvement was not considered in counting organs for risk-adjusted dosing), EF, age, New York Heart Association class, alkaline phosphatase value, serum creatinine value. Patients received 1 point each if any of the following were present: > 2 organs involved; age > 65 years; alkaline phosphatase > 4 times the institutional upper limit of normal. Patients were assigned 2 points each if any of the following were present: EF < 50%; serum creatinine was >176 mmol/l; New York Heart Association class was III (patients in New York Heart Association class IV were not eligible for transplant). Based on these criteria, dosing of melphalan was as follows:

• Low risk: 0–2 points: 200mg/m²

• Intermediate risk: 3 points: 140mg/m²

• High risk: >3 points: 100mg/m².

Expected Outcomes in the “modern” bortezomib/daratumumab era

Outcomes for newly diagnosed AL patients have improved vastly over the past decade with the incorporation of proteasome inhibitors and more recently CD38 monoclonal antibodies as part of standard induction therapy. The ANDROMEDA study ⁸ which evaluated Dara-VCD led to the first Food and Drug Administration approval of an upfront therapy in newly diagnosed AL amyloidosis patients with stage I-IIIA disease. Even among patients with stage IIIB disease, the EMN22, a phase 2 open-label, multinational study showed early profound hematologic and cardiac responses with no new safety concerns.⁶⁷ The primary outcome was hematological response rate and the results showed deep remissions including a complete response rate of 53% on par with ASCT-based approaches. While these response rates are impressive, it is important to remember that early death remains a challenge in this disease even in transplant-eligible patients forgoing up front ASCT. Eligibility criteria on ANDROMEDA mirrored transplant eligibility with ECOG ≤ 2, eGFR > 20, NT-proBNP < 8500 ng/L (median on study was 1388.6 in the daratumumab arm), systolic blood pressure > 90, and NYHA class I or II. The early mortality in the daratumumab arm was 13.8% overall after a median follow up of 11.4 months, importantly early mortality within the first 60 days of treatment was 6.6% with no difference compared to the control arm.⁸ Similar to ASCT, there is concern that wider utilization in sicker patients (those with poor performance status, advanced cardiac or renal stage) as well as outside of experienced amyloidosis-focused physicians, the true early mortality of this regimen will be higher in the real-world setting. Further, although Dara-VCD induces deep responses, long term durability remains in question both in regard to hematological response but also MOD-PFS as published follow up is just shy of one year.

As we move forward, the optimal consolidation following 3- and, now 4-, drug induction regimens in transplant-eligible patients remains unclear. Table 6 outlines the expected outcomes in the modern era for both transplant and non-transplant consolidation approaches. Unlike in MM where a number of randomized clinical trials have set expectations in transplant-deferred patients, defining with granularity expectations in transplant eligible patients who defer transplant in AL is challenging but the Europeans have led the way with the recent Alchemy report and the EMN23 study while most recently the pivotal ANDROMEDA study has set the benchmark moving forward. There is increasing appreciation that achieving a VGPR and even a CR may be inadequate for optimal long term PFS, OS, and critically deep organ responses, calling into question the primary outcome of ANDROMEDA but also approaches to stopping therapy in newly diagnosed AL amyloidosis patients. Bone marrow minimal residual disease negativity by next generation flow cytometry (NGF) may be the optimal response in AL amyloidosis patients even amongst those in CR based on the Pavia University study evaluating 92 AL patients who achieved CR which showed that amongst those who were MRD negative by NGF, higher rates of renal (90% vs 62%, p = 0.006) response, cardiac response (95% vs 75%, p = 0.023), and improved hematological PFS (p=0.001) were seen. ⁶ The Boston University group assessed retrospectively 65 patients in hematological CR showing improving renal responses at 88% vs 64% (P=0.06) in MRD negative vs positive patients. ⁶⁸ The National and Kapodistrian University of Athens group found similar results in 51 patients where after a median follow-up of 24 months post MRD testing, no MRD negative vs 6/28(21%) MRD positive patients relapsed (p=0.029) while when pooling hematologic and organ progressions together, 9 MRD positive patients had disease progression vs 1 MRD negative patient (p=0.026). ⁶⁹ Other techniques including next generation sequencing ⁷⁰ and free light chain mass spectrometry ⁷¹ have also shown discrimination of outcomes based on detection of measurable residual disease by these sensitive techniques.

Table 6:

Expected outcomes in the modern era for induction and consolidation therapy in newly diagnosed systemic light chain amyloidosis

	Number of Patients and Treatment Site	Treatment Prior to Transplant/Induction Treatment	Organs involved	Melphalan Dose mg/m2	Transplant Related Mortality including predictors	Hematological Progression Free Survival and Overall Survival	Hematological and Organ Response Rates	Predictors of Progression Free and Overall Survival:
Induction followed by high dose chemotherapy and ASCT
Cornell et al; TCT 2021 59	CIBMTR Repot; 294 patients who received bortezomib based induction	VCD: 242 VRD: 29 VR: 29 VD: 22 VTD: 1	Cardiac: 52% Renal: 70% Liver: 13% ≥3 organs: 24%	200: 42% 180: 14% 140: 30% 100: 14%	Day 100: 2%	2-year: 92%	ORR: 57% CR: 20%	PFS: bortezomib based induction; Cr > 2 mg/dL; KPS <90;_ Mel 200 mg/m2 v < 200 mg/m2 OS: Mel 200mg/m2 v < 200mg/m2
Fuchida et al; TCT 2022 105	Transplant Registry Japan; 110 patients of which 61 underwent induction therapy	Melphalan: 6 Bor: 33 IMID: 4 Other: 25	Cardiac: 57% Renal: 73.6% Liver: 15.5% ≥3 organs: 43.7%	200: 54.6% <200: 40.9	Day 100: 6% Predicators: ECOG 0–1 v 2–4; cardiac involvement, pre-transplant chemotherapy with treated patients having a TRM of 0%	Median NR 5-year: 70.1%	ORR: 77.6% CR: 49.3% Cardiac: 56.5% Renal: 56.4%	OS: ECOG 0–1 v 2–4, cardiac involvement, Mel 200mg/m2 v < 200mg/m2
Huang et al; BMC Medicine 2014 106	Single center Jinling Hospital China; 28 patients	VD X 2 cycles	Cardiac: 60.7% Renal: 100% Liver: 3.6% ≥1 organs: 60.7%	200: 50% 140: 50%	Day 100: 0%	2-year: 95%	ORR: 78.6% CR: 53.6% Cardiac: 70% Renal: 75%	OS: troponin-I > 0.03 ng/mL
Vaxman et al; BMT 2021 62	Single center Mayo Clinic Rochester; 128 patients	PI based: 93 IMID based: 15 PI+IMID: 9 Melphalan based: 7 Other: 3	Cardiac: 53% Renal: 49% ≥2 organs: 20%	200: 70% 140: 27% BEAM: 3%	Day 100: 3%	Median PFS: 48.5 months Median OS: NR (128-NR)	≥VGPR: 73.2% Overall organ response: 82%	PFS: depth of response prior to ASCT > VGPR v < VGPR OS: melphalan dose and depth of response prior to transplant > VGPR v < VGPR
Afrough et al; BBMT 2018 107	Single center MD Anderson Cancer Center; 108 patients	IMID/PI based: 83 CC based: 20	Cardiac: 28.9% Renal: 62.5% ≥2 organs: 28.2%	200: 18.5% <200: 81.5%	Day 100: 1%	2-year PFS: •CC group: 56% •IMID/PI group: 73% 2-year OS: •CC group: 76% •IMID/PI group: 87%	ORR: 81.3% CR: 20.5% Overall organ response : 49.5%	OS: low β2 microglobulin < 3.5 at diagnosis and induction therapy with IMID/PI
Minnema et al; Haem 2019 93	Prospective multicenter phase II in 15 centers in the Netherlands, Germany, and Belgium; 50 patients	VD x 4 cycles	Cardiac: 66% Renal: 66% Liver: 26% ≥2 organs: 72% ≥3 organs: 38%	200: 88.6% 100: 11.4%	Day 100: 0%	3-year PFS: 63% 3-year OS: 86%	ORR: 86% CR: 46% Cardiac: 78% Renal: 69%	No factors associated with OS*
Gupta et al; BBMT 2019 108	Single center Boston University; 35 patients	VD X 2 cycles	Cardiac: 54% Renal: 89% Liver/GI: 11%	200: 67% 140: 33%	Day 100: 8.5%	Median PFS: NR 5-year PFS: 62.9% Median OS: NR 5-year OS: 68.6%	≥VGPR: 100% CR: 76.9% Cardiac: 87% Renal: 56%	None reported
Kim et al; CLML 2022 109	Single center Korea Samsung Medical Center; 100 patients	PI based: 38% IMID based: 21% No induction: 23%	Cardiac: 50% Renal: 62% Liver: 10% ≥3 organs: 38%	200: 83% 140–150: 13%	Day 100: 3%	Median OS: NR 5-year OS: 61.1%	ORR: 79% CR: 48% VGPR: 20% Cardiac: 44% Renal: 37.1%	OS: achieving hematological CR
Induction therapy without high dose chemotherapy and ASCT consolidation
Manwani et al; Blood 2019 73	Multi center UK trial with referral to the UK National Amyloidosis Center; 915 patients	PI based: 100% VCD: 94.9% VD: 2.9%	Cardiac: 71.4% Renal: 68.1% Liver: 13.5% Median: 2(1–5)	Not applicable	Not applicable	Median TNT: NR** Median OS: NR	Not reported	OS: European modification of Mayo 2004 Stage [77] achieving a stringent dFLC response (<10 mg/L)
Palladini et al; BCJ 2023*** 110	EMN23 study: European multiinstitution retrospective study; 3065 patients	Bor based: 74.7% IMID based: 1.9% CC based: 8.7%	Cardiac: 69.7% Renal: 66% Liver: 13.3% ≥3 organs: 23%	Not applicable	Early mortality within 3 months of therapy initiation: 14.4%	Median OS: 46.7 months	ORR: 67.1% CR: 25% VGPR: 12	OS: hematological response of CR v VGPR v PR at both 3 and 6 months after treatment initiation; Mayo 2012 stage
Kastritis et al; NEJM 2021# 8	ANDROMEDA trial: Multi-institution US and Europe; 195 patients	Dara-VCD	Cardiac: 71.8% Renal: 59% Liver: 7.7%	Not applicable	Early mortality within 60 days of treatment initiation: 6.6%	Hematological progression occurred in 4.1% of patients and 25 patients (12.8%) have died after a median follow up of 11.4 months	ORR: 91.8 CR: 53.3% VGPR: 25.1 Cardiac: 41.5% Renal: 53%	None reported
Basset et al; Bld Adv 2020## 111	Single center Italy; 63	VCD	Overall Cohort: • Cardiac: 47% • Renal: 75% • Liver: 11% • > 2 organs: 12%	Not applicable	Not applicable	5-year OS: 84%	Not reported for the transplant deferred group	None reported

^*Cox regression prognostic baseline characteristics including type of hospital (high vs. low number of included patients), eGFR (>30 and <50 vs. ≥50 mL/min/1.73 m2, NYHA class (I vs. II), NT-proBNP (as a continuous variable), plasma cell infiltration (<10% vs. ≥10%), dFLC <180 mg/L vs. ≥180 mg/L, number of organs involved (≤2 vs. >2), Mayo stage, nervous system involvement and cardiac involvement were tested but none of these variables was statistically related to OS

^**: Time to next treatment and median overall survival reported here reflects a subset of patients on this registry trial that were considered eligible for transplant per UK criteria (age < 70 years, NT-proBNP < 5000 ng/L, cardiac troponin T < 60 ng/L, serum creatinine < 150 mmol/L, and organ involvement < 3)

^***Full report evaluated patients from 2004 to 2018 but only a subset reported her representing the modern cohort of post 2010 patients

^#: Patients on the daratumumab arm of reported here

^##: Starting in 2009 patients who were transplant eligible (age < 65 years, N-terminal pronatriuretic-peptide type B <5000 ng/L, glomerular filtration rate >50 mL/min, New York Heart Association class <3, Eastern Cooperative Oncology Group Performance Status ≤2, and ejection fraction > 45%) were offered upfront therapy with VCD with ASCT deferred if patients achieved a partial response or better. 63 patients deferred ASCT and are represented her unless otherwise specified.

ASCT: Autologous Stem Cell Transplantation

Bor: bortezomib Chemo: chemotherapy

CIBMTR: Center for International Blood & Marrow Transplant Research

CC: conventional chemotherapy

CR: complete hematological response

Cr: serum creatinin

Dara-VCD: daratumumab, bortezomib, cyclophosphamide, dexamethasone

dFLC: difference in involved amyloidogenic and uninvolved serum-free light chains

ECOG: Eastern Cooperative Oncology Group Performance Status

GI: gastrointestinal

IMID: Immunomodulatory drug

KPS: Karnofsky Performance Scale

Mel: melphalan

Mel200: melphalan at 200mg/m2

Mel≤140: melphalan at 140mg/m2 or 100mg/m2

NA: not available

NR: not reached

ORR: overall hematological response rate

OS: overall survival

PFS: hematological progression free survival

PI: proteasome inhibitor

PR: partial response

TnI: troponin I

TNT: time to next treatment

TRM: transplant related mortality

UK: United Kingdom

US: United States

VCD: bortezomib, cyclophosphamide, and dexamethasone

VD: bortezomib and dexamethasone

VGPR: very good partial response

VR: bortezomib, lenalidomide

VRD: bortezomib, lenalidomide, dexamethasone

VTD: bortezomib, thalidomide, dexamethasone

Optimal treatment needs consideration of important outcomes and efficacy endpoints for AL amyloidosis

Survival endpoints serve as crucial anchors for evaluating treatment efficacy. Specifically, overall survival, reflecting the time from start of treatment until death from any cause provides a clear and definitive measure of a treatment’s impact on patient longevity. However, it can be influenced by various other factors, including other comorbidities, ongoing aging, subsequent therapies after initial therapy, thus potentially leading to confounding. Progression-free survival, another key endpoint, measures the duration from start of treatment until disease progression or death, and can be useful to assess how effectively a treatment can control disease activity and delay progression. In AL amyloidosis, hematologic PFS is more straightforward to measure, however, progression in AL amyloidosis is a more challenging concept due to multi-organ involvement as patients can have worsening in organ function despite having hematologic response. Thus, a clear definition of what constitutes progression has remained elusive. Other endpoints such as event-free survival or time to next treatment, i.e., the time to the next treatment or death, are endpoints which may be more relevant in AL amyloidosis have been proposed by researchers and studied in large retrospective ⁷²as well as prospective observational cohorts. ⁷³

Major organ dysfunction PFS (MOD-PFS) is an emerging endpoint tailored for AL amyloidosis which adds to PFS, additionally, time until significant dysfunction occurs in critical organs affected by the disease such as the heart or kidneys. While MOD-PFS is a relevant endpoint given the profound impact of organ dysfunction on prognosis from AL amyloidosis, there are no clear standardized or validated definitions and thresholds for what constitutes ‘major dysfunction’ across different organs. Nevertheless, MOD-PFS was used as a key secondary endpoint in the ANDROMEDA trial which resulted in the first FDA approval in the treatment of AL amyloidosis. [8]

Surrogate endpoints are often used in practice as a pragmatic substitute for a survival endpoint for evaluating treatment efficacy. Commonly used biomarker-based endpoints include hematologic response using dFLC reduction and organ response as measured by NT-proBNP (cardiac), 24-hour urine protein (renal), and alkaline phosphatase (hepatic) responses. The amyloidosis community has long advocated for NT-proBNP as a surrogate end point in pivotal clinical trials in AL amyloidosis, ^{74, 75} with cardiac involvement based on disease pathophysiology with toxic free light chains stimulating cardiomyocyte production of NT-proBNP. Multiple clinical trials have demonstrated that NT-proBNP or BNP response predicts clinical outcome ⁷⁴ including response and overall survival. However, NT-proBNP can be nonspecific and be affected by a multitude of non-cardiac issues including but not limited to renal function, anemia, atrial fibrillation, obesity, activation of the sympathetic and renin-angiotensin-aldosterone system, medications (e.g., steroids). This is important to consider particularly in a multisystemic disease such as AL amyloidosis, where renal and cardiac combined involvement is common. ⁷⁵ Further work to detect meaningful changes, slope of change, or AUC curves is recommended by experts and warrants additional work.

Functional outcomes are an equally important endpoint in AL. The six-minute walk test (6MWT) is a standardized functional measure that has been validated as a surrogate endpoint and qualified as a Clinical Outcome Measure by regulatory agencies in various cardiopulmonary diseases, neuromuscular diseases, and orthopedic procedures.^{76, 77} In an expert convened review of the 6MWT as a prioritized cardiac endpoint in AL amyloidosis, ⁷⁵ the 6MWT was determined to be strongly prognostic and a 33-meter improvement was independent of hematologic response in predicting survival and improvement in at 12 months was observed in patients who achieved complete hematologic response. ⁷⁸ However, there was decline in 6MWT distance in patients receiving chemotherapy by 6 months followed by an increase by 12 months, potentially due to treatment toxicities. Other limitations to performing the 6MWT include confounding comorbidities such as neuromuscular impairment, orthostatic hypotension that may be associated with AL amyloidosis as well as bias in conducting the test. Further work is thus needed before the 6MWT can be used as a surrogate functional outcome endpoint in AL amyloidosis.

Quality of life/patient-reported outcomes can also serve as important outcomes to assess response to therapy. AL amyloidosis negatively impacts multiple domains including physical functioning, mental health, sleep, ability to participate in social roles and activities, among others.^{79, 80} In addition to the disease itself, aging, comorbidities, and toxicities of ongoing therapies can also impair quality of life. Among various PRO measures available to evaluate health-related quality of life in AL amyloidosis, the SF-36v2 and PROMIS instruments including the PROMIS-29 have been most tested in terms of psychometric properties demonstrating adequate validity and reliability among patients with AL amyloidosis. ⁸¹ The AL-PROfile, a PRO measure developed using PROMIS-29+2 and select items from the PRO-CTCAE, is a newly designed tool which has met initial validation for use in the context of AL amyloidosis.⁸² Multiple studies have shown the prognostic value as well as predictive value of PROs with hematologic and organ response in AL amyloidosis. ⁸¹ Further work is needed to understand longitudinal trajectories of change in PROs in AL amyloidosis as well as the minimal clinically important differences in scores with change in disease status.

Multiple imaging modalities have also been considered as potential endpoints, including global longitudinal strain on echocardiogram and cardiac magnetic resonance imaging for AL cardiomyopathy ⁷⁵ and hepatic dimensions and fiber elastography for hepatic AL.⁸³ Composite and multi-component endpoints represent a promising approach to enable earlier detection of effect of benefit by combining signals across different domains. The CHOR is one such composite organ and hematologic response model for early assessment of treatment outcomes in AL amyloidosis,⁸⁴ but additional stakeholder work is needed to identify other appropriate endpoints using novel analytical methodologies for developing and validating multi-domain endpoints in AL amyloidosis. Other important outcomes to consider in AL amyloidosis but need additional supporting literature include financial toxicity ⁸⁵ and health care resource utilization. ⁸⁶ Thus far, the ASCT literature has provided little understanding of how functional outcomes, PROs, imaging outcomes, and other surrogate outcomes may change in the peri- and post-transplant setting and more work is needed to collect these data and report longitudinal trajectories.

Conclusions and Future Considerations:

We have entered an unprecedented time in the treatment of AL amyloidosis. With the routine incorporation of CD38 directed therapy into induction regimens, transplant eligible patients are achieving deep remission with non-transplant approaches and even transplant-ineligible patients can achieve CR rates of over 50%. ⁸⁷ Thus, the optimal approach to therapy following Dara-VCD induction in transplant-eligible patients is as muddy as ever. Achieving a VGPR, traditionally thought to be an adequate depth of response to induction therapy, is no longer an adequate goal. It is increasingly evident that suppressing the iFLC deeper with lower dFLC (difference between the involved and uninvolved free light chain) leads to improved long-term outcomes including MOD-PFS.^{88, 89} Even patients in hematological CR do not always achieve organ responses and recent data point to the benefit of MRD-negativity in both the peripheral blood ⁹⁰ and bone marrow leading to improved organ response, hematological PFS, and potentially OS. ^{91, 92} Consolidation with either Dara-VCD and maintenance daratumumab or high dose chemotherapy and ASCT following deep responses with CD38 monoclonal antibody-based induction are both reasonable choices. However, it is unknown which will generate a deeper response translating to improved MOD-PFS and long-term outcomes particularly given the current short term follow up after CD38 monoclonal antibody-based approaches.

Defining the optimal consolidation in a randomized trial will be challenging as evidenced by the high TRM on the IFM randomized trial ²⁶ and high drop out on the HOVON 104 trial. ⁹³ But both distant (E4A97; S0115) and recent (S1702) cooperative group efforts as well as the ANDROMEDA trial which enrolled well ahead of schedule are promising indicators that there is interest and commitment in the AL amyloidosis community to answer these challenging questions. The recently opened S2213 (NCT06022939) will attempt to answer the optimal consolidation approach in newly diagnosed transplant-eligible AL amyloidosis patients. Eligible patients will receive 3 cycles of Dara-VCD induction followed by randomization to either 3 additional cycles or high dose chemotherapy and ASCT with patients on both arms then receiving 18 months of daratumumab maintenance. The primary endpoint is MOD-PFS. In addition, key secondary endpoints will be evaluated including MRD negativity rates in peripheral blood by mass spectrometry and bone marrow via NGF as well as health-related quality of life metrics. Both approaches are likely to yield excellent outcomes in terms of hematological PFS. However, as alluded to above, there are a multitude of critical end points in AL amyloidosis from organ response to health-related quality of life and others that are important to both patients and physicians that this trial will help define.

Other pertinent questions beyond the scope of this trial but relevant during induction therapy include the role of venetoclax in patients with t(11;14) either upfront or early use in patients with suboptimal FLC response to Dara-VCD, utility of daratumumab beyond the 18 months of maintenance with Dara-VCD, and the potential promise of amyloid-dissolving antibodies, including anselamimab and birtamimab, pending the completion of phase 3 clinical trials that could further change the early therapy landscape of systemic AL amyloidosis.

Practice points:

• The initial high morbidity and mortality seen with consolidative high dose melphalan and autologous stem cell transplantation in newly diagnosed systemic light chain amyloidosis was driven primary by poor patient selection and center inexperience

• Clearly defined and validated transplant eligibility criteria are available that center around the extent of cardiac involvement and when followed yield transplant related mortality on par with multiple myeloma

• In transplant eligible patients, bortezomib based induction, pre-transplant response, and utilization of full dose melphalan at 200mg/m2 are the most important factors impacting both progression free and overall survival

• The recent incorporation of daratumumb into induction therapy has led to unprecedented depth of response and is the current preferred induction approach in both transplant eligible and ineligible patients

• The optimal consolidation approach in transplant eligible patients followed daratumumab based induction remains uncertain

Research agenda

• A randomized trial evaluating optimal consolidation in newly diagnosed AL amyloidosis patients

• Rationally designed clinical trials evaluating optimal end points to guide treatment discontinuation in responding patients

• Further work to define meaningful changes in cardiac response criteria

• Further work to improve early mortality in transplant eligible and ineligible patients

Acronyms:

6MWT

6-minute walk test

AL

immunoglobulin light chain amyloidosis

ASCT

autologous stem cell transplantation

CR

complete hematological response

CrCl

creatinin clearance

Dara

daratumumab

Dara-VCD

daratumumab, cyclophosphamide, bortezomib, and dexamethasone

DLCO

diffusing capacity of the lungs for carbon monoxide

EBMT

European Society for Blood and Marrow Transplantation

EF

ejection fraction

eGFR

estimated glomerular filtration rate

ESRD

end stage renal disease

FLC

free light chain

HD

hemodialysis

iFLC

involved free light chain

IFM

Intergroupe francophone du myélome

IMID

immunomodulatory drug

ISA

international society of amyloidosis

LVEF

left ventricular ejection fraction

MM

multiple myeloma

MOD-PFS

modified progression free survival

MRD

minimal residual disease

OS

overall survival

PFS

progression free survival

SWOG

Southwest Cancer Chemotherapy Study Group

UK

United Kingdom