Outcomes from Autologous Hematopoietic Cell Transplantation versus Chemotherapy Alone for the Management of Light Chain Amyloidosis

Accepted Manuscript Title: Outcomes From Autologous Hematopoietic Cell Transplantation Versus Chemotherapy Alone for the Management of Light Chain (AL) Amyloidosis Author: Oluchi Oke, Tarsheen Sethi, Stacey Goodman, Sharon Phillips, Ilka Decker, Samuel Rubinstein, Beatrice Concepcion, Sarah Horst, Madan Jagasia, Adetola Kassim, Shelton L Harrell, Anthony Langone, Daniel Lenihan, Kyle T. Rawling, David Slosky, R. Frank Cornell PII: DOI: Reference:

S1083-8791(17)30467-6 http://dx.doi.org/doi: 10.1016/j.bbmt.2017.05.020 YBBMT 54681

To appear in:

Biology of Blood and Marrow Transplantation

Received date: Accepted date:

9-3-2017 17-5-2017

Please cite this article as: Oluchi Oke, Tarsheen Sethi, Stacey Goodman, Sharon Phillips, Ilka Decker, Samuel Rubinstein, Beatrice Concepcion, Sarah Horst, Madan Jagasia, Adetola Kassim, Shelton L Harrell, Anthony Langone, Daniel Lenihan, Kyle T. Rawling, David Slosky, R. Frank Cornell, Outcomes From Autologous Hematopoietic Cell Transplantation Versus Chemotherapy Alone for the Management of Light Chain (AL) Amyloidosis, Biology of Blood and Marrow Transplantation (2017), http://dx.doi.org/doi: 10.1016/j.bbmt.2017.05.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Outcomes from Autologous Hematopoietic Cell Transplantation versus Chemotherapy Alone for the Management of Light Chain (AL) Amyloidosis

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Light chain amyloidosis (AL) results in tissue deposition of misfolded proteins causing

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organ dysfunction. In an era of modern therapies such as bortezomib, reassessment of the

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benefit of autologous hematopoietic cell transplantation (AHCT) should be considered.

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This study compares the difference in outcomes between patients with AL receiving

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chemotherapy alone (CT) vs. AHCT. Seventy-four patients with AL were retrospectively

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analyzed. Two cohorts of patients were studied, those receiving CT (n=31) or AHCT

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(n=43). Of those receiving AHCT, 29 received induction chemotherapy prior to AHCT

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while 14 patients proceeded straight to AHCT without induction therapy. Patients in the

Oluchi Oke MD1, Tarsheen Sethi MD2, Stacey Goodman MD2, Sharon Phillips MSPH3, Ilka Decker MD1, Samuel Rubinstein MD1, Beatrice Concepcion MD5, Sarah Horst MD6, Madan Jagasia MD2, Adetola Kassim MD2, Shelton L Harrell NP2, Anthony Langone MD5, Daniel Lenihan MD4, Kyle T. Rawling2, David Slosky MD4, and R. Frank Cornell MD, MS2. Department of Medicine1, Division of Hematology/Oncology2, Division of Biostatistics and Quantitative Sciences3, Division of Cardiology4, Division of Nephrology5, Division of Gastroenterology6, Vanderbilt University Medical Center, Nashville, Tennessee Corresponding Author: Robert Frank Cornell, MD, MS 777 Preston Research Building Division of Hematology and Oncology Vanderbilt University Medical Center Nashville, TN 37232 [email protected] Manuscript Type: Original Article

Short Title: Transplantation vs Chemotherapy for AL Keywords: Light chain amyloidosis; organ response, chemotherapy; bortezomib; transplantation Abstract:

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AHCT cohort were younger, had higher ejection fractions, lower brain natriuretic peptide

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levels and higher proteinuria compared with the CT cohort. Among patients receiving

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chemotherapy, the majority (87%) received bortezomib-based treatment. Transplant

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related mortality (TRM) was 7%. Patients receiving AHCT were more likely to achieve

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complete or very good partial response (p=0.048). The median progression free survival

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(PFS) and overall survival (OS) were superior in the AHCT cohort compared with CT

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(not reached vs. 9 months (mo), p<0.01 and 74 mo vs. 8 mo, p=0.03, respectively).

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Multivariable analysis demonstrated that improved PFS [HR 3.86 95% CI 1.3-11.5,

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p=0.02] and OS [HR 5.6, 95% CI 1.9-16, p<0.001] were associated with use of AHCT

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compared with chemotherapy alone. Patients who received AHCT had deeper and longer

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response durations, with superior PFS and OS, compared to those who received CT

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alone. Despite the limitations of this study, AHCT should be considered for eligible

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patients with AL at experienced transplant centers that can offer this therapy with low

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risk of TRM.

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Introduction: Light-chain (AL) amyloidosis is a monoclonal plasma cell disorder that can result

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in multi-organ dysfunction from amyloid fibril deposition.(1) Amyloid fibrils are

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misfolded immunoglobulin light chains produced from plasma cell clones.(2) Common

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sites of involvement include the heart, kidney, gastrointestinal tract, and peripheral and

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autonomic nervous systems.(3)

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Management of AL amyloidosis involves optimal medical management of end-

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organ damage while instituting therapy to target the plasma cells producing amyloid

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fibrils.(4) Standard chemotherapeutic treatment strategies include use of chemotherapy

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alone, induction chemotherapy followed by autologous hematopoietic cell transplantation

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(AHCT) or upfront AHCT without induction. Historically, chemotherapy was with

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melphalan-based regimens, however more recently bortezomib-based therapies have been

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utilized.(1, 2, 5, 6)

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Routine use of AHCT was previously limited by high transplant related mortality

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(TRM). In recent years, TRM has decreased to 3-5% as a result of better patient selection

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and improved supportive care measures.(3, 6) While both AHCT and chemotherapy

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alone have independently demonstrated improvement of end-organ damage and

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hematologic response (HR), it remains unclear if one treatment strategy is superior.(2, 7-

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9) Our primary objective was to determine survival outcomes in patients with AL

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amyloidosis receiving AHCT as part of management compared to patients receiving

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chemotherapy alone (CT) without use of AHCT.

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Methods:

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Patients

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We report a retrospective analysis of 74 consecutive patients that received care

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from the Vanderbilt Amyloid Multidisciplinary Program from 2003-2015. AL subtype

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was confirmed by immunohistochemistry or laser microdissection-tandem mass

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spectrometry in all cases. Assessment of hematological responses, organ involvement,

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organ response and progression were based on consensus criteria.(7, 10) Patients

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receiving fewer than 2 cycles of chemotherapy were excluded. This parameter was

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selected to minimize the impact of advanced amyloid intolerant to chemotherapy and

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subjects who succumb to early cardiac death. Patients with concurrent multiple myeloma

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defined by myeloma attributed end organ damage such as hypercalcemia or bone lytic

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lesions were excluded. In order to mitigate age bias between the 2 cohorts, only patients

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up to age 72 (the upper age for AHCT in this study) were permitted on the CT cohort.

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Hematologic and organ responses were assessed every 3-4 months after treatment

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initiation. This study was approved by the Vanderbilt University Medical Center

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Institutional Review Board.

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Treatments Two cohorts of patients were studied: those receiving systemic chemotherapy

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alone CT (n=31) and those who underwent AHCT (n=43). In our program, AL patients

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were considered transplant ineligible if their Karnofsky performance status (KPS) was <

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70%, 3 or more organs were significantly affected, displayed advanced cardiac

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involvement in accordance with published guidelines (i.e. New York Heart Association

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(NYHA) functional class ≥ III), creatinine clearance ≤ 30 ml/min, significant effusions or

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hypotension (systolic blood pressure <90 mmHg)).(10, 11) Patients were permitted to

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proceed directly to AHCT without induction chemotherapy if the bone marrow clonal

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plasma cell burden was <10% and had no evidence of significant AL amyloid cardiac

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involvement (determined by cardio-oncology evaluation, brain natriuretic peptide (BNP),

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troponin I, electrocardiogram, transthoracic echocardiogram and cardiac MRI or

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endomyocardial biopsy in select cases).

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Cardiac Stage, Hematological and Organ Response and Progression A complete hematological response (CR) was defined as negative serum and

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urine immunofixation, as well as normal free light chain (LC) levels and ratio. A very

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good partial response (VGPR) was defined as a decrease in difference between involved

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and uninvolved free light chain level to less than 40 mg/L. A partial response (PR)

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required a greater than 50% reduction in the difference between involved and uninvolved

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free chain levels. Progression (PD) was defined as going from CR to any detectable M

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protein or abnormal LC ratio, a progression from PR with either a 50% increase in serum

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M protein to >0.5 g/dL or 50% increase in urine M protein to >200 mg/day, or a free light

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chain increase of 50% to >100 mg/L.(10)

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Modified cardiac biomarker staging was defined by elevated BNP (>100 pg/ml)

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and troponin I (>0.1 ng/ml). Stage I was defined as no elevation, stage II was defined by

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elevation in either BNP or troponin I, and stage III was defined by elevation in both

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markers.(12) To determine cardiac response, NT-proBNP was converted to BNP by 3.5:1

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conversion. Cardiac response was defined as a decrease of > 30% and 85 pg/ml in BNP

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(with minimum baseline 185 pg/ml) or a decrease ≥ 2 in NYHA class in subjects

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designated as NYHA class 3 or 4 at baseline. Cardiac progression was defined as either a

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> 30% and 85 pg/ml increase in BNP, ≥ 33% increase in troponin I, or ≥ 10% decrease in

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ejection fraction.(13, 14)

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Renal response was defined as a 50% decrease (at least 0.5 g/day) of 24-h urine

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protein in patients that displayed >0.5 g/day urine protein at baseline. Creatinine and

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creatinine clearance could not worsen by 25% over baseline. Renal progression was

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defined as a 50% increase (at least 1 g/day) of 24-h urine protein to >1 g/day or as a

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25% worsening of serum creatinine or creatinine clearance.(10)

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Outcome Measures

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The primary outcome was overall survival (OS). OS was defined as the time from

135

diagnosis until death from any cause or was censored at the date of the last follow-up for

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surviving patients. Secondary outcomes included organ responses and progression free

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survival (PFS). All time-to-event end points were measured from the beginning of

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treatment. Progression events were defined as death, disease progression or relapse,

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worsening organ function requiring a change in treatment, or initiation of a second line

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chemotherapy. In cases where patients proceeded to AHCT, this change in treatment was

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not censored since this was a planned event. Transplant related mortality (TRM)

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was defined as mortality due to any cause other than disease progression within 100 days

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of transplantation.

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Statistical Analysis

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Patient characteristics were summarized using descriptive statistics. Categorical

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variables were compared using Chi-square test. Continuous variables were compared

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using Wilcoxon rank sum test. Probabilities of PFS and OS were calculated using

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Kaplan-Meier estimator. Log-rank test was performed to calculate the 95% confidence

150

intervals for survival probabilities. Cox-proportional hazard model was used to evaluate

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the effect of prognostic factors on survival outcomes and disease progression. The

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primary objective of this study was to compare survival outcomes in patients receiving

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AHCT to those receiving CT alone. Other variables considered included age (<60 vs

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≥60), 24-hour urine proteinuria (<3.5g/24 hours vs. ≥3.5g/24 hours) and modified cardiac

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stage (stage III vs. stage I or II). A backward elimination model selection procedure was

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employed to identify statistically significant covariates to be added into the model. All

157

variables met the proportional hazards assumption. Cumulative incidence of relapse was

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calculated from the time of treatment initiation to the date of the first disease progression

159

or relapse. A statistical significance (alpha) level of 0.05 was used throughout. Analyses

160

were performed using statistical package R (version 2.3.1).

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Results:

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Patients

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Patient characteristics are summarized in Table 1. The median age of patients was

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61 years. Patients in the AHCT cohort were younger compared with the CT cohort.

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Although the median BNP was higher and the median EF was lower in the CT cohort,

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there was no statistically significant difference in modified cardiac stage or NYHA class

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between the two cohorts. Median 24 hour urine protein was higher in the AHCT group.

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Renal involvement was more common in the AHCT group (n=35; 88%) compared to the

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CT group (n=16; 59%).

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Outcomes of the CT group An overview of the treatments received by patients in the two cohorts is shown in

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Supplemental Figure 1. Of the 31 patients who received chemotherapy alone, the

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majority received bortezomib-based treatment (n=30, 97%). One (3%) received

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melphalan based therapy. The median number of treatment cycles was 4. Nine patients

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received maintenance chemotherapy with bortezomib (n=5) or lenalidomide (n=4).

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Seventeen patients (55%) achieved a hematologic response (HR) including 5 (17%) with

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CR, 6 (20%) with VGPR and 6 with (20%) PR (Table 2). Fourteen patients (45%) had at

180

least one organ response (Table 2). Of the 24 patients with cardiac involvement, 10

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(42%) achieved a cardiac response, while 4 of the 16 (25%) patients with renal

182

involvement achieved a renal response. Two of the 14 (14%) patients with both cardiac

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and renal involvement had a response to both. The median duration of response was 7

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months. The median PFS was 9 months while the median OS was 8 months. Seventeen

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patients (55%) in the CT cohort died (Table 3). The cause of death was mainly due to

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progressive disease (n=12; 71%). Two patients (12%) died due to cardiac arrest while the

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remaining 3 deaths were due to respiratory failure, stroke, or infection.

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Outcomes of the AHCT group Of the 43 patients who received AHCT, 14 patients (33%) received no induction therapy and proceeded straight to transplant (Supplemental Figure 1). Among the patients

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receiving induction therapy prior to AHCT, the majority received bortezomib-based

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treatment (n=24, 83%). Three received melphalan-based therapy while 2 received other

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forms of immunotherapy. The median number of cycles of chemotherapy administered

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prior to AHCT was 5. Six patients received maintenance chemotherapy in the AHCT

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cohort (4 bortezomib, 2 lenalidomide). Thirty-one patients (72%) achieved HR including

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12 (28%) with CR, 13 (30%) with VGPR and 6 with (14%) PR. Twenty-eight patients

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(65%) had at least one organ response. Ten of the 22 patients (45%) with cardiac

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involvement achieved a cardiac response. Eighteen of the 35 patients (51%) with renal

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involvement achieved a renal response. Nineteen patients had both cardiac and renal

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involvement. Of these 19 patients, 5 (26%) experienced both a cardiac and renal

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response. The median duration of response was 31 months. The median PFS was not

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reached, while the median OS was 74 months. Eight patients (19%) in the AHCT group

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died (Table 3). Four patients died of progressive disease; 1 had a cardiac arrest and 3

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patients died from TRM. The TRM rate in the AHCT cohort was 7%. There was no

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difference in TRM between patients proceeding straight to AHCT and those who

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received induction therapy prior to AHCT.

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Comparison of the CT versus AHCT group Median OS was superior in the AHCT cohort compared with the CT cohort (74

211

vs. 8 months, p=0.03; Figure 2). Death was more common in the CT cohort (n=17)

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compared to the AHCT cohort (n=8) and largely attributed to progressive disease.

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Multivariable analysis revealed that improved OS was associated with receiving AHCT

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compared with CT (HR 5.69, 95% CI 1.71-18.98, p<0.01). Modified cardiac stage was

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not predictive of OS. The median time between diagnosis and AHCT was 3 months,

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while the median time from diagnosis to first cycle of chemotherapy was 1 month.

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Patients receiving AHCT were more likely to experience a CR or VGPR

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hematological response compared with patients receiving CT (58% for AHCT vs. 35%

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for CT, p=0.048) (Table 2). There were no differences in overall HR rates (≥ PR)

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between cohorts (72% for AHCT vs. 55% for CT, p=0.11) (Table 2). The rates of cardiac

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response in patients with cardiac involvement were similar between cohorts (45% for

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AHCT and 42% for CT, p=0.23) (Table 2). More patients in the AHCT group had a renal

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response compared to the CT group (p=0.02).

224

The median duration of response was significantly longer in the AHCT cohort (31

225

vs. 7 months, p<0.01). At a median follow-up of 23 months for survivors (range: 6-145

226

months), the median progression free survival (PFS) was superior in the AHCT cohort

227

compared with CT (not reached vs. 9 months, p<0.01; Figure 1). Multivariable analysis

228

revealed increased PFS if AHCT was performed compared with receiving CT (HR 3.86,

229

95% CI 1.3-11.5, p=0.02). Modified cardiac stage III disease was not predictive of PFS.

230 231 232 233

Discussion/Conclusion In this analysis, we observed that patients receiving AHCT displayed extended

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PFS and enhanced OS compared to those that received CT alone. The observed

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correlations between AHCT and improved outcomes favor the use of AHCT over

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chemotherapy alone for the treatment of AL amyloidosis. These findings are best

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explained by deeper hematological responses and extended duration of response with use

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of AHCT and concurrent low TRM.

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In 1998, Comenza et al. reported successful treatment of AL amyloidosis with

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dose-intensive melphalan and AHCT. Thirteen patients achieved a complete

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hematological response and 11 of 17 surviving patients showed improvement in organ

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involvement after 3 months.(7) This early success led to further comparisons of AHCT to

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standard therapies. In a well-controlled study by Dispenzieri et al., 63 patients that

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underwent AHCT were compared to 63 control patients that were matched for age, sex,

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time to presentation, ejection fraction, serum creatinine, septal thickness, nerve

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involvement, 24-hour urine protein, and serum alkaline phosphatase. The number of

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deaths was significantly reduced in those patients undergoing AHCT (n=16 AHCT vs.

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n=50 controls) and 4-year survival rate was superior (71% vs. 41%).(9)

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In 2007, Jaccard et al. compared high-dose melphalan plus AHCT to standard-

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dose melphalan plus high-dose dexamethasone treatment in newly diagnosed patients

251

with AL amyloidosis in a prospective randomized trial. In contrast to the previous

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AHCT studies, no difference was observed in hematologic response and median OS was

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lower in patients receiving AHCT plus high-dose melphalan compared to those that

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received standard-dose melphalan and dexamethasone (22.2 vs. 56.9 months, p=0.04).

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This difference was largely due to a TRM of 24% (9/37) in the group that received

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AHCT.(15) In a study by Gertz et al., hematologic response and survival was similar

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between patients treated with AHCT or older therapies, such as melphalan plus

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dexamethasone. In light of these more recent studies, the use of AHCT as first-line

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therapy remains controversial.(10)

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Many patients with AL die from progressive disease as organ function

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deteriorates. In a disease such as AL amyloidosis where the cause of morbidity and

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mortality is related to end organ damage, improved organ function should translate to

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improved response. In our study, we observed a survival benefit with AHCT. Patients in

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the AHCT cohort experienced deeper responses, which has previously been associated

265

with improved survival, particularly in patients archiving CR.(16) While we report

266

increased frequencies of renal and overall organ responses following AHCT, this

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difference was not statistically significant. Furthermore, there was no difference in the

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frequency of cardiac responses between groups. The extent of cardiac involvement,

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specifically, has been shown to correlate with outcome.(10) Based on published reports,

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we anticipated cardiac stage to be a significant predictor of OS and PFS.(7) It is possible

271

that cardiac stage was not found to be of significance due to lack of statistical power. In

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our program, an integrated multi-disciplinary approach which includes co-management of

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patients with other subspecialties including cardio-oncologist may have overcome the

274

influence of cardiac biomarkers. In addition, evaluation of functional measures, such as

275

the six-minute walk test, should be studied to aide with cardiac stage severity and

276

predicted outcomes.(17, 18)

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There are important limitations to this study. At baseline there were differences

278

between cohorts. Patients who underwent AHCT were younger, had lower BNP, higher

279

ejection fractions and more proteinuria prior to treatment. Ultimately treatment choice

280

was the only variable of significance; however selection of patients to receive AHCT

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may have been biased due to baseline wellness differences. In addition, nearly one-third

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of the patients in this study underwent direct transplantation without pre-transplant

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chemotherapy and these patients in particular would not have significant amyloid

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cardiomyopathy. Since the aim for this research was to compare patients who received

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AHCT to those only receiving chemotherapy, the decision was made to combine those

286

receiving induction chemotherapy and no induction chemotherapy prior to AHCT.

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In conclusion, although the efficacy of AHCT as a first-line therapy has been

288

controversial in previous studies, our findings support AHCT as an effective treatment

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for AL amyloidosis. This study showed increased PFS, depth of response, and overall

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survival in patients who underwent AHCT versus chemotherapy alone. With

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advancement in transplant techniques and supportive care, TRM has decreased

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significantly. In this study, 100 day TRM was 7%. This was similar to the large Center

293

for International Blood and Marrow Research Transplant database registry study

294

published by D’Souza et al, which reported a 100 day TRM of 5% in patients

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transplanted for amyloidosis between 2007 and 2012.(2) Five and 10-year survival rates

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for patients that achieve a complete HR are 80% and 60%, respectively.(16, 19) AHCT

297

should be considered for eligible patients with AL amyloidosis at experienced transplant

298

centers that can offer this therapy with low TRM. Larger prospective trials with longer

299

follow-up periods are needed to further validate these observations.

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Author Contributions: Conception and design: RFC, OO Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors

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Acknowledgements:

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We thank the patients involved in this study and their families.

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References 1. Kastritis E, Dimopoulos MA. Recent advances in the management of AL Amyloidosis. British Journal of Haematology. 2016;172(2):170-86. 2. D'Souza A, Dispenzieri A, Wirk B, Zhang M-J, Huang J, Gertz MA, et al. Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study. Journal of Clinical Oncology. 2015;33(32):3741-9. 3. Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. New England Journal of Medicine. 2003;349(6):583-96. 4. Gertz MA, Landau H, Comenzo RL, Seldin D, Weiss B, Zonder J, et al. First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. Journal of Clinical Oncology. 2016. 5. Cornell RF, Zhong X, Arce-Lara C, Atallah E, Blust L, Drobyski WR, et al. Bortezomibbased induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. Bone Marrow Transplant. 2015;50(7):914-7. 6. Dhakal B, Strouse C, D'Souza A, Arce-Lara C, Esselman J, Eastwood D, et al. Plerixafor and Abbreviated-Course Granulocyte Colony–Stimulating Factor for Mobilizing Hematopoietic Progenitor Cells in Light Chain Amyloidosis. Biology of Blood and Marrow Transplantation. 2014;20(12):1926-31. 7. Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S, et al. DoseIntensive Melphalan With Blood Stem-Cell Support for the Treatment of AL (Amyloid LightChain) Amyloidosis: Survival and Responses in 25 Patients. Blood. 1998;91(10):3662-70. 8. Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood. 2007;110(10):3561-3. 9. Dispenzieri A, Kyle RA, Lacy MQ, Therneau TM, Larson DR, Plevak MF, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood. 2004;103(10):3960-3. 10. Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317-25. 11. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management. American Journal of Hematology. 2012;87(1):78-88. 12. Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, et al. Induction Therapy with Bortezomib Followed by Bortezomib-High Dose Melphalan and Stem Cell Transplantation for Light Chain Amyloidosis: Results of a Prospective Clinical Trial. Biology of Blood and Marrow Transplantation. 2015;21(8):1445-51. 13. Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, et al. New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes. Journal of Clinical Oncology. 2012;30(36):4541-9. 14. Girnius S, Seldin DC, Meier-Ewert HK, Sloan JM, Quillen K, Ruberg FL, et al. Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement. Bone Marrow Transplant. 2014;49(3):434-9. 15. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, et al. HighDose Melphalan versus Melphalan plus Dexamethasone for AL Amyloidosis. New England Journal of Medicine. 2007;357(11):1083-93.

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16. Sanchorawala V, Sun F, Quillen K, Sloan JM, Berk JL, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20 year experience. Blood. 2015. 17. Decker I, Goodman SA, Phillips SE, Lenihan DJ, Cornell RF. The six-minute walk test is a valuable measure of functional change following chemotherapy for AL (light-chain) cardiac amyloidosis. British Journal of Haematology. 2017:n/a-n/a. 18. Pulido V, Doros G, Berk JL, Sanchorawala V. The six-minute walk test in patients with AL amyloidosis: a single centre case series. British Journal of Haematology. 2017:n/a-n/a. 19. Kaufman GP, Dispenzieri A, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, et al. Kinetics of organ response and survival following normalization of the serum free light chain ratio in AL amyloidosis. American Journal of Hematology. 2015;90(3):181-6.

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Figure 1: Progression free survival in patients with AL amyloidosis treated with AHCT or chemotherapy alone.

Log-rank p<0.01

375 376 377 378 379 380

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Figure 2: Overall survival in patients with AL amyloidosis treated with AHCT or chemotherapy alone

Log-rank p=0.03

383 384 385 386 387

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Supplemental Figure 1: Consort flow diagram N=74 patients

43 AHCT patients

14 Straight to transplant

3 Melphalanbased

389 390 391 392 393 394 395

29 Chemotherapy prior to transplant

24 Bortezomibbased

31 CT patients

1 Melphalan-based

30 Bortezomibbased

2 Other

Patients receiving “other” treatments received immunomodulatory-based therapies.

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396 397

Table 1: Characteristics of 74 patients with AL amyloidosis treated with AHCT or chemotherapy alone Characteristics Age, median (range), years

AHCT (n=43) 56 (31-72)

CT (n=31) 60 (40-72)

p-value 0.01

24 (56)

22 (71)

0.19

9 (21) 32 (74) 8 (5-13.5)

11 (37) 17 (57) 13 (5-20)

22 (54)

24 (80)

22 (51) 10 (23) 11 (26)

5 (16) 11 (36) 15 (48)

Ejection fraction, median (range) BNP, pg/ml, median (range) Troponin I, ng/ml, median (range)

60.5 (45-75) 192 (25-1072) 0.03 (0.0-0.28)

55 (25-71) 501 (23-4476) 0.1 (0.0-3.02)

0.01 0.01 0.05

Renal, n (%) Creatinine, mg/dL, median (range) 24hr urine protein (g/24hr) (range)

35 (88) 1.1 (0.6-6.08) 4.4 (0.59-21.5)

16 (59) 1.1 (0.59-3.8) 0.9 (0.05-17)

0.01 0.76 0.04

Gastrointestinal, n (%)

4 (18)

7 (41)

0.11

Pulmonary, n (%)

2 (8)

2 (15)

0.48

Soft tissue, n (%)

9 (38)

6 (38)

1.00

Hepatic, n (%)

5 (17)

2 (11)

0.57

Number of organs involved, n (%) 1 organ 2 organ 3 or more organs

14 (33) 13 (30) 16 (37)

8 (26) 12 (39) 11 (35)

41.7 (0.37-223)

11 (0.76-83.57)

Gender Male, n (%) Monoclonal light chain, n (%) Kappa Lambda Plasma Cell content of the bone marrow, median (range), % Organ Involvement Cardiac, n (%) Modified Cardiac n (%) Modified Cardiac Stage I Modified Cardiac Stage II Modified Cardiac Stage III

Follow-up time of survivors in months, median (range)

0.27

0.16

0.02 0.08

0.19

398 399 400 401

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402

Table 2: Hematologic and Organ Response rates

Treatment CR

403 404 405 406 407 408 409 410 411 412

413 414

AHCT n, (%) CT n, (%) Combined n, (%)

12 (28) 5 (17) 17 (23)

Hematological Response CR+ PR ORR VGPR* 13 (30) 25 (58) 6 (14) 31 (72) 6 (20) 11 (35) 6 (20) 17 (55) 19 (26) 36 (49) 12 (16) 48 (65)

Median time to HR (Months)

VGPR

2.5 2.2

Organ Response Cardiac Renal Involvement Involvement 10 (45) 18 (51) 10(42) 4 (25) 20 (43) 22 (43)

CR complete response; VGPR very good partial response; PR partial response; ORR overall response rate; HR hematological response. AHCT autologous hematopoietic cell transplantation; CT chemotherapy alone. Total patients in AHCT cohort = 43. Total patients in CT cohort = 31. *p=0.048. Cardiac involvement in AHCT cohort =22, Cardiac involvement in CT cohort =24, Renal involvement in AHCT cohort = 35 and Renal involvement in CT cohort =16.

Table 3: Mortality Rate and Cause of Death Treatment Total Deaths

AHCT (n=43) 8 (19%)

CT (n=31) 17 (55%)

Cause of Death Progressive Disease Cardiac Arrest Respiratory Failure Stroke Infection TRM

4 1 0 0 0 3

12 2 1 1 1 N/A

N/A Not applicable

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