ORIGINAL ARTICLE

Patients with immunoglobulin light chain amyloidosis undergoingautologous stem cell transplantation have superior outcomescompared with patients with multiple myeloma: a retrospectivereview from a tertiary referral center.A Dispenzieri, K Seenithamby, MQ Lacy, SK Kumar, FK Buadi, SR Hayman, D Dingli, MR Litzow, DA Gastineau,DJ Inwards, IN Micallef, SM Ansell, PB Johnston, LF Porrata, MM Patnaik, WJ Hogan and MAA Gertz

The underlying plasma cell clones in multiple myeloma (MM) and Ig light-chain amyloidosis (AL) appear to be different not only interms of ‘tumor burden’ but also in terms of their underlying biology. High-dose chemotherapy with auto-SCT is one method ofreducing the clone size and thereby improving OS. Post-auto-SCT outcomes between the two diseases have never been formallycompared. Among all patients with a diagnosis of AL or MM who received auto-SCT as primary therapy at the Mayo Clinic,Rochester, there were higher CR rates (40% versus 29%, Po0.0001) in the AL group. The respective median OS for the AL and MMpatients was 113 and 59.5 months, respectively, Po0.0001. Among patients achieving CR, MM patients had a fivefold risk of deathas compared with AL patients. Although auto-SCT cannot be offered to all patients with either AL or MM, it appears that for thosewell enough to be chosen for the procedure, greater benefit is derived among the AL patients. This difference in survival is mostnotable among those patients who achieve CR, suggesting very different plasma cell biology between the two diseases.

Bone Marrow Transplantation advance online publication, 22 April 2013; doi:10.1038/bmt.2013.53

Keywords: amyloidosis; myeloma; survival prediction; response

INTRODUCTIONBoth multiple myeloma (MM) and Ig light-chain amyloidosis (AL)are plasma cell disorders.1–3 The diseases differ from each other interms of ‘tumor burden,’ tumor biology and the impact the clonalIg has on other vital organ systems aside from the hematopoieticsystem. Currently, treatment strategies for the two disorders aresimilar in terms of chemotherapeutic options as there are noapproved drugs that have been shown to directly remove amyloidfrom tissues.4,5 However, the therapeutic window of chemotherapyfor patients with AL is narrower than for MM, resulting in more TRMand mortality.6–8 Despite this, OS for both conditions has improveddramatically over the past decade in part due to the use of high-dose melphalan with auto-SCT, to new drugs like thalidomide,lenalidomide and bortezomib.9,10 The greatest improvements haveoccurred in younger patients, who are candidates for auto-SCT.11,12

Patients with AL undergoing auto-SCT are highly selected.13

Since the twenty-first century, the expected median OS from auto-SCT for both MM and AL patients is approximately 5 years. Therespective median unmaintained PFS rates are approximately 22and 31 months, respectively.14–17 Many authors have tied completehematologic response rates to better PFS and OS in both diseases,but rates of CR after auto-SCT appear to be comparable in patientswith AL and MM despite the fact that the former group typicallydoes not receive induction therapy before auto-SCT.

Reports from our center and elsewhere would suggest thatamong patients with AL and MM, who are fit enough to be selectedto undergo auto-SCT, patients with AL appear to do as well if not

better than patients with MM, but a formal analysis has never beperformed. Using our prospectively maintained AL and MM auto-SCT databases, we set out to test our hypothesis that patients withAL who undergo auto-SCT—especially those who achieve CR—farebetter than MM patients receiving the same therapy.

PATIENTS AND METHODSApproval for this study was obtained from the Mayo Clinic Institutional ReviewBoard. All patients with a diagnosis of AL or MM who received auto-SCT at theMayo Clinic, Rochester, between June 1996 and January 2011 were compiledfrom two prospectively maintained databases (M.A.G.) to compare outcomes.During the study interval, a total of 2245 patients with AL were seen at theMayo Clinic, Rochester, within 1 year of their diagnosis; 454 (20.2%) underwentauto-SCT—415 (18.4%) within 12 months of diagnosis. During that sameinterval, a total of 3160 patients with active MM were also seen within 1 year ofdiagnosis, and 1116 (35.7%) had auto-SCT at our institution—790 (25%) withina year of diagnosis. All patients with AL had biopsy-proven amyloid disease byCongo red stain. The diagnosis of MM was made using conventional criteria.1

All but 97 patients were conditioned with single-agent high-dose melphalan;81 MM patients and 16 AL patients received melphalan and TBI conditioning.Standard supportive care measures were employed, and maintenance therapywas not part of standard clinical practice for either group. All patients wereclassified as CR, very good PR (VGPR), PR or no response. Response for MMpatients was coded in accordance with the international uniform responsecriteria for MM.18,19 Hematologic response criteria for AL patients were definedaccording to the consensus opinion from the Tenth International Symposiumon Amyloid and Amyloidosis, but also included the recent consensus updatesthat allow for the VGPR category, which is defined as a reduction in theinvolved Ig free light-chain to 40 mg/L or less.20,21

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. Correspondence: Professor A Dispenzieri, Division of Hematology,Department ofInternal medicine, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA.E-mail: dispenzieri.angela@mayo.eduReceived 3 February 2013; revised 5 March 2013; accepted 6 March 2013

Bone Marrow Transplantation (2013), 1–6& 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13

www.nature.com/bmt

Statistical analysisDifferences between nominal groups were compared using Fisher’s exactand Kruskall–Wallace tests. All P-values were two sided. Survival and PFSwere calculated from the time of transplant using the Kaplan–Meiermethod, and differences between survival outcomes were calculated bylog-rank tests. Patients were censored at the time of last follow-up for bothsurvival and PFS estimates. Death due to any cause was considered aprogression event. Median follow-up of surviving patients was 59.5months. Risk ratios were calculated using Cox proportional hazards, andrisk was reported per unit value unless otherwise stated. For multivariateanalyses, Cox regression modeling was used, adding in factors that weresignificant in the univariate model in a stepwise manner. Separate modelswere also performed to determine how acquisition of CR, non-disease-specific parameters (age, time period of auto-SCT, number of priorregimens, time to auto-SCT from diagnosis), and disease-specificparameters (BM plasmacytosis, creatinine, b-2 microglobulin, lactatedehyrogenase (LDH), C-reactive protein (CRP), albumin, serum M spike,urine total protein) affected outcomes. All statistical analyses wereperformed using JMP (SAS, Cary, NC, USA) software.

RESULTSThe pre-transplant characteristics of the 454 AL and 1116 MMpatients who received auto-SCT are shown in Table 1. The age andgender mix of both populations were comparable, but there weresignificant differences between the two populations in terms ofnumber of prior regimens (0 versus 1), time to auto-SCT (4.0 versus7.2 months), intensity of conditioning regimen (non-attenuated in69.4% versus 89.1%), serum creatinine (1.1 versus 1.0 mg/dL),albumin (2.6 versus 3.50 g/dL), C-reactive protein (0.4 versus0.6 mg/dL), LDH (196 versus 182 U/L), BM plasmacytosis (6% versus9%), serum M spike (0.1 versus 0.8 mg/dL) and urine total protein(3.7 versus 0.09 g/24 h).

As shown in Table 2, 100-day TRM differed between the AL andMM groups (8.8% versus 1.4%, Po0.0001, respectively). Hemato-logic response rates were also significantly different, with higheroverall hematologic response (79.5% versus 90.9%, Po0.0001)and VGPR (13.4% versus 25.4%, Po0.0001) in the MM group, buthigher CR rates (40.1% versus 29.4%, Po0.0001) in the AL group.Despite the higher TRM in the AL group, which resulted in aninferior 1 year OS, the estimated median OS rates for the AL andMM groups were 113.3 and 59.5 months, Po0.0001 (Figure 1a),respectively, and the 5-year OS rates were 66.2% and 49.4%.Because time to transplant was so different for the AL and MMgroups with only 91.4% of AL and 71% of MM patientstransplanted within 12 months of diagnosis, Kaplan–Meierestimates were generated excluding the 385 patients who hadauto-SCT 12 months after diagnosis (Figure 1b). Once again, all

survival measures favored the AL group (Table 2). The survivaladvantage persisted when a landmark analysis was doneincluding only those 1158 patients transplanted within 12 monthsof diagnosis who also survived 100 days post-auto-SCT (Figure 1c).

Separate univariate analyses were performed to identify factorsthat influenced OS for the entire cohort and for that subset ofpatients transplanted within 12 months of diagnosis (Table 3). Inboth analyses, the following factors adversely affected OS: noattainment of CR; MM diagnosis; earlier time period of auto-SCT(1996–2002 versus 2003–2006 versus 2007–2010); BM plasmacy-tosis at transplant greater than 10%; lower dose intensity ofconditioning regimen; higher b-2 microglobulin; and higherproliferative rate of plasma cells (plasma cell labeling index(PCLI)). In the ‘all patient’ group, the following other factors werealso significantly associated with OS: longer time betweendiagnosis and auto-SCT; older age; male gender; greater than 1prior regimen; lower urinary total protein; and higher creatinine,LDH or serum M spike.

A multivariate analysis including only those patients trans-planted within 12 months of diagnosis was performed. Thosevariables that had a significant adverse effect on OS included: lackof CR, attenuated melphalan conditioning, MM diagnosis, BMplasmacytosis, high LDH, high plasma cell labeling index andearlier era of auto-SCT. To test the study’s underlying hypothesisthat patients with AL achieving CR have better outcomes than MMpatients achieving CR, a second multivariable analysis was donethat included only the 420 patients who achieved CR. With 137deaths, the only factors that increased a patient’s risk ofdeath were a diagnosis of myeloma, attenuated dose ofmelphalan conditioning and higher BM plasmacytosis (Table 4).The risk ratio of death for a diagnosis of MM as compared with ALwas 5.1 (3.3–8.3).

Kaplan–Meier curves were generated to further study thedifferential role of response between patients with AL and MMincluding only those patients undergoing auto-SCT within 12months of their diagnosis and using a 100-day landmark analysisfor OS. AL patients achieving a hematologic CR had superior OS ascompared with their MM counterparts with respective median OSof not reached and 84 months, Po0.0001, and 5-year OS rates of90.5 and 61.6%, Po0.0001 (Figure 2a). The uncorrected risk ratiofor death was 4.2 (95% CI: 2.7–6.7, Po0.0001) among the MMpatients. Similarly, AL patients achieving a hematologic VGPR alsohad better outcomes than their MM counterparts with 5-year OSrates of 74.4% and 59.4%, respectively (Figure 2b), with a risk ratioof death of 2.0 (95% CI: 1.2–3.5, P¼ 0.004). However, when thepatient populations were restricted to only those who achieved

Table 1. Patient characteristics pre-auto-SCTa

Characteristic All patients (n¼ 1570) AL (n¼ 454) MM (n¼ 1116) P-value

Age (years) 57.7 (23.8–75.3) 57.5 (25.9–75.2) 58.0 (23.8–75.3) NSMale gender, n (%) 940 (59.9) 272 (59.9) 668 (59.9) NSPrior regimens 1 (0–6) 0 (0–3) 1 (0–6) o0.0001Months to auto-SCT 6.3 (0–202.3) 3.9 (0–74.3) 7.2 (2–202.3) o0.0001Auto-SCT412 months from diagnosis, n (%) 365 (23.3) 39 (8.6) 326 (29.2) o0.0001Creatinine (mg/dL) 1 (0.4–12.4) 1.1 (0.4–12.4) 1 (0.5–10.1) o0.0001Beta-2 microglobulin (mg/dL) 2.6 (1–57.3) 2.6 (1–35.1) 2.5 (1–57.3) NSLDH (U/L) 186 (22–2244) 196 (92–442) 182 (22–2244) o0.0001C-Reactive protein (mg/dL) 0.5 (0–263.5) 0.4 (0–40.4) 0.6 (0–263.5) o0.0001Albumin (g/dL) 3.3 (0.8–4.8) 2.6 (0.8–4.4) 3.5 (1.7–4.8) o0.0001Serum M spike (mg/dL) 0.5 (0–8.7) 0.1 (0–2.8) 0.8 (0–8.7) o0.0001Urine total protein (g/dL) 0.2 (0.007–35.4) 3.7 (0.01–35.4) 0.09 (0.007–19.6) o0.0001% BM plasmacytosis at auto-SCT 7.1 (0–93) 6 (1–60) 9 (0–93) o0.0001Attenuated dose conditioning, n (%)b 269 (17.1) 147 (32.4) 122 (10.9) o0.0001

Abbreviation: AL¼ amyloidosis; LDH¼ lactate dehydrogenase; MM¼myeloma. aValues expressed as median (range) unless otherwise specified. bIncludesregimens other than melphalan 200mg/m2 or melphalan 140mg/m2 with TBI.

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hematologic PR, 5-year OS rates were comparable at 56.0% and52.5%, respectively, P¼NS (Figure 2c). Restricting the analyses tothose patients achieving less than a PR revealed a trend towardbetter outcomes among the MM patients 35.3% versus 41.4%,P¼NS (Figure 2d).

DISCUSSIONThe current study carries four important novel messages. First, theselection of patients for auto-SCT is more stringent among ALpatients than among MM patients, with fewer than one in five ALpatients moving to auto-SCT versus one in four MM patientsproceeding to early auto-SCT at our institution. Second, even in atertiary center that specializes in the care of AL, the TRM for auto-SCT is nearly fivefold higher for AL patients as compared with MMpatients. Third, although overall response rates and VGPR rates arehigher among the MM patients, CR rates are higher in patientswith AL. Fourth, long-term OS of patients with AL undergoingauto-SCT is better than that of patients with MM undergoing thesame procedure, with the most dramatic benefits seen amongthose patients achieving CR.

These data highlight both the benefit of transplant among ALpatients healthy enough to undergo auto-SCT and the differencesbetween these two disease entities, most notably in terms of theirtumor biology. This latter point is an indirect measurement, but asdemonstrated in the multivariable analysis, when all externalfactors like timing of transplant, dose of melphalan and number ofprior regimens are corrected for, diagnosis and attainment of CRwere the most powerful predictors of outcome. Despite the factthat patients with AL can have severely impaired organ function,patients with AL on the whole fared better than MM patients. Thisadvantage was enjoyed by the 53% of AL patients who achieved aVGPR or better, with a fourfold better OS for the AL patientsachieving CR as compared with MM patients and a twofold betterOS for the AL patients achieving VGPR again as compared withMM patients. Even without maintenance therapy, the Kaplan–Meier estimate of a 10-year survivorship for AL patients achievingCR was 75% even without maintenance therapy.

The take-home message of this study should not be that morepatients with AL should receive auto-SCT since even in this highlyselected patient population TRM was not trivial. Our practice ofbringing only about 20% of our AL patients to transplant differsfrom the practice at other institutions, where 45% of patientsreceive auto-SCT.22 At our institution, over time, the stringency ofselecting AL patients for auto-SCT has fluctuated, moving fromstringent to less stringent (but with attenuated melphalan doses),to more stringent, with our highest rates of auto-SCT for ALpatients from 2001–2006 at 25%. Our practices have beeninfluenced by data. The only method for bringing more, that is,sicker, patients to auto-SCT is to attenuate the conditioning doseof melphalan. The current data as well as prior reportsdemonstrate that although reducing conditioning doses ofmelphalan allows for sicker patients to make it through auto-SCT, response rates and OS rates suffer.14,23,24 Using standard-dose melphalan conditioning is also not an option for the sickestpatients because patients with more severe cardiac involvement

Table 2. Transplant-related outcomes based on underlyingdiagnosis

All patients

Characteristic Amyloid(n¼ 454)

Myeloma(n¼ 1116)

P-value

100 day TRM, n (%) 40 (8.8) 16 (1.4) o0.0001

Hematological responsePR or better, n (%) 361 (79.5) 1014 (90.8) o0.0001VGPR, n (%) 61 (13.4) 284 (25.4) o0.0001CR, n (%) 182 (40.1) 328 (29.4) o0.0001

OSMedian (95% CI),months

113.3 59.5 o0.0001

1-Year, % 86.6 91.05-Year, % 66.2 49.4

Patients transplanted within 12 months ofdiagnosis

Amyloid(n¼ 415)

Myeloma(n¼ 790)

P-value

100 day TRM,n (%)

36 (8.7%) 11 (1.4) o0.0001

Hematological responsePR or better, n(%)

328 (79.0) 721 (91.3) o0.0001

VGPR, n (%) 54 (13.0) 194 (24.5) o0.0001CR, n (%) 164 (39.5) 256 (32.4) 0.02

OSMedian (95%CI), months

113.3 (89.9, NR) 72.3 (62.7, 78.7) o0.0001

1-Year, % 86.7% 92.8%5-Year, % 65.5% 55.4%

Abbreviations: CI¼ confidence interval; NR¼no response; VGPR¼ verygood PR.

1.0

0.8

0.6

0.4Su

rviv

ing

0.00 12

AL

N N

415790 405

159 113.3 379779 394

123 161.973.572.3

Deaths Deaths

Myeloma Myeloma

AL amyloidosis AL amyloidosis

P <0.0001 P <0.0001

Myeloma

AL amyloidosis

P <0.0001

Median OS, mo Median OS, mo N Deaths Median OS, mo

MMALMM

ALMM1116

454 174 113.3618 59.5

24 36 48 60 72

Months post-ASCT Months post-ASCT Months post-ASCT

84 96 108 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108

0.2

Figure 1. OS based on diagnosis. (a) All 1570 patients. (b) Excluding patients who received auto-SCT more than 12 months after diagnosis.(c) Landmark analysis at 100 days, including only those patients who had auto-SCT within 12 months of diagnosis.

Auto-SCT in AL versus MMA Dispenzieri et al

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& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013), 1 – 6

have TRM rates of 28–43%.8,25 In addition, the one randomizedtrial that compared melphalan and dexamethasone to auto-SCTdid not show superiority of auto-SCT over conventionalchemotherapy in part due to high rates of treatment mortalityand in part due to attenuated conditioning doses of melphalan inthe sicker patients.24

So where to go from here? Several approaches are being triedfor AL patients, including non-transplant options like melphalanand dexamethasone, bortezomib-based treatments and immunemodulator-based regimens.2,26–32 There have been two phase 2trials that employ risk-adapted melphalan conditioning followedby post-auto-SCT consolidation with either thalidomide anddexamethasone or bortezomib and dexamethasone.33,34

Although these authors have observed upgrading in responsequality with this approach, to date there is no information abouthow this approach affects OS. There are also anecdotal reports oftreating patients with non-transplant chemotherapy in order toimprove the AL patients’ performance status and then using auto-SCT as a consolidative therapy.35 These data bring the question ofwhether all patients with AL should be treated until they achieveCR to the forefront. Because biology often trumps treatment, andthe functional status of a patient can morph a potentially effectivetherapy into a fatal therapy as has been repeatedly been shown inthe earliest AL transplantation studies8,25 and in several myeloma

studies, most notably those treating elderly MM patients.36,37 Thedecision to treat patients until they reach a VGPR or CR21 must bemade balancing the toxicity of therapy against the urgency ofneeding an organ response.

Studies addressing differences between the biology of ALplasma cells and MM plasma cells are limited. Girnius et al.38

addressed a slightly different question when they reported ontheir experience transplanting 16 patients with AL and concurrentMM. They found that the CR rate was 25% and the OS for thesepatients was 54 months. In contrast, the average patient with ALhas a lower tumor burden and plasma cells that are lessproliferative. Gene expression profiling would suggest thatplasma cells from patients with AL are more like MGUS plasmacell (PC).39 The chromosomal abnormalities found in AL are highlyweighted toward what would be deemed favorable among MMpatients,40,41 with a paucity of high-risk cytogenetic abnor-malities like t(4;14), t(14;16), deletion 17p and increased copynumbers of 1q21. These favorable genetics may in part explain thesuperior outcomes enjoyed by the majority of AL patients in thisseries. Because FISH was not available for the majority of the ALpatients, we could not specifically prove this point.

Our study leaves investigators and readers with as manyquestions as answers. Further study is required to understand thebiology of the plasma cells of patients with AL, but even without

Table 3. OS, univariate analysis

All patients (n¼ 1570) Patients transplanted within12 months (n¼ 1205)

Characteristic RR (95% CI) P-value RR (95% CI) P-value

No CR 2.1 (1.8–2.5) o0.0001 2.1 (1.8–2.6) o0.0001MM diagnosis 1.7 (1.4–2.0) o0.0001 1.4 (1.2–1.7) o0.0001Auto-SCT 412 mo. from diagnosis 1.7 (1.5–2.0) o0.0001 NA (NA) NAGreater than 1 prior regimen 1.7 (1.5–2.0) o0.0001 1.2 (0.9–1.5) 0.1Attenuated dose conditioning 1.4 (1.2–1.7) 0.0001 1.7 (1.4–2.0) o0.0001Male gender 1.3 (1.1–1.5) 0.002 1.3 (1.1–1.5) 0.009Timing of auto-SCT: 1996-2002 vs 2003–06 vs 2007–10 1.3 (1.1–1.4) o0.0001 1.2 (1.1–1.4) 0.001Age by decade 1.1 (1.0–1.2) 0.01 1.1 (1.0–1.2) 0.01Plasma cell labeling index X1% 2.2 (1.9–2.6) o0.0001 2.1 (1.7–2.6) o0.0001BM plasmacytosis 410% 1.7 (1.5–1.9) o0.0001 1.6 (13–1.8) o0.0001LDH, elevated 1.3 (1.1–1.5) 0.0007 1.3 (1.1–1.6) 0.002Creatinine 1.1 (1.03–1.17) 0.008 1.1 (1.1–1.2) 0.002Beta-2 microglobulin 1.0 (1.0–1.1) o0.0001 1.0 (1.0–1.1) o0.0001Serum M spike 1.1 (1.1–1.2) o0.0001 1.0 (1.0–1.0) 0.1Urine total protein 1.0 (0.9–1.0) 0.01 1.0 (1.0–1.0) 0.06Albumin o3.5 g/dL 0.9 (0.8–1.1) 0.4 0.9 (0.8–1.1) 0.5

Abbreviations: LDH¼ lactate dehydrogenase; MM¼multiple myeloma; mo.¼month; RR¼ response rate.

Table 4. Multivariate analysis of predictors of OS

Patients with auto-SCT within 12 modiagnosis (n¼ 1205)

CR patients, auto-SCT within 12months of diagnosis (n¼ 420a)

Characteristic RR (95% CI) P-value RR (95% CI) P-value

No CR 1.8 (1.5–2.2) o0.0001 NA NAMM (vs AL) 1.3 (1.1–1.1.6) 0.005 5.1 (3.3–8.3) o0.0001Attenuated dose conditioning 1.8 (1.4–2.2) o0.0001 2.4 (1.4–3.9) 0.002BMPC, % 1.0 (1.0–1.0) 0.007 1.0 (1.0–1.0) 0.009LDH abnormal 1.4 (1.2–1.6) 0.001 NS NSPCLI 41% 1.8 (1.4–2.2) o0.0001 NS NSAuto-SCT date 1996–2002; 2003–06; 2007–10 1.2 (1.1–1.4) 0.001 NS NS

Abbreviations: AL¼ amyloidosis; BMPC¼bone marrow plasma cells; LDH¼ lactate dehydrogenase; MM¼multiple myeloma; NA¼not applicable. Greaterthan 1 prior regimen, auto-SCT date, male gender, age and creatinine were NS on multivariable analysis. aPopulation comprised of 164 AL patients and 256MM patients.

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Bone Marrow Transplantation (2013), 1 – 6 & 2013 Macmillan Publishers Limited

that additional study, the current manuscript provides empiricinformation about the differences between AL and MM. CRin AL means more than it means in MM, perhaps in part due tothe inadequacy of the present day definitions of CR. The standardapproach of induction, followed by auto-SCT, followedby consideration of maintenance therapy that is employed inpatients with MM is not necessarily appropriate in the majority ofpatients with AL destined for auto-SCT. Further clinical directionsshould focus on how one can improve upon outcomes for the38% of patients with AL who survive 100-days post auto-SCT, butachieve a PR or less.

CONFLICT OF INTERESTAD: Research dollars from Celgene, Janssen and Millennium. MQL: Clinical trial dollarsfrom Celgene. SKK: Research dollars from Celgene and Millennium. M.A.G.: Honorariafrom Binding Site. The remaining authors declared no conflict of interest.

ACKNOWLEDGEMENTSThis work was supported in part by the JABBS foundation, the Predolin Foundationand the Robert A Kyle Hematologic Malignancies Fund. This was also supported inpart by a generous gift from Mr Howard Weitzman’s 2011 Gala in Support of AmyloidResearch and Awareness.

AUTHOR CONTRIBUTIONSAD: Designed study, collected and reviewed data, performed data analyses,cared for patients, wrote and reviewed manuscript. KS: Collected and revieweddata, performed data analyses, assisted in the writing of manuscript. MQL, SKK,FKB, SRH, MRL, DAG, DJI, INM, SMA, PBJ, LFP, MMP, WJH: Cared for patients andprovided critical review of the manuscript. DD: Cared for patients and reviewedmanuscript. MAAG: Collected and reviewed data, cared for patients andreviewed manuscript.

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clonal gammopathies, multiple myeloma and related disorders: a report of theInternational Myeloma Working Group. Br J Haematol 2003; 121: 749–757.

2 Dispenzieri A, Gertz MA, Buadi F. What do I need to know about immunoglobulinlight chain (AL) amyloidosis? Blood Rev 2012; 26: 137–154.

3 Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006; 108: 2520–2530.4 Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and

management. Am J Hematol 2012; 87: 78–88.5 Gertz MA. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis,

risk-stratification, and management. Am J Hematol 2011; 86: 180–186.6 Dispenzieri A, Dingli D, Kumar SK, Rajkumar SV, Lacy MQ, Hayman S et al.

Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treatedwith immune modulatory drugs. Am J Hematol 2010; 85: 757–759.

7 Dispenzieri A, Lacy MQ, Rajkumar SV, Geyer S, Witzig TE, Fonseca R et al. Poortolerance to high doses of thalidomide in patients with primary systemic amy-loidosis. Amyloid 2003; 10: 257–261.

8 Moreau P, Leblond V, Bourquelot P, Facon T, Huynh A, Caillot D et al. Prognosticfactors for survival and response after high-dose therapy and autologous stemcell transplantation in systemic AL amyloidosis: a report on 21 patients.Br J Haematol 1998; 101: 766–769.

9 Kumar SK, Gertz MA, Lacy MQ, Dingli D, Hayman SR, Buadi FK et al. Recentimprovements in survival in primary systemic amyloidosis and the importance ofan early mortality risk score. Mayo Clin Proc 2011; 86: 12–18.

10 Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al.Improved survival in multiple myeloma and the impact of novel therapies.Blood 2008; 111: 2516–2520.

11 Ludwig H, Bolejack V, Crowley J, Blade J, San Miguel J, Kyle RA et al. Survival andyears of life lost in different age cohorts of patients with multiple myeloma.J Clin Oncol 2010; 28: 1599–1605.

12 Pulte D, Gondos A, Brenner H. Improvement in survival of older adults withmultiple myeloma: results of an updated period analysis of SEER data. Oncologist2011; 16: 1600–1603.

13 Dispenzieri A, Lacy MQ, Kyle RA, Therneau TM, Larson DR, Rajkumar SV et al. Elig-ibility for hematopoietic stem-cell transplantation for primary systemic amyloidosisis a favorable prognostic factor for survival. J Clin Oncol 2001; 19: 3350–3356.

14 Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM et al.Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell

1.0

0.8

Myeloma

N

AmyloidMyeloma

AmyloidMyeloma

164255 111

25 NR84.1

Deaths OS, mo N

53192 85

18 NR75.7

Deaths OS, mo

AL amyloidosisAL amyloidosis

Myeloma

P <0.001

Myeloma Myeloma

N

AmyloidMyeloma

Amyloid 54 36 40.156.24764Myeloma

10837 151

44 75.663.8

Deaths OS, mo N Deaths OS, mo

AL amyloidosis

AL amyloidosis

P =0.15 P =0.2

P =0.006

0.6

0.4

Pro

po

rtio

n s

urv

ivin

g0.2

0.0

1.0

0.8

0.6

0.4

Pro

po

rtio

n s

urv

ivin

g

0.2

0.0

1.0

0.8

0.6

0.4

Pro

po

rtio

n s

urv

ivin

g

0.2

0.00 12 24 36 48

Months post-ASCT

60 72 84 96 108 120

0 12 24 36 48

Months post-ASCT

60 72 84 96 108 120

1.0

0.8

0.6

0.4

Pro

po

rtio

n s

urv

ivin

g

0.2

0.00 12 24 36 48

Months post-ASCT

60 72 84 96 108 120

0 12 24 36 48

Months post-ASCT

60 72 84 96 108 120

Figure 2. OS based on diagnosis and depth of response*. (a) Patients achieving a complete hematologic response. (b) Patients achieving avery good partial hematologic response. (c) Patients achieving a partial hematologic response. (d) Patients not achieving at least a partialresponse. *Three month landmark, excluding patients transplanted more than 12 months after diagnosis.

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