Translocation t(11;14) Is Associated With Adverse

VOLUME

33

䡠

NUMBER

12

䡠

APRIL

20

2015

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens Tilmann Bochtler, Ute Hegenbart, Christina Kunz, Martin Granzow, Axel Benner, Anja Seckinger, Christoph Kimmich, Hartmut Goldschmidt, Anthony D. Ho, Dirk Hose, Anna Jauch, and Stefan O. Schönland Tilmann Bochtler, Ute Hegenbart, Anja Seckinger, Christoph Kimmich, Hartmut Goldschmidt, Anthony D. Ho, Dirk Hose, and Stefan O. Schönland, Amyloidosis Center, University Hospital Heidelberg; Christina Kunz and Axel Benner, German Cancer Research Center; Martin Granzow and Anna Jauch, Institute of Human Genetics, University Heidelberg; and Hartmut Goldschmidt and Dirk Hose, National Center for Tumor Diseases, Heidelberg, Germany. Published online ahead of print at www.jco.org on March 16, 2015. Supported in part by grants from the Dietmar-Hopp Foundation “Heidelberger Konzept zur Optimierung der Diagnostik und Therapie des Multiplen Myeloms” (H.G.), the Bundesministerium für Bildung und Forschung (GERAMY; A.J. and S.O.S.), and Janssen-Cilag (S.O.S.). Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Stefan O. Schönland, MD, Medical Department V, Amyloidosis Center, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3312w-1371w/$20.00

A

B

S

T

R

A

C

T

Purpose Bortezomib has become a cornerstone in the treatment of AL amyloidosis. In this study, we addressed the prognostic impact of cytogenetic aberrations for bortezomib-treated patients. Patients and Methods We analyzed a consecutive series of 101 patients with AL amyloidosis treated with bortezomibdexamethasone as first-line treatment by interphase fluorescence in situ hybridization (iFISH). Patients were ineligible for high-dose chemotherapy, which would put them at risk for cardiac or renal failure, and thus represented a poor-risk group. Results Presence of t(11;14), versus its absence, was associated with inferior hematologic event-free survival (median, 3.4 v 8.8 months, respectively; P ⫽ .002), overall survival (median, 8.7 v 40.7 months, respectively; P ⫽ .05), and remission rate (ⱖ very good partial remission; 23% v 47%, respectively; P ⫽ .02). In multivariable Cox regression models incorporating established hematologic and clinical risk factors, t(11;14) was an independent adverse prognostic marker for hematologic event-free survival (hazard ratio, 2.94; 95% CI, 1.37 to 6.25; P ⫽ .006) and overall survival (hazard ratio, 3.13; 95% CI, 1.16 to 8.33; P ⫽ .03), but not for remission (ⱖ very good partial remission). Markedly, the multiple myeloma high-risk iFISH aberrations t(4;14), t(14;16), del(17p), and gain of 1q21 conferred no adverse prognosis in this bortezomibdexamethasone–treated group. After backward variable selection, the final multivariable model was validated in a consecutive series of 32 patients treated with bortezomib, dexamethasone, and cyclophosphamide. Conclusion iFISH results are important independent prognostic factors in AL amyloidosis. In contrast to our recently published results with melphalan and dexamethasone standard therapy, bortezomib is less beneficial to patients harboring t(11;14), whereas it effectively alleviates the poor prognosis inherent to high-risk aberrations. Given the discrepant response to different treatment modalities, iFISH may help to guide therapeutic choices in these poor-risk patients requiring rapid hematologic response. J Clin Oncol 33:1371-1378. © 2015 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2014.57.4947

INTRODUCTION

The proteasome inhibitor bortezomib (Velcade; Janssen-Cilag, Neuss, Germany) has become a wellestablished treatment option in systemic light chain (AL) amyloidosis.1 In a phase I/II study,2 the efficacy and feasibility of bortezomib monotherapy were first demonstrated in patients with relapsed disease, with remission rates up to 70%. One-year overall survival (OS) and progression-free survival rates were reported as high as 94% and 75%, respectively. Markedly, remission in responding patients was

achieved quickly, by the completion of the first or second cycle. Further studies have confirmed the efficacy of bortezomib in AL amyloidosis.3-5 Bortezomib is now also established as an up-front treatment option.6 The success of combination protocols including bortezomib in multiple myeloma (MM) has prompted the development of comparable protocols in AL amyloidosis. Encouraging response rates have already been reported for the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD).7,8 However, these previous studies have not specified the response according to © 2015 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on October 21, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.

1371

Bochtler et al

Table 1. Baseline Hematologic and Clinical Characteristics of the Vel-Dex and the CyBorD Cohorts Characteristic

Vel-Dex Cohort (n ⫽ 101)

Clinical Age, years Median 61 Range 36-77 Sex, %ⴱ Male 59 Female 41 Hematologic Plasma cell dyscrasia, % AL 87 AL ⫹ MM stage I 13 Bone marrow plasmacytosis, % Median 12 Range 2-57 Light chain, % ␬ 21 ␭ 79 dFLC, mg/L Median 317 Range 0-7,554 dFLC ␬ Median 563 Range 36-7,086 dFLC ␭ Median 280 Range 0-7,554 Intact immunoglobulin, % No 60 Yes 40 Organ involvement Organs involved, No. Median 3 Range 1-5 No. of organs involved, % 1 17 2 24 3 27 4 29 ⱖ5 4 Heart involvement, % 91 Mayo score, % 1 10 2 24 3 63 ND 3 NT-proBNP, ng/L Median 7,445 Range 40-565,442 NYHA class, %† ⬍ II 15 II 11 II-III 15 ⱖ III 58 ND 1 Renal involvement, % 51 MDRD GFR, mL/min‡ Median 49 Range ⬍ 10-93 (continued in next column)

1372

© 2015 by American Society of Clinical Oncology

Table 1. Baseline Hematologic and Clinical Characteristics of the Vel-Dex and the CyBorD Cohorts (continued)

CyBorD Cohort (n ⫽ 32)

Characteristic

Vel-Dex Cohort (n ⫽ 101)


57 44-74

Soft tissue involvement, % GI involvement, % Liver involvement, % Peripheral polyneuropathy, %

50 43 22 20

47 28 22 16

59 41

97 3 13 3-62 6 94

Abbreviations: CyBorD, cyclophosphamide, bortezomib, and dexamethasone; dFLC, difference in free light chains; MDRD GFR, Modified Diet in Renal Disease glomerular filtration rate; MM, multiple myeloma; ND, not determined; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; Vel-Dex, bortezomib-dexamethasone. ⴱ For the categorical variables sex, plasma cell dyscrasia, light chain, intact immunoglobulin, organ number, and organ involvement, the data set is complete in the Vel-Dex and CyBorD with n ⫽ 101 and n ⫽ 32, respectively, and therefore only percentages are given. †Listed only for patients with cardiac involvement. ‡Listed only for patients with renal involvement.

292 5-3,309

cytogenetic aberrations, although their prognostic role is well recognized in the related plasma cell dyscrasia MM. Therefore, in this study, we addressed the prognostic impact of cytogenetic aberrations in patients with newly diagnosed and bortezomib-treated AL amyloidosis.

3,249 3,189-,3309

PATIENTS AND METHODS

249 5-1,098 50 50

2 1-6 25 28 31 6 9 88 9 38 50 3 4,834 70-18,477 29 14 14 43 0 56 69 31-109

Patient Characteristics This study retrospectively analyzed all patients with AL amyloidosis admitted to the University Hospital Heidelberg who received bortezomib as first-line therapy, either in combination with dexamethasone (Vel-Dex, n ⫽ 101) or in combination with cyclophosphamide and dexamethasone (CyBorD, n ⫽ 32). The rationale to offer patients a bortezomib-based regimen instead of the standard treatment with melphalan-dexamethasone (M-Dex) was the urgent clinical need for a rapid lowering of the amyloidogenic light chains.2,3 This applied to patients with severe cardiac or kidney involvement threatened by early death or renal failure (for patient characteristics, see Table 1). Accordingly, the study population comprised a clinically poor risk and non–transplant-eligible cohort; 91% of patients in the Vel-Dex cohort had cardiac involvement, most of them with New York Heart Association class III and a cardiac Mayo score of 3, 34% had severe renal insufficiency (Modified Diet in Renal Disease glomerular filtration rate ⬍ 50 mL/min), and 69% displayed a high difference in free light chains (dFLC) greater than the 180 mg/L cutoff.9-11 The Vel-Dex and CyBorD cohorts were recruited from August 2008 to August 2013 and from February 2012 to September 2013, respectively. Patients gave written informed consent for interphase fluorescence in situ hybridization (iFISH) and data analysis in accordance with the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University of Heidelberg. Patients who received Vel-Dex or CyBorD as a planned induction therapy before high-dose chemotherapy were excluded from this analysis to avoid heterogeneity of the patient set. Patients with stage II or III MM as underlying plasma cell dyscrasia or an immunoglobulin (Ig) M paraprotein were also not considered for this analysis as a result of their different biologic features.12 The distribution of hematologic and clinical parameters among the cytogenetic groups is shown in Appendix Table A1 (online only). The t(11;14) positive and negative groups were balanced with the exception of the known association of t(11;14) with a light chain– only gammopathy and fewer concomitant stage I MMs.13,14 In the patients with high-risk aberrations, only sex was not well balanced. Treatment In the Vel-Dex cohort, 81 patients received an every-3-week protocol with bortezomib 1.0 mg/m2 administered twice weekly on days 1, 4, 8, and 11 JOURNAL OF CLINICAL ONCOLOGY


t(11;14) Confers Poor Response to Bortezomib in AL Amyloidosis

with dexamethasone 8 mg administered orally on the day of injection and the following day. Twenty patients were treated with an every-5-week protocol, with bortezomib 1.3 mg/m2 administered once weekly on days 1, 8, 15, and 22 with dexamethasone ⱖ 8 mg administered orally on the day of injection and the following day. The starting dose of Vel-Dex had to be reduced in five and six patients in these two protocols, respectively. In the CyBorD protocol adapted from Palladini et al,15 bortezomib 1.0 mg/m2 was given twice weekly, together with cyclophosphamide 300 mg/m2 orally once weekly and dexamethasone 20 mg on days 1 to 4. Patients received a median of three cycles (range, one to nine cycles) in the Vel-Dex cohort and four cycles (range, one to eight cycles) in the CyBorD cohort. Patients responding after three cycles typically proceeded to another three cycles. Patients who at this time point failed to achieve at least a partial remission were either given a second-line regimen with M-Dex (n ⫽ 14) or lenalidomide-dexamethasone (n ⫽ 2) or escalated to CyBorD (n ⫽ 4) or bortezomib plus M-Dex (n ⫽ 2). Another 22 initially responding patients later on received second-line therapy at hematologic relapse or progression, mostly Vel-Dex again (n ⫽ 8), M-Dex (n ⫽ 4), or lenalidomide-dexamethasone (n ⫽ 5). Outcome Assessment Outcome was assessed based on remission after three cycles, hematologic event-free survival (hemEFS), and OS. Remissions were determined according to consensus criteria for very good partial remission (VGPR).16 Early deaths were counted as remission failures on an intent-to-treat-basis. For hemEFS, hematologic relapse, hematologic progression, start of a second-line therapy, and death were defined as events. iFISH CD138⫹ bone marrow plasma cells were purified by automagneticactivated cell sorting with CD138 immunobeads. In the study period, the plasma cell yield was sufficient for iFISH in all punctured patients subsequently receiving Vel-Dex or CyBorD, although the material did not allow the full panel in all patients (Table 2). Controls to ensure plasma cell purity have been previously described in detail.14 Hybridization was performed with commercial two-color probe sets according to the manufacturer’s protocols (Kreatech, Amsterdam, the Netherlands and MetaSytems GmbH, Altlussheim, Ger-

Table 2. Baseline Cytogenetic Parameters of the Vel-Dex and the CyBorD Cohorts Vel-Dex Cohort (n ⫽ 101)


many), and a minimum of 100 interphase nuclei per probe were evaluated using a DM RXA fluorescence microscope (Leica, Wetzlar, Germany) or an automated FISH spot counting system (Applied Spectral Imaging, EdingenNeckarhausen, Germany). Similar to previous studies, the threshold was homogeneously set at 10% for gains, losses, and translocations. In analogy to MM t(4;14), t(14;16) and deletion 17p13 were subsumed as high-risk aberrations. For hyperdiploidy classification, we used the score of Wuilleme et al,17 which requires trisomies of at least two of the following three chromosomes: 5, 9, and 15. Statistical Analysis Pairwise comparisons of clinical and hematologic factors with respect to chromosomal aberrations were performed using Wilcoxon rank sum test for continuous factors and Fisher’s exact test for categorical factors. Remission rates for chromosomal subgroups were compared using Fisher’s exact test. Survival distributions of OS and hemEFS were estimated using the Kaplan-Meier method and compared using the log-rank test. When comparing two groups of patients, the P values of the corresponding log-rank tests are reported. Median follow-up time was estimated using the reverse KaplanMeier method.18 Multivariable analysis of OS and hemEFS was done using Cox regression models; for remission, we used a logistic regression model. For dFLC and N-terminal prohormone of brain natriuretic peptide (NTproBNP), the log-transformed values were used. For all end points, a complete case analysis (n ⫽ 90 patients) and an analysis on multiple imputed data (using chained equations with 20 imputed data sets) were performed. Analyzing multiply imputed data did not change the results; we present only the results of the complete case analysis. Backward variable selection based on P values (selection limit P ⫽ .5) was performed to identify a final prediction model for each end point. Each prediction model is characterized by a linear predictor, a weighted sum of selected model variables with the regression coefficients as weights. Prediction models were externally validated on the CyBorD population with respect to calibration and prediction performance following Royston and Altman.19 Calibration refers to the agreement between observed outcomes and predictions. The estimated calibration factor indicates the extent that predictions are systematically too low or too high. A factor smaller than 1 reflects overfitting of a model. Prediction performance was assessed via prediction error and R2 statistics. The prediction error was compared between the calibrated data models, including the linear predictor, and the null model describing the average outcome in CyBorD. For OS and hemEFS, prediction error was measured by the (integrated) Brier score.20,21 For remission, prediction error was measured as misclassification rates including 95% CIs. For all statistical tests, a significance level of 5% was used. The statistical analysis was performed using R version 2.15.3 and R package pec (www.r-project.org).

Cytogenetic Parameter

No./Total No.

%

No./Total No.

%

t(11;14) IgH translocation with unknown partner Deletion of 13q14 Gain of 1q21 Hyperdiploidyⴱ Gain of 5p15/5q35 Gain of 9q34 Gain of 15q22 Gain of 19q13 High-risk aberrations† t(4;14) t(14;16) Deletion of 17p13

64/101

63

19/32

59

RESULTS

12/101 34/101 27/98 19/95 13/91 28/96 19/91 17/92 13/98 3/101 5/100 6/99

12 34 28 20 14 29 21 18 13 3 5 6

6/32 9/32 8/32 5/30 4/30 7/30 3/30 5/29 2/32 2/32 0/32 0/32

19 28 25 17 13 23 10 17 6 6 0 0

HemEFS in the Vel-Dex Cohort The median hemEFS time in the Vel-Dex cohort was 4.7 months (95% CI, 3.5 to 7.0 months), with a median follow-up of 24.0 months and hematologic events in 84 of 101 patients. The t(11;14)-positive group displayed an inferior median hemEFS of 3.4 months compared with 8.8 months in the t(11;14)-negative group (P ⫽ .002; median follow-up, 22.2 v 25.4 months, respectively; Fig 1A). The median hemEFS in the high-risk group was 10.3 months compared with 3.9 months in the patients with non– high-risk aberrations, although statistical significance was not reached (P ⫽ .15; median follow-up, 25.4 v 24.0 months, respectively; Fig 1C). No statistically significant differences regarding hemEFS in the Vel-Dex cohort were observed for deletion of 13q14 (median, 4.7 months; P ⫽ .14), gain of 1q21 (median, 7.5 months; P ⫽ .75), hyperdiploidy (median, 7.4 months; P ⫽ .61), and IgH translocation with an unknown partner (median, 4.1 months; P ⫽ .35).

Abbreviations: CyBorD, cyclophosphamide, bortezomib, and dexamethasone; IgH, immunoglobulin H; Vel-Dex, bortezomib-dexamethasone. ⴱ Hyperdiploidy is defined by the detection of at least two of the following three trisomies: gain of 5p15/5q35, gain of 9q34, and gain of 15q22, according to Wuilleme et al.17 †High risk is defined by the detection of t(4;14) or t(14;16) or deletion of 17p13.

www.jco.org



1373

Bochtler et al

B

Event-Free Survival (%)

100

P = .002

80

60

40

20

0

100

t(11;14) No t(11;14)

Overall Survival (%)

A

12

24

36

48

60

t(11;14) No t(11;14) P = .05

80

60

40

20

0

12

Time (months)

D


100

P = .15

60

40

20

12

24

36

48

60

100

High risk No high risk

80

0

36

Time (months)

48

60

Time (months)


C

24

High risk No high risk P = .04

80

60

40

20

0

12

24

36

48

60

Time (months)

Fig 1. Hematologic event-free survival and overall survival in the bortezomib-dexamethasone cohort according to (A and B) t(11;14) and (C and D) t(4;14), t(14;16), and del(17p) subsumed as high-risk aberrations.

OS in the Vel-Dex Cohort The median OS time in the Vel-Dex cohort was 15.7 months (95% CI, 8.2 months to not reached), with a median follow-up time of 24.1 months and 53 observed deaths. Detection of t(11;14) again predicted for a shorter OS (median OS, 8.7 v 40.7 months in the t(11;14)-positive and -negative groups, respectively; P ⫽ .05; median follow-up, 22.2 v 27.0 months, respectively; Fig 1B), whereas high-risk aberrations conferred a favorable prognosis (median OS, not reached for high-risk aberrations v 10.6 months for absence of high-risk aberrations; P ⫽ .04; median follow-up, 11.5 v 24.1 months, respectively; Fig 1D). A statistically significant effect was not observed in any of the other cytogenetic groups; median OS was 35.5 months in deletion 13q14 (P ⫽ .56), 15.7 months in gain of 1q21 (P ⫽ .82), 15.7 months in hyperdiploidy (P ⫽ .83), and 8.2 months in IgH translocation with an unknown partner (P ⫽ .19). Remission Rates in the Vel-Dex Cohort In the Vel-Dex cohort, 95 (94%) of 101 patients displayed an initial dFLC greater than 50 mg/L and were thus evaluable for the ⱖ VGPR criterion. Among these 95 patients, 30 (32%) attained ⱖ VGPR after three cycles, 24 (25%) attained a partial response, and 21 (22%) did not achieve remission. Another 20 patients (21%) suffered early death before remission assessment. 1374


Markedly, ⱖ VGPR rates achieved by Vel-Dex were worse in t(11;14)-positive patients compared with t(11;14)-negative patients (14 [23%] of 61 patients v 16 [47%] of 34 patients, respectively; P ⫽ .02; Appendix Table A2, online only). Patients with high-risk aberrations displayed a favorable remission rate compared with patients without high-risk aberrations (eight [67%] of 12 patients v 21 [26%] of 80 patients, respectively; P ⫽ .008). All other cytogenetic aberrations were not prognostically significant for hematologic response, with response rates as follows: deletion of 13q14, 44% (14 of 32 patients; P ⫽ .10); gain of 1q21, 35% (nine of 26 patients; P ⫽ .80); hyperdiploidy, 42% (eight of 19 patients; P ⫽ .27); and IgH translocation with an unknown partner, 9% (one of 11 patients; P ⫽ .16). Multivariable Testing of Clinical and Cytogenetic Factors in the Vel-Dex Cohort In multivariable analysis of hemEFS, OS, and remission, we tested the major cytogenetic aberrations together with the relevant hematologic and clinical variables. In detail, age and sex were chosen as standard baseline parameters, light chain restriction (␬ v ␭) and dFLC as hematologic parameters, and NT-proBNP and Modified Diet in Renal Disease glomerular filtration rate as clinical parameters (for univariable results of these cofactors, see Appendix Table A3, online JOURNAL OF CLINICAL ONCOLOGY



Table 3. Results of Multivariable Cox Regression Models Analyzing Risk Factors for the Vel-Dex Cohort Hematologic Event-Free Survival

Overall Survival Variable

HR

95% CI

P

HR

95% CI

P

Ageⴱ Sex (male v female) Light chain (␬ v ␭) dFLC (log)† t(11;14) (positive v negative) Hyperdiploidy (positive v negative) Gain of 1q21 (positive v negative) High-risk aberration (positive v negative) NT-proBNP (log)† MDRD GFR† Dose reduction (yes v no)

1.03

0.74 to 1.44

.85

1.11

0.85 to 1.44

.44

1.23 1.20 1.81

0.64 to 2.38 0.55 to 2.60 1.13 to 2.90

.53 .64 .01

1.27 1.48 1.69

0.74 to 2.17 0.76 to 2.86 1.17 to 2.45

.38 .25 .005

3.13

1.16 to 8.33

.03

2.94

1.37 to 6.25

.006

1.58

0.61 to 4.09

.35

1.22

0.54 to 2.73

.63

1.76

0.83 to 3.72

.14

1.56

0.84 to 2.93

.16

0.55 2.07 1.14

0.15 to 1.97 1.18 to 3.63 0.65 to 2.00

.36 .01 .66

0.70 1.39 1.14

0.28 to 1.72 0.95 to 2.06 0.77 to 1.69

.43 .09 .51

1.30

0.47 to 3.59

.62

1.93

0.81 to 4.61

.14

NOTE. NT-proBNP was given priority over the New York Heart Association and Mayo staging scores, which were less discriminating in our cohort as a result of its poor-risk features, with, for example, two thirds of patients displaying Mayo stage III. Missing data were not replaced; thus, the analysis is based on 90 of 101 patients with a full data set. Abbreviations: dFLC, difference in free light chains; HR, hazard ratio; MDRD GFR, Modified Diet in Renal Disease glomerular filtration rate; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; Vel-Dex, bortezomib-dexamethasone. ⴱ For age, a 10-year change is used as characteristic effect to determine the HR. †For other continuous variables, HRs were computed for the difference between upper and lower quartiles.

only). Dose reductions were also included to account for the negative selection and possibly reduced efficacy. In the full Cox regression models, t(11;14) and dFLC emerged as the only two statistically significant prognostic markers for both OS and hemEFS (Table 3). NT-proBNP also reached statistical significance for OS. Thus, this multivariable model establishes t(11;14) as an independent risk factor in the Vel-Dex–treated cohort. High-risk cy-

A

100



Validation and Calibration of Results in the CyBorD Cohort In the CyBorD validation cohort, the ⱖ VGPR rate after three cycles was 24% (four of 17 patients) in t(11;14)-positive patients compared with 80% (eight of 10 patients) in t(11;14)-negative patients. Median hemEFS was 5.7 months in all 32 patients, 4.0 months in t(11;14)-positive patients, and not reached in t(11;14)-negative patients (P ⫽ .01; Fig 2A). Median OS for both groups has not been reached (Fig 2B). The median follow-up was 7.5 months. Calibration analysis of the final models was performed on the CyBorD validation cohort. The regression coefficients of the corresponding linear predictors serve as calibration factors. The calibration factors for hemEFS and OS were obtained as 1.02 and 0.58, respectively, which reflect possible overfitting in Vel-Dex for OS. However, this effect was not statistically significant (hemEFS, P ⫽ .49; OS, P ⫽ .21). The prediction error curves (hemEFS, R2 ⫽ 0.079; OS, R2 ⫽ 0.070) show better performance for the trained predictors compared with the average survival probabilities (Kaplan-Meier reference; Figs 3A and 3B). For remission, the misclassification error for the trained predictor was lower (error rate, 37.0%; 95% CI, 19.4% to 57.6%) than the average effect (error rate, 44.4%; 95% CI, 25.5% to 64.7%). In

B

100

80

60

40

20

togenetics displayed favorable estimated hazard ratios of 0.55 and 0.36, but CIs were large as a result of the rarity of these high-risk aberrations in AL amyloidosis (n ⫽ 13 in Vel-Dex), and statistical significance was accordingly missed. In the multivariable logistic regression analysis of remission, the effects of t(11;14) and high-risk cytogenetics were not significant (P ⫽ .22 and P ⫽ .17, respectively), with older age being a significant risk factor in this analysis (P ⫽ .05). A backward variable selection was performed to derive a final model for each outcome. Each final model was then characterized by a linear predictor, a weighted sum of selected model variables. For hemEFS, the selected linear predictor consists of t(11;14) and the variables sex, dFLC, NT-proBNP, and dose reduction (with the regression coefficients as weights, 0.88, ⫺0.36, 0.34, 0.22, and 0.72, respectively). For OS, the selected predictor includes t(11;14) and the variables dFLC and NTproBNP (weights, 0.61, 0.39, and 0.42, respectively). The linear predictor for outcome remission ⱖ VGPR was obtained using a combination of t(11;14) and age (weights, ⫺1.2344 and ⫺0.0762, respectively). The final models were externally validated on the CyBorD cohort.

t(11;14) No t(11;14)

80

60

40

20

P = .01

0

t(11;14) No t(11;14) P = .71

3

6

Time (months)

9

12

0

3

6

9

12

15

Time (months)

Fig 2. (A) Hematologic event-free survival and (B) overall survival in the cyclophosphamide, bortezomib, and dexamethasone cohort according to t(11;14). www.jco.org



1375

Bochtler et al

Prediction Error—HemEFS

0.30

B

0.25 0.20 0.15 0.10 0.05

0

0.30

Average effect Trained predictor

Prediction Error—OS

A

1

2

3

4

5

6

Time (months)

Average effect Trained predictor

0.25 0.20 0.15 0.10 0.05

0

2

4

6

8

10

12

Time (months)

Fig 3. Prediction error curves for (A) hematologic event-free survival (hemEFS) and (B) overall survival (OS) in the cyclophosphamide, bortezomib, and dexamethasone cohort. The panels show the results for the null model (Kaplan-Meier estimate, depicting the average effect in the population) and the Cox model using the linear predictor derived from the bortezomib-dexamethasone cohort.

total, all trained predictors showed a trend for better prediction of the outcome in the CyBorD validation cohort. DISCUSSION

In this study, cytogenetic aberrations as detected by iFISH predicted response to bortezomib-based first-line therapy. Markedly, t(11;14), which is the most prevalent cytogenetic aberration in AL amyloidosis13,14,22-24 with 62% positive patients in this study, carried a poorer prognosis. In the Vel-Dex cohort, the adverse prognostic effect was most pronounced for hemEFS; this also translated into poorer OS. In multivariable regression analysis for hemEFS and OS, although not for remission, t(11;14) was confirmed as a statistically significant independent risk factor along with dFLC and NT-proBNP. Thus, multivariable analysis recapitulates and confirms established risk models, where high circulating amyloidogenic light chains and an advanced cardiac involvement weigh in as the most severe risk factors,11 but broadens these models now by iFISH aberrations. Finally, we confirmed the negative effect of t(11;14) in our CyBorD validation cohort, which recruited somewhat younger and fitter patients with better renal function. Although the CyBorD cohort was smaller and had a shorter follow-up, we observed a strong discriminating effect of t(11; 14) in univariable analysis. Furthermore, the multivariable predictors trained on the Vel-Dex cohort showed in the CyBorD cohort a trend forimprovedpredictionoftheoutcomecomparedwiththeaverageeffect. At first look, the poorer prognosis of t(11;14)-positive patients is surprising given the trend for a slightly improved OS for the t(11;14)positive group when treated with M-Dex at our center.25 Markedly, two other amyloidosis studies, which did not stratify for treatment, reported an inferior prognosis for patients with t(11;14) or with the respective overexpression of cyclin D1.24,26 Thus, it seems that t(11; 14), although associated with an indolent nature24 and not a risk factor by itself, confers a poor susceptibility to bortezomib. Possibly, this poor susceptibility of t(11;14)-positive plasma cells to proteasome inhibition could be inherent to all plasma cell dyscrasias. The large myeloma trials establishing the intermediate to favorable prognosis of t(11;14) in MM were performed in the era before the broad application of novel agents like bortezomib.27,28 Some recent 1376


trials in MM incorporating bortezomib treatment have indeed hinted at a poorer response of t(11;14)-positive myelomas.14,29-33 However, because in MM bortezomib is now typically given in combination therapies or as induction,32,34,35 it is hard to discern the contribution of individual substances to response. In this respect, AL amyloidosis, where the severity of organ involvement often precludes combination chemotherapy, can serve as a model for all plasma cell dyscrasias to discern the efficacy of individual substances. In MM, there is a broad consensus to offer patients with high-risk aberrations harboring t(4;14), t(14;16), or del(17p) a bortezomibcontaining regimen.36 In these cytogenetic entities, bortezomib has repeatedly been shown to alleviate, if not overcome, the adverse prognosis inherent to these cytogenetic entities.32,35,37-43 In tune with these results, our study showed no adverse prognosis for high-risk aberrations. Therefore, these patients with high-risk aberrations should be considered for bortezomib treatment in first-line therapy. In addition, bortezomib could also overcome the adverse prognosis of gain of 1q21, which is another known risk factor in MM44 and in AL amyloidosis in the context of M-Dex therapy.25 In AL amyloidosis, bortezomib-based regimens are typically offered to patients with severe cardiac insufficiency, threatening renal failure, or high involved serum free light chains, who urgently require a rapid remission and who benefit less from M-Dex.45 In our study population, these poor-risk features are reflected by 65% of patients with a Mayo risk score of 311 and 69% of patients with a dFLC greater than the published 180 mg/L cutoff. The median OS of 10.3 months for our Vel-Dex Mayo stage III group closely corresponded to other studies,46,47 suggesting that our study population is comparable to bortezomib-treated patient groups at other centers. Inconclusion,cytogeneticaberrationsasdetectedbyiFISHareprognostically significant factors in patients treated with bortezomib. t(11;14)positive patients responded less to bortezomib, whereas patients with high-riskaberrationsbenefitedfromthistreatment.Markedly,thereverse situation occurred in our recently published M-Dex cohort, which also included mostly patients with advanced amyloidosis.25 The different outcomes between the M-Dex and Vel-Dex cohorts highlight that the prognostic impact of cytogenetic markers largely depends on the administered therapy and should therefore be judged only in the context of a JOURNAL OF CLINICAL ONCOLOGY



specific therapy. Thus, t(11;14) should only be regarded as a predictor of poorresponsetobortezomib,butnotasanadverseprognosticmarkerper se. Pending the confirmation by other groups, the discrepant response of the distinct cytogenetic categories to different therapy regimens offers the prospect to better individualize therapy for these critically ill patients and to assign patients to treatment protocols depending on the genetic signature of the underlying plasma cell dyscrasia. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.

REFERENCES 1. Dubrey SW, Reece DE, Sanchorawala V, et al: Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: Cardiac responses and overall effects. QJM 104:957-970, 2011 2. Reece DE, Hegenbart U, Sanchorawala V, et al: Efficacy and safety of once-weekly and twiceweekly bortezomib in patients with relapsed systemic AL amyloidosis: Results of a phase 1/2 study. Blood 118:865-873, 2011 3. Kastritis E, Anagnostopoulos A, Roussou M, et al: Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 92:1351-1358, 2007 4. Wechalekar AD, Lachmann HJ, Offer M, et al: Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica 93:295-298, 2008 5. Kastritis E, Wechalekar AD, Dimopoulos MA, et al: Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 28:1031-1037, 2010 6. Dimopoulos MA, Kastritis E: Bortezomib for AL amyloidosis: Moving forward. Blood 118:827828, 2011 7. Venner CP, Lane T, Foard D, et al: Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 119:4387-4390, 2012 8. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al: Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 119: 4391-4394, 2012 9. Bochtler T, Hegenbart U, Heiss C, et al: Evaluation of the serum-free light chain test in untreated patients with AL amyloidosis. Haematologica 93:459-462, 2008 10. Kumar S, Dispenzieri A, Katzmann JA, et al: Serum immunoglobulin free light-chain measurement in primary amyloidosis: Prognostic value and correlations with clinical features. Blood 116:51265129, 2010 11. Kumar S, Dispenzieri A, Lacy MQ, et al: Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 30:989-995, 2012 12. Fonseca R, Barlogie B, Bataille R, et al: Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 64:1546-1558, 2004 www.jco.org

AUTHOR CONTRIBUTIONS Conception and design: Tilmann Bochtler, Ute Hegenbart, Stefan O. Schönland Provision of study materials or patients: Tilmann Bochtler, Anja Seckinger, Christoph Kimmich, Stefan O. Schönland Collection and assembly of data: Tilmann Bochtler, Ute Hegenbart, Anja Seckinger, Christoph Kimmich, Dirk Hose, Anna Jauch, Stefan O. Schönland Data analysis and interpretation: Tilmann Bochtler, Ute Hegenbart, Christina Kunz, Martin Granzow, Axel Benner, Anja Seckinger, Hartmut Goldschmidt, Anthony D. Ho, Dirk Hose, Anna Jauch, Stefan O. Schönland Manuscript writing: All authors Final approval of manuscript: All authors

13. Bochtler T, Hegenbart U, Cremer FW, et al: Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability. Blood 111:4700-4705, 2008 14. Bochtler T, Hegenbart U, Heiss C, et al: Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14). Blood 117:3809-3815, 2011 15. Palladini G, Milani P, Foli A, et al: Treatment of AL amyloidosis with bortezomib combined with alkylating agents: Results from a prospective series of unselected patients. Blood 118:3977, 2011 (abstr) 16. Palladini G, Dispenzieri A, Gertz MA, 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. J Clin Oncol 30:4541-4549, 2012 17. Wuilleme S, Robillard N, Lodé L, et al: Ploidy, as detected by fluorescence in situ hybridization, defines different subgroups in multiple myeloma. Leukemia 19:275-278, 2005 18. Schemper M, Smith TL: A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343-346, 1996 19. Royston R, Altman D: External validation of a Cox prognostic model: Principle and methods. BMC Med Res Methodol 13:1-15, 2013 20. Graf E, Schmoor C, Sauerbrei W, et al: Assessment and comparison of prognostic classification schemes for survival data. Stat Med 18:2529-2545, 30. 1999 21. Gerds TA, Cai T, Schumacher M: The performance of risk prediction models. Biom J 50:457479, 2008 22. Hayman SR, Bailey RJ, Jalal SM, et al: Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood 98:22662268, 2001 23. Harrison CJ, Mazzullo H, Ross FM, et al: Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis. Br J Haematol 117:427-435, 2002 24. Bryce AH, Ketterling RP, Gertz MA, et al: Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 94:380386, 2009 25. Bochtler T, Hegenbart U, Kunz C, et al: Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients

treated with melphalan/dexamethasone. Amyloid 21:9-17, 2014 26. Zhou P, Hoffman J, Landau H, et al: Clonal plasma cell pathophysiology and clinical features of disease are linked to clonal plasma cell expression of cyclin D1 in systemic light-chain amyloidosis. Clin Lymphoma Myeloma Leuk 12:49-58, 2012 27. Moreau P, Facon T, Leleu X, et al: Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100:1579-1583, 2002 28. Gertz MA, Lacy MQ, Dispenzieri A, et al: Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with highdose therapy. Blood 106:2837-2840, 2005 29. Sasaki K, Lu G, Saliba RM, et al: Impact of t(11;14)(q13;q32) on the outcome of autologous hematopoietic cell transplantation in multiple myeloma. Biol Blood Marrow Transplant 19:1227-1232, 2013 30. An G, Xu Y, Shi L, et al: T(11;14) multiple myeloma: A subtype associated with distinct immunological features, immunophenotypic characteristics but divergent outcome. Leuk Res 37:1251-1257, 2013 31. Chang H, Trieu Y, Qi X, et al: Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 31:779-782, 2007 32. Mateos MV, Gutiérrez NC, Martin-Ramos ML, et al: Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood 118:4547-4553, 2011 33. Tan D, Teoh G, Lau LC, et al: An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era. Am J Hematol 85:752-756, 2010 34. San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906-917, 2008 35. Neben K, Lokhorst HM, Jauch A, et al: Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 119:940-948, 2012 36. Chesi M, Bergsagel PL: Molecular pathogenesis of multiple myeloma: Basic and clinical updates. Int J Hematol 97:313-323, 2013 37. Cavo M, Tacchetti P, Patriarca F, et al: Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in



1377

Bochtler et al

newly diagnosed multiple myeloma: A randomised phase 3 study. Lancet 376:2075-2085, 2010 38. Harousseau JL, Attal M, Avet-Loiseau H, et al: Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: Results of the IFM 2005-01 phase III trial. J Clin Oncol 28:4621-4629, 2010 39. Mateos MV, Oriol A, Martinez-López J, et al: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: A randomised trial. Lancet Oncol 11:934-941, 2010 40. Kapoor P, Rajkumar SV: Update on risk stratification and treatment of newly diagnosed multiple myeloma. Int J Hematol 94:310-320, 2011

41. Avet-Loiseau H, Leleu X, Roussel M, et al: Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28:4630-4634, 2010 42. Moreau P, Avet-Loiseau H, Facon T, et al: Bortezomib plus dexamethasone versus reduceddose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 118:5752-5758, 2011 43. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al: Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: Results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 30:29462955, 2012 44. Hanamura I, Stewart JP, Huang Y, et al: Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridiza-

tion: Incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 108:1724-1732, 2006 45. Palladini G, Milani P, Foli A, et al: Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: Long-term results of a risk-adapted approach. Haematologica 99:743750, 2014 46. Wechalekar AD, Schonland SO, Kastritis E, et al: A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 121:3420-3427, 2013 47. Palladini G, Barassi A, Klersy C, et al: The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood 116:3426-3430, 2010

■ ■ ■

Order the ASCO Answers Palliative Care Booklet for Patients and Their Families Cancer and its treatment often cause discomfort and challenges that greatly affect a person’s life and well-being. Cancer.Net’s ASCO Answers Palliative Care Booklet contains trusted information on how palliative care is used to manage symptoms and side effects, how to provide support to family, friends, and caregivers, how to access palliative care services, and more. Order the booklet in quantities of 125 for your practice at cancer.net/estore.

1378





AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With BortezomibBased Regimens The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Tilmann Bochtler Travel, Accommodations, Expenses: Teva Ute Hegenbart Honoraria: Janssen, Binding Site Travel, Accommodations, Expenses: Pfizer, Janssen Christina Kunz No relationship to disclose Martin Granzow No relationship to disclose Axel Benner Research Funding: Bayer Health Care Anja Seckinger No relationship to disclose Christoph Kimmich No relationship to disclose

Speakers’ Bureau: Janssen, Celgene, Novartis, Chugai, Onyx, Millennium Research Funding: Janssen (Inst), Celgene (Inst), Novartis (Inst), Chugai (Inst) Anthony D. Ho Consulting or Advisory Role: Genzyme, Sanofi Dirk Hose Honoraria: Celgene Consulting or Advisory Role: Celgene Research Funding: Celgene, Novartis, Merck Anna Jauch No relationship to disclose Stefan O. Schönland Honoraria: Janssen Research Funding: Janssen, Celgene Travel, Accommodations, Expenses: Celgene, Janssen, Medac, Fresenius

Hartmut Goldschmidt Consulting or Advisory Role: Janssen (Inst), Celgene (Inst), Novartis (Inst), Onyx (Inst), Millennium (Inst)

www.jco.org



Bochtler et al

Acknowledgment We thank Rita Ziehl for excellent data management. Appendix

Table A1. Distribution of Hematologic and Clinical Parameters in the Vel-Dex Cohort According to the t(11;14) and High-Risk Cytogenetic Subgroups t(11;14) Parameter Age, years Median Range Sex, No. of patents Male Female BM plasmacytosis, % Median Range Plasma cell dyscrasia, No. of patients AL AL ⫹ MM I Light chain, No. of patients ␬ ␭ dFLC, mg/L Median Range Intact immunoglobulin, No. of patients No Yes No. of organs Median Range Mayo score, No. of patients 1 2 3 ND NT-proBNP, ng/L Median Range MDRD GFR, mL/min Median Range Dose, No. of patients Full Reduced ND

Yes (n ⫽ 64)

No (n ⫽ 37)

59 42-77

63 36-77

39 25

21 16

12 2-41

12 3-57

60 4

28 9

16 48

5 32

362 8-7,554

264 0-4,270

51 13

10 27

3 1-5

3 1-5

5 15 42 2

5 9 22 1

8,371 66-565,442

7,045 40-58,660

63 ⬍ 10-138

60 17-166

56 6 2

32 5 0

High Risk P

Yes (n ⫽ 13)

No (n ⫽ 85)

63 42-77

61 36-77

4 9

56 29

10 3-40

12 2-57

10 3

75 10

1 12

65 20

248 44-4,270

328 0-7,554

6 7

54 31

3 1-4

3 1-5

1 3 8 1

9 21 53 2

8,683 289-58,660

7,073 40-565,442

58 21-91

63 ⬍ 10-166

11 1 1

75 9 1

.37

P 1.0

.68

.03

.92

.36

.01

.37

.21

.29

.19

.36

⬍ .001

.24

.74

.99

.66

1.0

.45

.79

.74

.58

.74

1.0

NOTE. Regarding the relevant factors of age, BM plasmacytosis, light chain restriction, dFLC, organ number, Mayo stage, NT-proBNP, MDRD GFR, and dose-intensity, the cytogenetic groups were well balanced. Reported are P values of Fisher’s exact tests (categorical factors) or of Wilcoxon tests (continuous factors). P values were not adjusted for multiple testing to avoid concealing imbalances between the groups. Abbreviations: BM, bone marrow; dFLC, difference in free light chains; MDRD GFR, Modified Diet in Renal Disease glomerular filtration rate; MM, multiple myeloma; ND, not determined; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; Vel-Dex, bortezomib-dexamethasone.





Table A2. Remission Rates Based on Consensus Criteria for VGPR in the Vel-Dex Cohort Vel-Dex Cohort (n ⫽ 95) VGPR

No VGPR

Early Death

Cytogenetics

No./Total No.

%

No./Total No.

%

No./Total No.

%

All patients t(11;14) Positive Negative Deletion of 13q14 Yes No Hyperdiploidy Yes No Gain of 1q21 Yes No High risk Yes No IgH unknown Yes No

30/95

32

45/95

47

20/95

21

14/61 16/34

23 47

33/61 12/34

54 35

14/61 6/34

23 18

14/32 16/63

44 25

10/32 35/63

31 56

8/32 12/63

25 19

8/19 20/71

42 28

6/19 36/71

32 51

5/19 15/71

26 21

9/26 20/67

35 30

13/26 31/67

50 46

4/26 16/67

15 24

8/12 21/80

67 26

3/12 40/80

25 50

1/12 19/80

8 24

1/11 29/84

9 35

7/11 38/84

64 45

3/11 17/84

27 20

P .02

.10

.27

.80

.008

.16

NOTE. On an intent-to-treat basis, patient cases of early death before remission assessment are listed and counted as remission failures in statistical analysis. Reported are P values of Fisher’s exact tests (categorical factors) or of Wilcoxon rank sum tests (continuous factors). Translocation t(11;14) is associated with inferior remission prospects, whereas high-risk aberrations confer improved remission prospects. Abbreviations: IgH, immunoglobulin H; Vel-Dex, bortezomib-dexamethasone; VGPR, very good partial remission.

www.jco.org



Bochtler et al

Table A3. Exploratory Univariable Analysis of Hematologic and Clinical Parameters in the Vel-Dex Cohort Overall Survival Parameter Baseline Age (higher age) Sex Male Female Hematologic Light chain restriction ␬ ␭ dFLC, continuous (log) dFLC, mg/mL ⱖ 180 ⬍ 180 Bone marrow plasmacytosis (higher plasmacytosis) Clinical Organ number (more involved organs) NYHA stage (higher NYHA stage) Mayo score 3 1⫹2 Higher NT-proBNP Lower MDRD GFR Therapy dosage Bortezomib and dexamethasone dose Full Reduced

Median (months)

Hematologic Event-Free Survival P

Median (months)

.17 .38 8.8 35.5

.15 .52 4.7 4.0

.32 7.4 18.5

.05 2.9 5.0

.001 .003 8.4 Not reached

.001 .004 3.8 7.4

.04

.05

.03 ⬍ .001 .04

.25 ⬍ .001 .07

10.3 Not reached

3.9 5.1 ⬍ .001 .13

.001 .31

.42 15.7 4.0

P

.04 4.8 2.2

NOTE. Reported are the P values of logrank tests (categorical factors) or of score tests (continuous factors). Given the exploratory character of the analysis, P values are not adjusted for multiple testing. Abbreviations: dFLC, difference in free light chains; MDRD GFR, Modified Diet in Renal Disease glomerular filtration rate; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; Vel-Dex, bortezomib-dexamethasone.


