Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry

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Journal of the Formosan Medical Association (2018) xx, 1e10

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

Original Article

Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry Tzu-Chuan Huang a, Shang-Yi Huang b, Ming Yao b, Chen-Yuan Lin c, Wen-Li Hwang d, Jyh-Pyng Gau e, Tran-Der Tan f, Po-Nan Wang g, Yi-Chang Liu h,i, Shih-Chiang Lin j, Ruey-Ho Kao k, Sung-Nan Pei l, Ming-Sun Yu m, Hsuan-Yu Lin n, Yung-Cheng Su o, Chih-Cheng Chen p,q, Sin-Syue Li r, Yi-Ying Wu a,* a Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan b Hematology-Oncology Section, National Taiwan University Hospital, Taipei, Taiwan c Division of Hematology and Oncology, Department of Medicine, China Medical University Hospital, Taiwan d Division of Hematology/Medical Oncology, Taichung Veterans General Hospital, Taiwan e Division of Hematology, Taipei Veterans General Hospital, National Yang-Ming University, Taiwan f Department of Hematology and Medical Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taiwan g Division of Hematology, Chang Gung Medical Foundation, Linkou Branch, Taiwan h Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan i Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan j Division of Oncology-Hematology, Far Eastern Memorial Hospital, Taiwan k Department of Hematology and Oncology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan l Kaohsiung Chang-Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan m Hematology/Oncology Division, Dept. of Medicine Veterans General Hospital, Kaohsiung, Taiwan n Changhua Christian Hospital, Internal Medicine Department, Hematology and Oncology Division, Taiwan o Division of Hemato-Oncology, Taipei Medical University-Shuang Ho Hospital, Taiwan p Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan

https://doi.org/10.1016/j.jfma.2018.07.020 0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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T.-C. Huang et al. College of Medicine, Chang Gung University, Tao-Yuan, Taiwan Division of Hematology/Oncology, National Cheng Kung University Hospital, Tainan, Taiwan

Received 7 November 2017; received in revised form 1 June 2018; accepted 26 July 2018

KEYWORDS Multiple myeloma; Transplantation; Survival

Background/Purpose: Multiple myeloma (MM) is a monoclonal plasma cell malignancy. The primary choice of treatment for MM is induction therapy followed by autologous stem cell transplantation (ASCT). This study aimed to analyze the treatment efficacy of ASCT in a Taiwanese cohort and evaluate possible prognostic factors. Methods: From the database of the Taiwan Blood and Marrow Transplantation registry, data on 396 patients with MM who underwent ASCT were reviewed. Results: The average age of participants was 54.8 years, and there were more men than women (57.6% vs. 42.4%). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). Patients with Durie Salmon Staging System (DSS) III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 46.5 months and 70.4 months, respectively. DSS III was a poor prognostic factor affecting both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages (p Z 0.006 and p Z 0.03, respectively). In addition, patients with better treatment response before ASCT had better PFS and OS compared with those who did not show a response (both p < 0.0001). The overall incidence of organ toxicities associated with transplantation was low. Conclusion: In conclusion, our cohort showed that myeloma patients with early DSS and better treatment response before ASCT had better long-term survival outcomes. Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction Multiple myeloma (MM) is caused by the abnormal proliferation of neoplastic plasma cells in the bone marrow, which results in complications such as renal failure, pathological fractures, cytopenia, and end organ damage. Using data gathered between 1997 and 2013 in a Taiwanese nationwide database, Chen et al. reported an increase in the incidence of MM from 0.75 to 1.83 per 100,000 people, lower than that reported for Western countries.1 At the same time, the average mortality rate gradually decreased from 0.59 to 0.44 per 100,000 cases.1,2 The mean age at diagnosis was 68.71 years, and the proportion of male patients was higher than that of female patients (59.90%).1 Before the development of novel agents in the 2000s, including immunomodulatory drugs (IMiDs) and proteasome inhibitors, the melphalan-prednisolone (MP) regimen was the standard therapeutic modality for MM, particularly in elderly patients and those in fragile health. No survival benefit was gained from adding additional alkylating agents to the MP regimen.3 Since the 1990s, several studies have reported that high-dose consolidation therapy (HDT) followed by autologous stem cell transplantation (ASCT) significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with conventional chemotherapy in patients with newly diagnosed MM.3e6 Furthermore, a meta-analysis of nine trials concluded that HDT

plus ASCT achieved a high depth of response and low risk of progression or death. A minimal but statistically significant survival benefit was noted in this analysis.7 In the setting of lenalidomide combination therapy for induction, consolidation, and maintenance, a phase 3 trial showed that consolidation therapy with high-dose melphalan plus ASCT resulted in longer median PFS and OS than melphalanprednisone-lenalidomide in patients younger than 65 years (43.0 months vs. 22.4 months, p < 0.001; 4-year OS, 81.6% vs. 65.3%, p Z 0.02, respectively).6 For many years, the vincristine-doxorubicin-dexamethasone (VAD) regimen was the standard combination for induction chemotherapy prior to ASCT. However, the VAD regimen is no longer used because induction therapy combined with IMiDs (thalidomide, lenalidomide) and/or proteasome inhibitors (bortezomib) demonstrated better treatment response and outcomes, regardless of whether patients are eligible for ASCT or in the relapse or upfront setting.4,8 In addition, these novel agents can be used as consolidation and maintenance therapy to maintain better treatment response. Concerns regarding the best timing of ASCT (upfront vs. late) in the era of novel agents have therefore been raised.4 Although additional valid data are not yet available, induction therapy with novel agents followed by upfront HDT plus ASCT is still recommended and widely accepted in patients with MM eligible for transplantation. In Taiwan, at least 15 hospitals were performing hematopoietic stem cell transplantation (HSCT) by the end of

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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Autologous stem cell transplantation in multiple myeloma in Taiwan 2006. Based on a 2005 survey, 7% of patients undergoing transplantation were diagnosed with MM.9 To date, retrospective or prospective studies to evaluate the treatment outcomes of HSCT in Taiwan are limited. Therefore, the Taiwan Bone Marrow Transplant Registry (TBMTR) was established in 2006 to collect information regarding HSCT patients from all hospitals in Taiwan.10 The present retrospective study aimed to evaluate the demographic characteristics, treatment outcomes, and prognostic factors of patients with MM who underwent HDT plus a single ASCT and were included in the TBMTR database between October 2006 and June 2015.

Materials and methods Patients and study design Data on 423 patients with MM who underwent HDT plus a single ASCT between October 2006 and June 2015 in any of the participating hospitals were retrieved from the TBMTR database. MM accounted for 16.8% of all hematological malignancies treated with HSCT in the TBMTR database. A difficulty arose in the attempt to retrospectively retrieve and record all clinical information from different hospitals or medical charts; for example, 396 patients in the TBMTR database were classified using the Durie-Salmon Staging System (DSS),11 whereas 386 were classified according to the International Staging System (ISS).12 Therefore, we decided to include patients staged using the DSS rather than the ISS in order to obtain a larger study population for our cohort. Only patients treated with high-dose melphalan as the conditioning regimen for ASCT were enrolled. To minimize the bias resulting from heterogeneity and imperfect medical records of induction and/or salvage therapies prior to ASCT from the TBMTR database, we focused only on analysis of post-transplant survival outcomes and identification of important confounding factors. Clinical information collected included the following: age, sex, laboratory data, myeloma subtypes, doses of melphalan and CD34þ stem cells, post-transplant survival duration, neutrophil and platelet engraftment, causes of death, and any episodes of infection after ASCT conditioning therapies. The date of first disease progression following transplantation was recorded in the database. “Disease progression” in the TBMTR was defined as any clinical relapse event after transplantation, such as increase in immunoglobulin level, abnormal plasmacytosis in follow-up bone marrow biopsies, newly developed extramedullary or osteolytic bony lesions, and occurrence of pathological fractures. Treatment response before HDT plus ASCT was classified according to the International Myeloma Working Group criteria, including stringent complete response (stringent CR), complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD).13 The Charlson Comorbidity Index (CCI) was calculated to evaluate the confounding influence of comorbidities in our study population.14 Neutrophil engraftment after transplantation was defined as an absolute neutrophil count exceeding 500/mL for three consecutive days. Platelet engraftment was

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defined as the time required to achieve blood platelet counts exceeding 20,000/mL and 50,000/mL without transfusion support for seven consecutive days. Finally, major adverse events with organ damage within 100 days after ASCT were also documented. Analysis of TBMTR data was performed in accordance with the guidelines of the Helsinki Declaration and approved by the Human Subjects Protection Offices (IRB) of each participating institute.

Statistical analysis All descriptive data are expressed as mean  standard deviation. Student’s t-test and the Chi-square test were used to assess the differences among groups at different stages. OS and PFS after ASCT were estimated using the KaplaneMeier (KM) method, and differences in survival among groups were compared using the log-rank test. To investigate the factors associated with OS, univariate and multivariate Cox proportional hazard models were used. The results are presented as hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). All data analyses were performed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA).

Results Patient characteristics and treatment A total of 396 patients with MM were recruited in this study. The average age was 54.8  7.9 years, and there were more men than women (57.6% vs. 42.4%). The most common diagnosis was IgG-type myeloma (52.4%), followed by IgAtype (23.2%) and light-chain type (21.4%). Baseline characteristics, melphalan doses, infused CD34 þ stem cells, engraftment duration, and outcomes among the three groups classified according to the DSS are shown in Table 1. Patients with DSS III disease had the highest disease progression rate compared with patients with DSS I and II disease (41.4% vs. 16.4% and 26.9%, respectively, p < 0.0001). All patients achieved neutrophil engraftment in a median of 11 days. The median durations to platelet engraftment greater than 20,000/mL and 50,000/mL were 20 and 21 days, respectively. The clinical characteristics of 386 patients staged using the ISS were also analyzed, and the disease progression rate was not significantly higher in stage III than in stage I or II (p Z 0.757; Supplemental Table 1). In addition, there was no survival difference among the three groups based on ISS classification (Supplemental Figs. 1A and 1B).

Organ damage and mortality analysis Organ damage within 100 days after transplantation and causes of reported mortality are presented in Table 2. The overall incidence of organ toxicities, such as hepatic, renal, and pulmonary toxicities, was low. Of the 72 patients who died during the follow-up period, the most common cause of death was disease relapse/progression, followed by

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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T.-C. Huang et al. Table 1

Clinical characteristics of the three groups classified according to the Durie Salmon stage system.

Durie Salmon stage

1

2

3

Case number Age (years)

57 (14.4%) 54.0  6.6 (38e66) 32 25 8068  4989 12.8  1.9 259.0  105.0 208.6  92.7 3.8  1.1 6.5  3.4 1.3  1.6 3.5  2.2 31 8 1 0 16 3 15 14 20 3 0 150  55 6.1  3.4 9 46 27 30 23 34 11 20 22

94 (23.7%) 54.9  8.7 (16e70) 51 43 6491  2622 10.1  2.0 224.3  92.1 190.5  87.2 3.5  0.7 6.9  3.6 1.2  0.9 4.1  2.9 52 21 1 2 16 8 22 38 22 4 0 152  52 6.5  5.3 25 68 54 40 41 53 11 18 19

245 (61.9%) 55.0  7.9 (30e73) 145 100 6864  4375 9.1  2.3 198.9  99.4 242.9  232.6 3.4  0.8 8.4  3.4 1.7  2.9 6.4  5.3 123 62 2 6 52 18 53 82 63 11 6 151  50 5.8  4.8 99 140 145 100 109 135 10 20 22

Gender (n) White blood cell (uL) Hemoglobin (g/dL) Platelet (103/uL) LDH (U/L) Albumin (g/dL) Calcium (mg/dL) Creatinine (mg/dL) b2-microglobulin Subtype (n)

Pre-ASCT Status (n)

Melphalan dose (mg/m2) CD34 þ cells (10^6/Kg) Disease progression (n) Infection while Treatment (n) CCI  8 (n) CCI < 8 (n) Neu engraftment (days) PLT engraftment (days)

Male Female

IgG IgA IgM IgD Light chain sCR CR VGPR PR SD PD

Yes No Yes No

20 (103/uL) 50 (103/uL)

p value 0.714 0.694 0.090 <0.0001 <0.0001 0.167 0.024 <0.0001 0.219 0.015 0.554

0.517

0.975 0.503 <0.0001 0.267 0.839 0.316 0.633 0.202

LDH Z lactate dehydrogenase; ASCT Z autologous stem cell transplantation; sCR Z stringent complete response; CR Z complete response; VGPR Z very good partial response; PR Z partial response; SD Z stable disease; PD Z progressive disease; CCI Z charlson comorbidity index; Neu Z neutrophil; PLT Z platelet.

infection. Notably, the coexistence of both conditions was observed in 30 patients in the TBMTR database.

Impact of variable contributing factors on posttransplant survival outcome

Infection etiologies and sources after conditioning therapies for ASCT

The median duration from transplantation until myeloma progression was 46.5  5.0 months, and HDT plus ASCT followed by sequential therapies resulted in a median survival duration of 70.4 months. We analyzed post-transplant PFS using the KM method. Patients with DSS III disease had the shortest post-transplant PFS compared with those with stages I and II disease (35.9  6.1 months vs. not reached and 62.8 months, respectively; p Z 0.006). Patients whose MM was diagnosed from 2005 to 2009 (early era) also had shorter posttransplant PFS than those diagnosed from 2010 to 2015 (latter era) (32.5  6.0 months vs. not reached; p Z 0.006). The most significant factor affecting post-transplant PFS was treatment status before ASCT; we observed that patients without at least PR prior to ASCT experienced more rapid

Bloodstream infections, skin infections, mucositis, and pneumonia were the most frequently reported types of infections, as summarized in Table 3. Bacteria (50.1%) were the major leading causative pathogens, followed by viruses (42.8%). Of the viral species, cytomegalovirus (CMV) was commonly detected in the blood samples via antigen test or polymerase chain reaction, while the varicella zoster virus (VZV) was the most common cause of skin infections. Surprisingly, the incidence of herpes simplex virus (HSV)associated mucositis was relatively high after transplantation in our analysis (9.1%).

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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Autologous stem cell transplantation in multiple myeloma in Taiwan Table 2

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The summary of organ damage after transplant and mortality causes during the study period.

Organ damage within 100 days after transplant

Number

Interstitial pneumonitis Receive endotracheal intubation/mechanical ventilation Cirrhosis Congestive heart failure/pulmonary edema Hemorrhagic cystitis/hematuria (requiring medical intervention) Hemolytic anemia/thrombotic thrombocytopenia purpura Renal failure Acute hepatitis Gastrointestinal tract bleeding Skin Deep vein thrombosis

2 3 1 2 1 1 2 1 7 2 1

Main mortality causes recorded during follow-up

Number

Remark

Disease progression Infection Hemorrhage 2nd malignancy Others Unknown

55 37 2 2 2 4

(30 coexisted with infection)

Table 3

Remark

Acute hepatitis B

Intracranial/pulmonary hemorrhage S-colon cancer/Burkitt’s lymphoma HBV reactivation related liver failure/suicide

Any infectious episodes recorded after the conditioning therapies of transplantation.

Infection types

Pathogen

Episode numbers (n Z 507) n (%)

Blood stream

bacteria virus candida bacteria VZV bacteria HSV candida Influenza bacteria TB PJP Influenza candida bacteria candida CMV Clostridium NA NA bacteria bacteria HSV HSV bacteria HBV

108 (21.3%) 45 (8.9%) 5 (1.0%) 10 (2.0%) 95 (18.7%) 1 (0.2%) 46 (9.1%) 14 (2.8%) 7 (1.4%) 51 (10.1%) 3 (0.6%) 6 (1.2%) 2 (0.4%) 1 (0.2%) 6 (1.2%) 4 (0.8%) 1 (0.2%) 18 (3.6%) 3 (0.6%) 3 (0.6%) 30 (6.0%) 4 (0.8%) 2 (0.4%) 14 (2.8%) 23 (4.5%) 5 (1.0%)

Skin infection Osteomyelitis Mucositis Upper airway tract Pneumonia

Upper GI tract Colitis

Acute appendicitis Typhlitis Urinary tract infection Perianal abscess Genital region Catheter related Acute hepatitis

CMV: 41, EBV: 3, HSV: 1 Cellulitis

Influenza A: 6, Influenza B: 1

Esophagus candidiasis

All HBV reactivation

CMV Z cytomegalovirus; EBV Z EpsteineBarr virus; HSV Z human simplex TB Z mycobacterium tuberculosis; PJP Z pneumocystis jirovecii; NA Z not available.

disease progression after transplantation than those with good treatment response (PD: 7.4  4.3 months, SD: 18.6  5.2 months, PR: 43.3  4.4 months, VGPR: 40.6  4.9 months, CR: 75.6 months, stringent CR: not reached; p < 0.0001).

Remark

virus;

VZV

Z

Varicella-zoster

virus;

Using the KM method for post-transplant OS analysis, we also found that DSS III (69.0  5.2 months, p Z 0.03) and treatment status not reaching SD prior to ASCT were poor survival factors in our cohort. Patients with PD status had

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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worse survival compared to those with other response status (PD: 14.0  5.1 months, SD: 45.7  8.6 months, PR/CR/ stringent CR: not reached, VGPR: 70.4 months; p < 0.0001). Moreover, patients with any infection after conditioning therapies for ASCT also experienced shorter survival than those without any infection (70.4 months vs. not reached, p Z 0.013). Other variables, including sex, myeloma types, ISS, conditioning doses of melphalan, and CCI did not show statistically significant associations with OS or PFS (data not shown).

Cox regression analysis of post-transplant progression-free and overall survival The HRs from the univariate and multivariate Cox regression analyses of the association between each variable and survival are shown in Tables 4 and 5. Risk factors were defined as those associated with an HR greater than 1, whereas protective factors were those with an HR less than 1. Using univariate Cox regression models, we found

that age was a risk factor for disease progression after ASCT in our cohort. As a continuous variable, each increment of age correlated with a 2.7% increase of disease progression rate (p Z 0.021). DSS III (HR Z 2.8, CI Z 1.4e5.6, p Z 0.003), and treatment response of PD prior to ASCT (HR Z 6.6, CI Z 1.8e23.5, p Z 0.004) was also a risk factor. In contrast, MM diagnosed in the latter era was a protective factor for disease progression after transplantation compared with diagnosis earlier than 2010 (HR Z 0.6, CI Z 0.4e0.9, p Z 0.005). Analysis of the factors affecting post-transplant OS revealed that only two factors significantly influenced survival duration, namely, treatment status prior to ASCT (p < 0.0001) and infection after the conditioning therapies for ASCT (HR Z 2.127, CI Z 1.2e3.7, p Z 0.007). However, the post-transplant survival significance of DSS was only marginal (p Z 0.051); the HR for stage III disease is 4.241 compared with stage I (p Z 0.015). The multivariate Cox proportional hazards method was used to evaluate clinical factors associated with posttransplant PFS and OS. The stepwise approach using a

Table 4 The univariate and multivariate Cox regression analyses of the association between each variable and progression free survival after transplantation. Factors

Age Durie Salmon Stage

Diagnostic era Response before ASCT

Univariate

Stage I Stage II Stage III 2010e2015 sCR CR VGPR PR SD PD

Multivariate

HR

95% CI

p value

HR

95% CI

p value

1.027

1.004e1.051

1.030

1.004e1.058

2.106 2.804 0.604

0.982e4.519 1.416e5.552 0.426e0.856

2.311 2.652 0.382

1.059e5.043 1.321e5.325 0.252e0.579

0.839 0.972 1.252 2.159 6.577

0.341e2.061 0.413e2.286 0.529e2.964 0.767e6.078 1.841e23.506

0.021 0.008 0.056 0.003 0.005 0.002 0.702 0.949 0.610 0.145 0.004

0.604 0.722 0.91 2.388 6.259

0.092e1.257 0.059e0.548 0.076e0.653 0.075e0.657 0.093e1.147

0.023 0.023 0.035 0.006 <0.0001 <0.0001 0.289 0.468 0.836 0.110 0.006

HR Z hazard ratio; CI Z confidence interval; ASCT Z autologous stem cell transplantation; sCR Z stringent complete response; CR Z complete response; VGPR Z very good partial response; PR Z partial response; SD Z stable disease; PD Z progressive disease.

Table 5 The univariate and multivariate Cox regression analyses of the association between each variable and overall survival after transplantation. Factors

Durie Salmon Stage

Response before ASCT

Infection

Univariate

Stage I Stage II Stage III sCR CR VGPR PR SD PD

HR

95% CI

3.723 4.241

1.077e12.875 1.326e13.567

0.778 0.744 1.237 1.503 10.792 2.127

0.219e2.760 0.220e2.515 0.370e4.134 0.371e6.088 2.407e48.393 1.225e3.694

Multivariate p value 0.051 0.038 0.015 <0.0001 0.698 0.635 0.730 0.568 0.002 0.007

HR

95% CI

3.489 3.728

1.003e12.140 1.151e12.071

0.690 0.680 1.034 1.312 9.367 2.186

0.192e2.480 0.200e2.309 0.306e3.495 0.321e5.359 2.059e42.616 1.184e4.036

p value 0.090 0.049 0.028 <0.0001 0.569 0.536 0.958 0.705 0.004 0.012

HR Z hazard ratio; CI Z confidence interval; ASCT Z autologous stem cell transplantation; sCR Z stringent complete response; CR Z complete response; VGPR Z very good partial response; PR Z partial response; SD Z stable disease; PD Z progressive disease.

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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Autologous stem cell transplantation in multiple myeloma in Taiwan multivariate model was used. After adjusting for each confounding factor, effective variables were selected through the same process as that in the univariate regression analyses (Tables 4 and 5). Patients who responded to treatment have better post-transplant PFS (Fig. 1A) and OS (Fig. 1B). In addition, patients with early DSS disease and those diagnosed in the recent era experienced better posttransplant PFS (Fig. 2A and B). However, patients with advanced DSS disease and infectious episodes had poor post-transplant OS (Fig. 2C and D).

Discussion In this retrospective analysis, several simple but clinically informative findings were demonstrated. First, treatment response prior to HDT plus ASCT remained the most relevant factor affecting survival outcomes, particularly in patients who did not achieve PR prior to ASCT. Critical issues regarding improved treatment responses and optimal timing for ASCT have been examined in various studies and meta-analyses. Although some studies showed no or only minor significant differences in OS according to response level achieved via conventional chemotherapy prior to ASCT,15,16 most studies demonstrated that improvements in the quality of treatment response obtained with novel agents across all stages (induction-ASCT-consolidation) were associated with better disease control and prolonged survival.17e19 Adding novel agents to induction therapy increases pre-transplant CR rates (13%e47%), and a long response duration helps extend survival in patients with MM.20e23 For example, in the VISTA trial, the median CR duration was 24 months in patients achieving CR with melphalan-bortezomib-prednisolone, whereas that in patients achieving CR with MP was only 12.8 months.20

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Therefore, we aimed in the present study to analyze the impact of induction therapy. Because information regarding induction regimens was not available in the TBMTR database, we divided our patients into two groups based on year of diagnosis, namely, the early era (2005e2009) and the latter era (2010e2015). Patients with MM diagnosed between 2010 and 2015 were expected to receive novel agents as induction therapy because thalidomide has been used as the first-line treatment and post-transplant maintenance therapy for MM since 2009, and bortezomib has been covered for induction therapy prior to ASCT since 2011 by the Taiwan National Health Insurance Bureau. Patients diagnosed in the latter era had longer post-transplant PFS than those diagnosed in the early era (not reached vs. 32.5  6.0 months, p Z 0.006), but post-transplant OS did not significantly differ between the two groups (not reached vs. 70.4 months, p Z 0.31). Patients in the 2010e2015 group achieved higher treatment response prior to ASCT (CR rate, 34.2%; VGPR rate, more than 70.8%) than those in the 2006e2009 group (CR rate, 23.6%; VGPR rate more than 55.4%) (p Z 0.002). These results reflect the superiority of treatment response induced by novel agents, which can delay disease progression. However, no difference in survival after ASCT was noted upon comparison of the two groups. Two main factors may explain this absence of any difference: first, the duration of follow-up in the 2010e2015 group was too short; second, patients in the 2006e2009 group could also receive treatment upon disease progression or relapse with novel agents for salvage therapy, such as bortezomib, which had been approved by the Taiwan National Health Insurance Bureau as third-line therapy since 2007 and as second-line therapy since 2010. Because post-transplant treatment information was lacking in our database, an exact and detailed analysis was not performed.

Figure 1 Treatment response before ASCT significantly affected post-transplant PFS (p < 0.0001, Figure 1A) and OS (p < 0.0001, Figure 1B).

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Figure 2 In the analysis of post-transplant PFS, DSS III was still an adverse factor (HR Z 2.652, p Z 0.006, Figure 2A), but diagnosis in the latter era was a protective factor (HR Z 0.382, p < 0.0001, Figure 2B). Patients with DSS III disease had shorter post-transplant OS compared with those with DSS I (HR Z 3.728, p Z 0.028, Figure 2C). Patients with clinical significant infection during and after transplantation also had poor survival (HR Z 2.186, p Z 0.012, Figure 2D).

Another important issue was infection after conditioning therapies for ASCT. Several mechanisms contribute to the development of various types of infection in patients with myeloma treated with HDT plus ASCT, including prolonged neutropenia and mucositis caused by conditioning chemotherapeutic agents, as well as impaired cell-mediated immunity following engraftment.24 Unlike bacteremia, pneumonia, or cellulitis prior to engraftment, latent infections caused by the herpes virus, Pneumocystis jiroveci pneumonia (PJP), and CMV usually occur after engraftment and during disease progression or terminal stage. These infectious diseases may cause a decline in patient status along with organ damage, and may interrupt anti-myeloma therapies. One of our previous studies reported that infectious diseases, particularly pneumonia, were the leading causes of death in 101 patients with myeloma who were

ineligible for ASCT in Taiwan.25 Pneumonia and other infections resulted in early mortality (within 60 days after diagnosis) in nearly two-thirds of patients with myeloma (37 of 57, 65%).26 Huang et al. also reported that patients with myeloma with bloodstream infections had poorer survival outcomes than those without (mortality rate: 50% vs. 20.9%, p < 0.001).27 These real-world results from Taiwan support our finding that the occurrence of any infectious diseases after conditioning therapies for ASCT is a negative prognostic factor for survival (HR Z 2.127, p Z 0.007). Although the most common cause of death in our study was disease progression/relapse (55/72, 76.4%), 30 patients with refractory disease died from active infection. Therefore, effective infection control and prophylactic strategies are important for patients with myeloma. In Taiwan, the national health insurance policy allows routine prophylaxis

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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Autologous stem cell transplantation in multiple myeloma in Taiwan for hepatitis B reactivation with the use of entecavir or tenofovir in patients with positive hepatitis B surface antigen, but not in patients with only positive hepatitis B core antibody, which may explain why five patients in the present study still developed acute hepatitis B. However, in Taiwan, no standard consensus has been achieved regarding prevention of herpes viruses, fungal infections, and PJP infections after engraftment, during disease progression, or during salvage treatment. In this study, a high prevalence of VZV and HSV infection was observed during the follow-up period, accounting for 31.1% of all infectious episodes, slightly lower than the prevalence of bacterial infections (46.0%). The results of our data analysis show that physicians must pay more attention to the development of herpes virus infection in patients following ASCT. A retrospective study demonstrated that the early suspension of acyclovir after recovery from neutropenia could be safe, but extended prophylaxis of acyclovir for as long as a year may also be considered, particularly for elderly patients and those with myeloma.28 Interestingly, DSS was a more favorable predictor of post-transplant survival than ISS in our study. Hari et al.29 tried to compare the two staging systems in patients with myeloma undergoing ASCT. Most patients (92%) received induction therapies with the VAD regimen or alkylatorbased chemotherapy, and only 6% of patients were treated with thalidomide-based therapies. The results indicated that the DSS was superior to predictably discriminate all three stages compared with the ISS.29 However, the opposite result was reported in a retrospective study in Korea that enrolled 152 patients with myeloma treated with a VAD induction regimen followed by upfront ASCT.30 Whether aggressive upfront ASCT can offset the prediction effect of different staging systems, particularly in patients treated with traditional induction chemotherapies, is unclear. More valid evidence is needed to identify the best staging system to predict survival outcomes after ASCT in the era of novel agents. Furthermore, a new staging system that incorporates treatment response, cytogenetic risks, and results of whole-body positron emission tomography scans may be more suitable to predict post-transplant survival outcomes. For example, response-adjusted ISS was suggested to replace standard ISS for evaluating PFS after ASCT.31 The present study has several limitations based on its retrospective setting. No information was available in the current TBMTR database regarding the types and average numbers of MM therapies prior to transplantation, status of treatment response, and types of consolidation or maintenance therapies following transplantation. Therefore, we divided our population into two groups according to year of diagnosis and interpreted the role of pre-transplant therapies as concisely as possible. Although the benefit of maintenance therapies was unclear in this study, thalidomide and/or prednisolone have been commonly used in Taiwan after ASCT in patients with myeloma with high-risk cytogenetic features or those who do not achieve CR prior to ASCT. Current evidence demonstrates that IMiD maintenance significantly improves PFS in patients with myeloma treated with and without ASCT, but maintenance therapy extending OS remains controversial.32e34

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Subsequent analyses should be performed to complete the clinical picture. Finally, the present study included only 194 patients who had conventional cytogenetic data at diagnosis; only 32 among these were considered to have high-risk myeloma with hypodiploid karyotypes and/or abnormal deletions of chromosome 13 and 17. In Taiwan, fluorescence in situ hybridization is not routinely performed, and is only available in a few medical centers. Therefore, determining the actual proportion of high-risk patients in our cohort was not possible. Nevertheless, the preliminary analysis in our cohort showed that patients with high-risk cytogenetic features had significantly shorter post-transplant OS than those without such features (38.4 months vs. 70.4 months, p Z 0.03), but no difference in post-transplant PFS was noted between the groups (p Z 0.48). These results indicate that combined therapy with HDT plus ASCT is inadequate to overcome the negative survival impact of high-risk cytogenetic features. Additional treatment strategies after transplantation are needed to extend survival as long as possible, particularly in the highrisk population.

Conclusion In summary, this retrospective analysis showed that patients with early DSS and better pre-transplant treatment response had longer PFS and OS after ASCT. The low incidence of acute organ damage in our analysis indicated that HDT plus ASCT was a safe treatment modality. In managing patients with myeloma, treatment response and subsequent complications, particularly infection, should be balanced. Infections across any stages after ASCT should be identified promptly and treated carefully because these may result in the development of other complications and death.

Conflicts of interest The authors have no conflicts of interest relevant to this article.

Financial disclosure The authors have nothing to disclose.

Acknowledgments The authors thank all transplant centers participating in the Taiwan Blood and Marrow Transplantation Registry that have provided data for this study. We thank Dr. Ming-Yang, Lee of Chia-Yi Christian Hospital and Dr. Yeu-Chin, Chen of Tri-Service General Hospital for assisting in data collection. We also thank Chia-Ling Yu and Hui-Fen Chiang for their assistance in data analysis.

Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.jfma.2018.07.020.

Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020

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Please cite this article in press as: Huang T-C, et al., Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/ j.jfma.2018.07.020