Publications by authors named "Kazutaka Sunami"

73 Publications

A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma.

Int J Hematol 2021 Feb 27. Epub 2021 Feb 27.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD), [n = 7]; 300 mg QD, [n = 6]). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951).
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http://dx.doi.org/10.1007/s12185-021-03096-9DOI Listing
February 2021

Phase II, Multicenter, Single-Arm, Open-Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination with Bortezomib and Dexamethasone in Japanese Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma.

Acta Haematol 2020 Dec 4:1-11. Epub 2020 Dec 4.

Department of Hematology/Oncology, Higashi Nagoya National Hospital, Nagoya, Japan.

Introduction: Panobinostat, bortezomib, and dexamethasone combination therapy demonstrated progression-free survival (PFS) benefit over bortezomib and dexamethasone alone in the PANORAMA-1 study in relapsed/refractory multiple myeloma (MM). Here, we present data from a phase II study (NCT02290431) of this combination in Japanese patients with relapsed or relapsed-and-refractory MM.

Methods: Patients received 3-week cycles of 20-mg oral panobinostat (weeks 1 and 2), 1.3-mg/m2 subcutaneous bortezomib (days 1, 4, 8, and 11), and 20-mg oral dexamethasone (day of and the day following bortezomib administration) for a total of 8 cycles (24 weeks; treatment phase 1). Patients with treatment benefit had an option to enter the extension phase to receive 6-week (42-day) cycles of panobinostat (weeks 1, 2, 4, and 5) plus bortezomib (days 1, 8, 22, and 29) and dexamethasone (day of and the day following bortezomib treatment) for 24 weeks. The primary objective was complete response (CR) + near CR (nCR) rate after treatment phase 1 as per the modified European Society for Blood and Marrow Transplantation criteria.

Results: Of the 31 patients, 4 (12.9%) completed the treatment and 27 (87.1%) discontinued; 17 (54.8%) entered the extension phase. In total, 24 patients (77.4%) entered the survival follow-up phase and followed until study closure when the last patient was treated for 1 year after treatment phase 1. The CR + nCR rate was 48.4% (90% CI: 33.6-63.2). The overall response rate (CR + nCR + partial response) was 80.6%. The median PFS, duration of response, time to response, and time to progression were 15.3, 22.7, 1.4, and 15.3 months, respectively. All patients experienced adverse events (AEs), with diarrhea (80.6%), decreased appetite (58.1%), and thrombocytopenia (54.8%) being the most frequent, regardless of relationship to the study treatment. Thrombocytopenia (48.4%), fatigue (25.8%), diarrhea (22.6%), neutrophil count decrease (22.6%), platelet count decrease (22.6%), and lymphocyte count decrease (22.6%) were the most frequent grade 3/4 AEs.

Conclusion: The study met the primary objective with 48.4% CR + nCR rate. The AEs associated with the combination treatment were safely managed using the existing AE management guidelines, including dose interruption/modification and/or supportive medical intervention. This treatment regimen is an effective option with a favorable benefit/risk profile for Japanese patients with relapsed/refractory MM.
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http://dx.doi.org/10.1159/000508529DOI Listing
December 2020

Comparison of prognostic scores in transplant-ineligible patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective study from the national hospital organization in Japan.

Leuk Lymphoma 2021 Apr 9;62(4):819-827. Epub 2020 Nov 9.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS,  = 100) and angioimmunoblastic T-cell lymphoma (AITL,  = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.
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http://dx.doi.org/10.1080/10428194.2020.1845336DOI Listing
April 2021

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

Haematologica 2020 09 1;105(9):2308-2315. Epub 2020 Sep 1.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).
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http://dx.doi.org/10.3324/haematol.2019.231076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556618PMC
September 2020

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Cancer Sci 2020 Dec 15;111(12):4526-4539. Epub 2020 Oct 15.

Department of Hematology and Oncology, Nagoya City University Institute of Medical and Pharmaceutical Sciences, Nagoya, Japan.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.
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http://dx.doi.org/10.1111/cas.14657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734004PMC
December 2020

Pembrolizumab plus lenalidomide and dexamethasone in treatment-naive multiple myeloma (KEYNOTE-185): subgroup analysis in Japanese patients.

Int J Hematol 2020 Nov 19;112(5):640-649. Epub 2020 Sep 19.

Japanese Red Cross Medical Center, Tokyo, Japan.

The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.
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http://dx.doi.org/10.1007/s12185-020-02953-3DOI Listing
November 2020

Evaluation of prognosis following early disease progression in peripheral T-cell lymphoma.

Int J Hematol 2020 Dec 4;112(6):817-824. Epub 2020 Sep 4.

Department of Hematology, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya, 460-0001, Japan.

Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.
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http://dx.doi.org/10.1007/s12185-020-02987-7DOI Listing
December 2020

Daratumumab therapy for relapsed or refractory multiple myeloma: a single-center retrospective study.

Int J Clin Oncol 2020 Dec 26;25(12):2151-2157. Epub 2020 Jul 26.

Department of Hematology, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Kita-ku, Okayama, 701-1192, Japan.

Background: Significant advancements have been achieved in the quality of treatment for relapsed/refractory multiple myeloma (RRMM). Currently, daratumumab (DARA) is a highly effective drug widely used for RRMM; however, the knowledge on its efficacy and safety in Japanese patients remains limited. Accordingly, we aimed to evaluate the efficacy and safety of DARA therapy for RRMM.

Methods: We reviewed the medical records of patients who received DARA combination therapy and evaluated its efficacy and safety in our hospital.

Results: DARA was administered to 44 patients between October 2017 and March 2019. The median number of previous therapies was three (range 1-9). The rates of ≥ complete response and overall response were 27.3% and 61.4%, respectively. The median progression-free survival (PFS) duration was 12.3 months [95% confidence interval (CI) 5.1 to not reached (NR)] and estimated 2-year overall survival rate was 63.7% (95% CI 46.9-76.5%). In the multivariate analysis, patients with ≥ three previous lines of therapy and mass lesions showed significantly shorter PFS durations. The observed grade 3/4 adverse events (≥ 10%) included neutropenia (59.0%), thrombocytopenia (29.5%), anemia (36.4%), lymphopenia (38.6%) and febrile neutropenia (18.2%). None of the patients discontinued DARA therapy in spite of these AEs.

Conclusion: DARA is an effective treatment option for most patients and is tolerable. However, patients with heavy treatment before DARA therapy and mass lesions are likely to show poorer outcomes. Our findings suggest the use of DARA therapy early in the course of the disease.
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http://dx.doi.org/10.1007/s10147-020-01754-2DOI Listing
December 2020

[Multiple myeloma: a focus on drugs under development].

Authors:
Kazutaka Sunami

Rinsho Ketsueki 2020 ;61(5):520-527

Department of Hematology, National Hospital Organization Okayama Medical Center.

The introduction of proteasome inhibitors and immunomodulatory and antibody drugs has dramatically improved the prognosis of multiple myeloma (MM) in the 21st century. Despite the development of such highly effective MM therapeutics, however, patients may develop drug resistance and become refractory to standard therapies, and thus cannot be cured. New molecular targeted (venetoclax, selinexor), immunomodulatory (iberdomide), and antibody drugs (isatuximab, belantamab mafodotin), as well as bispecific T-cell engagers (BiTE) and chimeric antigen receptor T-cell (CAR T-cell) therapy, have been developed in the past 1-2 years, and promising results have been reported. In this article, we mainly review these drugs currently under development.
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http://dx.doi.org/10.11406/rinketsu.61.520DOI Listing
August 2020

Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.

Mycoses 2020 Aug 28;63(8):794-801. Epub 2020 May 28.

Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Background: Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required.

Objective: We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever.

Methods: Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d).

Results: Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07).

Conclusion: ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.
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http://dx.doi.org/10.1111/myc.13100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497187PMC
August 2020

Pomalidomide-bortezomib-dexamethasone in relapsed or refractory multiple myeloma: Japanese subset analysis of OPTIMISMM.

Cancer Sci 2020 Jun 13;111(6):2116-2122. Epub 2020 May 13.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression-free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow-up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment-emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.
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http://dx.doi.org/10.1111/cas.14415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293071PMC
June 2020

Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.

Ann Hematol 2020 May 4;99(5):1063-1072. Epub 2020 Apr 4.

Higashi Nagoya National Hospital, Nagoya, Japan.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.
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http://dx.doi.org/10.1007/s00277-020-03988-6DOI Listing
May 2020

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma.

Blood Cancer J 2020 02 13;10(2):17. Epub 2020 Feb 13.

Dana-Farber Cancer Institute, Boston, MA, USA.

The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
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http://dx.doi.org/10.1038/s41408-020-0273-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018731PMC
February 2020

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial.

Acta Med Okayama 2019 Dec;73(6):547-552

Department of Hematology, Disaster Medical Center of Japan, Tachikawa, Tokyo 190-0014, Japan.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.
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http://dx.doi.org/10.18926/AMO/57722DOI Listing
December 2019

[Diffuse large B-cell lymphoma relapsing with intravascular large B-cell lymphoma-like perivascular and intravascular lesions].

Rinsho Ketsueki 2019 ;60(10):1455-1461

Department of Hematology, National Hospital Organization Okayama Medical Center.

A 64-year-old woman was diagnosed with diffuse large B-cell lymphoma (DLBCL) in 2013. After eight courses of R-CHOP therapy followed by local irradiation of the remaining retroperitoneal soft tissue shadow, complete response was confirmed on 18F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Early in 2016, patient's serum LDH and soluble IL-2 receptor levels elevated. With suspected recurrence of DLBCL, FDG-PET/CT was performed that showed no lymphadenopathy or abnormal FDG uptake. By the end of July 2016, the patient developed fever and night sweating. Intravascular large B-cell lymphoma (IVLBCL) was suspected, and the patient underwent random skin biopsies, which revealed large atypical cells infiltrating peripheral and intravascular regions of the subcutaneous adipose tissue. Cell morphology, immunostaining, and PCR analysis of the immunoglobulin heavy chain gene suggested the recurrence of DLBCL. Despite salvage chemotherapy and autologous peripheral stem cell transplantation with high-dose chemotherapy, approximately 15 months later, DLBCL recurred and involved the lungs. The patient again received chemotherapy and achieved a second remission. Because DLBCL may recur like intravascular lymphoma, the same tests used for IVLBCL diagnosis are required in cases of suspected recurrence of DLBCL based on clinical and laboratory findings.
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http://dx.doi.org/10.11406/rinketsu.60.1455DOI Listing
November 2019

Comparison between autologous and allogeneic stem cell transplantation as salvage therapy for multiple myeloma relapsing/progressing after autologous stem cell transplantation.

Hematol Oncol 2019 Dec 23;37(5):586-594. Epub 2019 Nov 23.

Department of Hematology/Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.

Allogeneic stem cell transplantation (allo-SCT) offers a clinical option to young patients with multiple myeloma (MM) relapsing/progressing after autologous SCT (ASCT); however, this claim remains debatable. Thus, in this retrospective study, we analyzed 526 patients with MM who underwent SCT for MM relapsing/progressing after the prior ASCT using the registry data of the Japan Society for Hematopoietic Cell Transplantation (2001-2015) and compared overall survival (OS) between allo-SCT (n = 192) and autologous stem cell retransplantation groups (ReASCT; n = 334) based on risk factor points. Significant adverse factors for OS in all patients were (1) male sex, (2) less than partial response to SCT, (3) performance status of 2 to 4, and (4) short duration from the prior ASCT. We scored factor 2 as 1 point, factor 3 as 2 points, and factor 4 as 0, 1, or 2 points for more than 30, 9 to 30, or less than 9 months, respectively. We categorized patients into three risk subgroups based on their total points (0, 1-3, and 4-5 points), indicating the usefulness of this scoring system for prognosis prediction and treatment selection. Subgroup comparison revealed OS after ReASCT to be higher than that after allo-SCT in the intermediate-risk subgroup comprising the largest population (28.2% vs 21.5%, P < .004). We observed no significant advantages of allo-SCT over ReASCT in the low- and high-risk subgroups. These findings suggest that ReASCT is more advantageous than allo-SCT in many patients with MM relapsing/progressing after the prior ASCT. However, long-term survival patients were noted only in the allo-SCT group, and allo-SCT could exhibit clinical efficacy, particularly in the low-risk group. While further examination is warranted, allo-SCT could be a potential tool for a specific population with MM relapsing/progressing after the prior ASCT.
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http://dx.doi.org/10.1002/hon.2688DOI Listing
December 2019

Final results of a phase I study of carfilzomib, lenalidomide, and dexamethasone for heavily pretreated multiple myeloma.

Int J Hematol 2020 Jan 29;111(1):57-64. Epub 2019 Oct 29.

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.

We report the final results from a multicenter, open-label phase I study of carfilzomib plus lenalidomide and dexamethasone in Japanese patients with heavily pretreated relapsed and/or refractory multiple myeloma (RRMM). Twenty-six RRMM patients were enrolled and received a median of 4.0 prior regimens; 12/26 patients (46.2%) completed the planned 18 administration cycles (mean number of cycles: 14.5 ± 4.9). The safety profile was consistent with that of previous carfilzomib studies. All patients experienced adverse events (AEs), but no new safety concerns were observed. The most common grade ≥ 3 AEs (incidence: ≥ 10%) were lymphocyte count decreased (46.2%), platelet count decreased (42.3%), and neutrophil count decreased (34.6%). The overall response rate was 88.5% (23/26; 90% confidence interval: 72.8-96.8). Complete response (CR) or better was achieved by 30.8% of patients compared with 3.8% in the interim analysis. The median time to CR or better response was 9.4 months. Median progression-free survival and duration of response were 19.5 months and 20.3 months, respectively. Median overall survival was not reached. Long-term administration of carfilzomib produced deep response and long-term disease control. The combination of carfilzomib plus lenalidomide and dexamethasone was well tolerated and showed promising clinical efficacy for heavily pretreated RRMM patients. CLINICAL TRIAL REGISTRATION: This clinical trial was registered in the database clinicaltrials.jp (clinical trial registration number: Japic CTI 142677).
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http://dx.doi.org/10.1007/s12185-019-02754-3DOI Listing
January 2020

Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study.

Cancer Sci 2019 Sep 10;110(9):2924-2932. Epub 2019 Aug 10.

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

This multicenter, open-label phase 1/2 study evaluated single-agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m . Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m group at this final analysis was 4.7 months (range: 0.3-39.4). Overall response rate in the 20/27 mg/m group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3-37.5) with 2.5% (n = 1) stringent complete response. Median progression-free survival and overall survival in the 20/27 mg/m group were 5.1 months (95% CI, 2.8-13.6) and 22.9 months (95% CI, 14.1-not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long-term carfilzomib monotherapy led to long-term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.
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http://dx.doi.org/10.1111/cas.14139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726678PMC
September 2019

Report of phase I and II trials of melphalan, prednisolone, and thalidomide triplet combination therapy versus melphalan and prednisolone doublet combination therapy in Japanese patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplantation.

Int J Hematol 2019 Oct 19;110(4):447-457. Epub 2019 Jul 19.

Department of Hematology/Oncology, National Hospital Organization Higashi Nagoya National Hospital, 5-101, Umemorizaka, Meito-ku, Nagoya, Aichi, Japan.

We conducted a phase I study to determine the recommended dose of thalidomide combined with melphalan plus prednisolone (MPT) and a phase II study evaluating the efficacy and safety of this MPT regimen in transplant-ineligible Japanese patients with untreated multiple myeloma. The recommended dose was determined to be 100 mg/day in the phase I study. In the phase II, randomized, double-blind, parallel-group study, patients were allocated to either MPT (n = 52) or MP (n = 51), with 21 and 29 patients completing the study, respectively. Overall response rate, the primary endpoint, was significantly higher in the MPT [40.4% (21/52 patients), 95% confidence interval (CI) 27.0-54.9%] than in the MP [19.6% (10/51 patients), 95% CI 9.8-33.1%] group (P = 0.022). Time to response was also significantly shorter in the MPT group. Incidences of hematological toxicities were similar in the two groups, suggesting that addition of thalidomide did not increase hematological toxicity. Although incidences of some non-hematological toxicities tended to be higher in the MPT group, the low incidence of ≥ Grade 3 toxicities suggests that MPT therapy was well tolerated. These results support the safety and efficacy of MPT therapy in untreated Japanese multiple myeloma patients.
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http://dx.doi.org/10.1007/s12185-019-02700-3DOI Listing
October 2019

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial.

Lancet Oncol 2019 06 13;20(6):781-794. Epub 2019 May 13.

National and Kapodistrian University of Athens, Athens, Greece.

Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.

Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β microglobulin at screening. Bortezomib (1·3 mg/m) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.

Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).

Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.

Funding: Celgene.
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http://dx.doi.org/10.1016/S1470-2045(19)30152-4DOI Listing
June 2019

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

Ann Hematol 2019 Jul 2;98(7):1703-1711. Epub 2019 May 2.

Department of Hematology/Oncology, Higashi Nagoya National Hospital, Nagoya, Japan.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10 and p = 4.0 × 10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10 and p = 1.4 × 10, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.
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http://dx.doi.org/10.1007/s00277-019-03702-1DOI Listing
July 2019

Bortezomib-based strategy with autologous stem cell transplantation for newly diagnosed multiple myeloma: a phase II study by the Japan Study Group for Cell Therapy and Transplantation (JSCT-MM12).

Int J Clin Oncol 2019 Aug 1;24(8):966-975. Epub 2019 Apr 1.

Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance.

Methods: Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year.

Results: Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group.

Conclusions: The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.
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http://dx.doi.org/10.1007/s10147-019-01436-8DOI Listing
August 2019

Efficacy and safety of autologous stem cell transplantation in patients aged ≥ 65 years with multiple myeloma in the era of novel agents.

Bone Marrow Transplant 2019 10 19;54(10):1595-1604. Epub 2019 Feb 19.

Division of Hematology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan.

Clinical trials evaluating the role of autologous hematopoietic stem cell transplantation (auto-HCT) in multiple myeloma have mostly included patients aged <65 years. Therefore, this study was aimed to evaluate the efficacy and safety of auto-HCT in elderly patients with multiple myeloma in the era of novel agents. We retrospectively analyzed 2056 patients with multiple myeloma, who underwent auto-HCT in 2007-2014 (287 were aged ≥65 years). We evaluated the 100-day treatment-related mortality (TRM) and overall survival (OS) in two groups; elderly patients ( ≥65 years) who underwent auto-HCT compared with younger patients ( <65 years). In the propensity score-matched-pair analysis used to adjust for possible selection bias, the incidence of 100-day TRM between patients aged <65 (0.4%; 95% confidence interval [CI]: 0.0-2.0%) and ≥65 years (1.2%; 95% CI: 0.3-3.1%) showed no statistically significant difference (p = 0.31). The probability of the 5-year OS after transplantation in those aged <65 (62.5%; 95% CI: 58.6-66.1%) and ≥65 (63.5%; 95% CI: 52.2-72.7%) years was also not significantly different (p = 0.56). This study showed that the safety and efficacy of auto-HCT in elderly patients with multiple myeloma in the era of novel agents compared with younger patients were similar.
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http://dx.doi.org/10.1038/s41409-019-0478-4DOI Listing
October 2019

Improved survival outcomes and relative youthfulness of multiple myeloma patients with t(4;14) receiving novel agents are associated with poorer performance of the revised international staging system in a real aging society.

Oncotarget 2019 Jan 15;10(5):595-605. Epub 2019 Jan 15.

Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, Chiba, Japan.

The Revised International Staging System (R-ISS) was developed for a more accurate risk stratification of patients with symptomatic multiple myeloma (MM). However, original and subsequent validation studies of the R-ISS included relatively younger patients, many of whom were treated without bortezomib. Hence, we investigated the real-world prognostic performance of the R-ISS in 400 patients with MM treated with novel agents in Japan, an aging society. The patients had a median age of 72 years, and 96.0% were treated with bortezomib. Patients in R-ISS stage II were significantly older and failed to show significantly longer overall survival (OS) compared to patients in R-ISS stages III (median age; 74 and 70 years, respectively; = 0.001, and median OS; 63.4 vs. 54.7 months, respectively; = 0.32). However, OS differed significantly among patients with all conventional ISS stages. ISS stage III patients recategorized to R-ISS stage III were significantly younger than those recategorized to R-ISS stage II and had a relatively longer OS. As a reason for these findings, patients with the high-risk cytogenetic abnormality t(4;14) were significantly younger and had an improved OS compared to others, which can be attributed to a young age and bortezomib therapy, as previously suggested. In conclusion, the R-ISS was less successful than the ISS in discriminating between stages II and III among bortezomib-treated patients with MM in an aging society, which might be attributable to the inclusion of t(4;14) in the R-ISS categorization strategy.
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http://dx.doi.org/10.18632/oncotarget.26562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355174PMC
January 2019

[Safety and management of adverse events of ixazomib/lenalidomide/dexamethasone therapy in Japanese patients with relapsed/refractory multiple myeloma].

Rinsho Ketsueki 2018;59(11):2399-2407

Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited.

Based on the outcomes of the TOURMALINE-MM1 trial-a global, randomized, double-blind, placebo-controlled phase III clinical study-the use of an oral proteasome inhibitor has been approved in combination with lenalidomide and dexamethasone (Rd) for the treatment of relapsed/refractory multiple myeloma (MM). In this study, we enrolled 41 Japanese patients, who constituted the safety population. The overall incidence of adverse events (AEs) was similar in IRd and placebo-Rd groups. AEs including thrombocytopenia, skin disorders (rash), vomiting, nausea, and diarrhea occurred more frequently in the IRd group than in the placebo-Rd group. There were no cumulative toxicities, and most toxicities were usually manageable with close monitoring, supportive care, and dose modifications. Compared with the overall safety population, the safety profile of Japanese patients was consistent. Moreover, in Japanese patients, there were no on-study deaths and the incidence of serious AEs was less frequent.
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http://dx.doi.org/10.11406/rinketsu.59.2399DOI Listing
May 2019

Clinical Implications of t(11;14) in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 03 10;25(3):474-479. Epub 2018 Nov 10.

Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan.

Conventional cytogenetic analyses and fluorescent in situ hybridization (FISH) are helpful for stratifying patients with multiple myeloma (MM) into high-risk [t(4;14), t(14;16), and/or del 17p] and standard-risk [t(11;14)] categories. However, the prognosis of patients with MM treated with autologous stem cell transplantation (ASCT) stratified according to these categories remains unclear. This retrospective observational study analyzed 97 patients with MM who received a single, planned ASCT after treatment with 200 mg/m melphalan between 2001 and 2011. The patients were grouped according to chromosomal abnormality, including t(11;14) (n = 45), t(4;14) (n = 31), del 17p (n = 10), t(11;14) with del 17p (n = 7), and t(4;14) with del 17p (n = 4). Median overall survival (OS) of the t(11;14) group (64.1 months) was not significantly different from that of the t(4;14) group (not reached), but it was significantly longer than that of the del 17p group (23.0 months; P = .002). G-banding revealed that the median OS of the t(11;14) group with additional chromosomal abnormalities (ACAs) (46.2 months) was significantly shorter than that of the t(11;14) group without ACAs (not reached; P = .005) and the t(4;14) group (not reached; P = .010). These findings highlight the importance of G-banding in patients with t(11;14) MM.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.003DOI Listing
March 2019

Correction to: A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma.

Int J Hematol 2019 Jan;109(1):131

Karatsu Higashimatsuura Medical Association, Karatsu, Japan.

In the original publication of this article, "Conflict of interest" was published incorrectly. The corrected "Conflict of interest" is given below for your reading.
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http://dx.doi.org/10.1007/s12185-018-2557-5DOI Listing
January 2019

A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma.

Int J Hematol 2019 Jan 4;109(1):107-114. Epub 2018 Oct 4.

Karatsu Higashimatsuura Medical Association, Karatsu, Japan.

The efficacy and safety of lenalidomide (LEN) consolidation therapy and subsequent LEN maintenance therapy after high-dose therapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in patients with newly diagnosed symptomatic multiple myeloma (MM). Forty-one patients were enrolled and received high-dose dexamethasone (DEX) therapy as an initial induction. The patients who did not respond to the DEX therapy were further treated with four cycles of bortezomib plus DEX (BD) induction therapy. For patients who responded to BD, PBSC harvesting was scheduled following high-dose cyclophosphamide and filgrastim administration. After PBSC harvesting, high-dose chemotherapy of melphalan with auto-PBSCT was performed. One hundred days after auto-PBSCT, patients received consolidation therapy consisting two cycles of LEN plus low-dose DEX (Ld) and LEN maintenance therapy. Only one death occurred during mobilization therapy, but the protocol developed in this study was considered generally safe to provide. Overall response rates after consolidation and maintenance therapies were 73.7% and 81.6%, respectively. Two-year progression-free survival and overall survival were 76.3% and 92.1%, respectively. These observations suggest that LEN consolidation and maintenance therapy are effective and safe, and provide favorable response rates in patients with MM.
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http://dx.doi.org/10.1007/s12185-018-2543-yDOI Listing
January 2019

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma.

Hematol Oncol 2018 Dec 19;36(5):792-800. Epub 2018 Sep 19.

Department of Hematology/Oncology, Higashi Nagoya National Hospital, Nagoya, Japan.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and β2-microglobulin levels. In the two determinants, β2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.
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http://dx.doi.org/10.1002/hon.2559DOI Listing
December 2018