Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma

Ozaki, Shuji; Handa, Hiroshi; Saitoh, Takayuki; Murakami, Hirokazu; Itagaki, Mitsuhiro; Asaoku, Hideki; Suzuki, Kenshi; Isoda, Atsushi; Matsumoto, Morio; Sawamura, Morio; Konishi, Jun; Sunami, Kazutaka; Takezako, Naoki; Hagiwara, Shotaro; Kuroda, Yuko; Chou, Takaaki; Nagura, Eiichi; Shimizu, Kazuyuki

doi:10.1038/bcj.2015.79

Cited by 64 publications

(57 citation statements)

References 14 publications

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“…Multiple myeloma (MM) is a malignant plasma cell dyscrasia, typically developing in elderly patients . It is characterized by monoclonal gammopathy and clonal plasma cell infiltration in bone marrow .…”

Section: Introductionmentioning

confidence: 99%

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

et al. 2019

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p97/VCP is an endoplasmic reticulum (ER)‐associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50, 100‐500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of DBeQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell‐free ATPase assays, OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition.

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Section: Introductionmentioning

confidence: 99%

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

et al. 2019

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“…Front-line treatment with high-dose melphalan (HD-MEL) and autologous stem cell transplantation (ASCT) has improved the prognosis of patients with multiple myeloma (MM) [1]. However, disease progression occurs after up-front ASCT at 10-15% per year [2].…”

Section: Introductionmentioning

confidence: 99%

Significance of Salvage Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma: A Nationwide Retrospective Study in Japan

et al. 2018

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Autologous stem cell transplantation (ASCT) has been employed for patients with relapsed multiple myeloma (MM) after up-front ASCT. The present retrospective study aimed to examine the survival benefit from salvage ASCT. Among 446 patients with relapsed MM after up-front single ASCT, 70 patients received salvage ASCT, the employment of which reduced the risk of mortality after relapse (p = 0.041). Using the parameters before initial ASCT, the advantage of salvage ASCT compared to standard therapy was confirmed in the subgroup with an international staging system stage of I or II (p = 0.040), good performance status (PS; p = 0.043), or no/mild renal comorbidity (p = 0.029). The advantage of salvage ASCT was also confirmed in the subgroup excluding those with early relapse within 7 months after initial ASCT (p = 0.026). Among patients who received salvage ASCT, a favorable prognosis is apparent for those with a time to relapse after initial ASCT of longer than 24 months. The overall survival after salvage ASCT was favorable excluding patients with the following factors: early relapse, poor PS, moderate/severe renal comorbidity, and progressive disease (p < 0.001). In conclusion,our results reinforced the evidence for encouraging salvage ASCT for eligible patients.

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“…Patients treated with BD had better outcomes than those treated with TD with regard to 1 The introduction of PI and immunomodulatory imide drugs into clinical practice has remarkably prolonged the OS of patients with MM. 1,2 In October 2006, the first-generation PI, bortezomib, was approved for use in patients with RRMM in Japan based on the results of a phase I/II study carried out in the country. 3 In the phase I part, the patients received i.v.…”

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confidence: 99%

Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma

et al. 2018

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A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal‐naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m2) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3‐week cycle) were followed by maintenance phase (5‐week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end‐point was 1‐year progression‐free survival (PFS). Forty‐four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow‐up of 34.3 months, the 1‐year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%‐64.3%) and 31.8% (95% CI, 14.2%‐51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3‐year overall survival (OS) was 70.0% (95% CI, 44.9%‐85.4%) in the BD, and 48.8% (95% CI, 25.1%‐69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1‐year PFS and 3‐year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal‐naïve RRMM patients. (Clinical trial registration no. UMIN000003135.)

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Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma

Cited by 64 publications

References 14 publications

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

Significance of Salvage Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma: A Nationwide Retrospective Study in Japan

Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma

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