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The prognosis for multiple myeloma (MM) patients has improved with the advent of new drugs, but the prognosis with renal impairment (RI) is poor. The choice of treatment in such cases is critical, but there are no set criteria. We examined the impact of RI on initial therapy in transplant-ineligible MM patients. We selected symptomatic MM patients who met the following criteria: age ≥ 65 years, fit, and ineligible for transplantation from the database. We analyzed the impact of age, treatment, International Staging System (ISS) stage, karyotype abnormalities, performance status, and estimated glomerular filtration rate (GFR < 50 or ≥ 50 ml/min/1.73m 2 ) on overall survival (OS). We also analyzed the OS by eGFR for each treatment. We selected 349 symptomatic MM patients. The regimens used were lenalidomide, bortezomib and dexamethasone (RVd), daratumumab, bortezomib, melphalan, and prednisolone (D-VMP), daratumumab, lenalidomide and dexamethasone (D-Rd) and daratumumab, bortezomib, and dexamethasone (D-Vd) in 184, 41, 74 and 50 patients, respectively. The median age was 74 years old; ISS stage was I/II/III in 85/112/131 patients; and 161 patients showed eGFR < 50. The OS was shorter with ISS stage III (p = 0.029) and eGFR < 50 (p < 0.001) by multivariate analysis. The OS under the RVd/D-Rd regimens were significantly shorter for patients with eGFR < 50, but OS under the D-VMP/D-Vd regimens were not significantly different between patients with eGFR < 50 and eGFR ≥ 50. The OS of the transplant-ineligible MM patients with higher ISS stage and RI was poor. Initial treatment with a D-VMP/D-Vd regimen might be less affected by RI., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs., (© 2024. The Author(s).)

Background: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab., Objective: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment., Methods: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment., Results: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen., Conclusion: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results., (© 2024. The Author(s).)

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS., Competing Interests: TF has received honoraria from Takeda Pharmaceutical; TT has received honoraria from Bristol Myers Squibb (BMS), Janssen Pharmaceutical, Sanofi, Kyowa Kirin and Chugai Pharmaceutical; YS has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical and Chugai Pharmaceutical; SM has received honoraria from Sanofi and Ono Pharmaceutical; and NU has received honoraria from BMS and Takeda. JK is a consultant for Janssen Pharmaceutical, Abbvie and BMS; has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Shionogi and BMS; and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi and BMS. None of the pharmaceutical companies aforementioned benefited from the present research or played any role in our study. All other authors declare that they have no competing interests., (Copyright: © Inoue et al.)

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs ( n  = 338, 72 %) was 6.5 years, patients with del(17p) ( n  = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) ( n  = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) ( n  = 18, 4 %) was 2.1 years ( p  = 0.032). Patients with double-positive CAs had a significantly worse prognosis., Competing Interests: All authors received research funding from ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb Company. JKU is appointed as an officer or advisor at Kansai Medical Net. JKU received lecture honoraria from Bristol-Myers Squibb Company, Janssen Pharmaceutical K. K., Sanofi K.K., ONO PHARMACEUTICAL CO., LTD., AbbVie GK., Takeda Pharmaceutical Company Limited, and Novartis Pharma KK. AT received lecture honoraria from Bristol-Myers Squibb Company, Novartis Pharma KK, Kyowa Kirin Co., Ltd., Astellas Pharma Inc., Nippon Shinyaku Co., Ltd., JANSSEN PHARMACEUTICAL K.K., Otsuka Pharmaceutical Co., Ltd. MH received lecture honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Company, Limited, Bristol-Myers Squibb., Otsuka Pharmaceutical Co., Ltd. IM received lecture honoraria from Novartis Pharma KK, Bristol-Myers Squibb Company, Pfizer Japan Inc., DAIICHI SANKYO COMPANY, LIMITED., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K, AbbVie GK., Takeda Pharmaceutical Company Limited, ONO PHARMACEUTICAL Co., Ltd., SymBio Pharmaceuticals Limited. HS received lecture honoraria from Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD., Novartis Pharma K.K., Bristol-Myers Squibb K.K., JANSSEN PHARMACEUTICAL K.K., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., AstraZeneca K.K. TI received lecture honoraria from Bristol-Myers Squibb, Mundipharma K.K., Novartis Pharma K.K., Pfizer Japan Inc., Takeda Pharmaceutical Company, Limited., AbbVie GK., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Nippon Shinyaku Co., Ltd., CSL Behring K.K., Otsuka Pharmaceutical Co., Ltd., NIHON PHARMACEUTICAL CO., LTD., JANSSEN PHARMACEUTICAL K.K.. SF received lecture honoraria from Takeda Pharmaceutical Company, Ltd., Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K. TT received lecture honoraria from Sanofi K.K.. JKU received writing fees from JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K. JKU received grants for research from Bristol-Myers Squibb Company, ONO PHARMACEUTICAL CO., LTD., Sysmex Corporation, Takeda Pharmaceutical Company, Limited, Otsuka Pharmaceutical Co., Ltd., Incyte Corporation, JANSSEN PHARMACEUTICAL K.K., Pfizer Japan Inc., CHUGAI PHARMACEUTICAL Co., Ltd., Kyowa Kirin Co., Ltd., IQVIA Services Japan K.K. AT received grants for research from ONO PHARMACEUTICAL Co., Ltd., COGNANO, Inc., DKS Co., Ltd.. IM received grants for research from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., AbbVie GK., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited., Alexion, Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. NH received grants for research from Otsuka Pharmaceutical Co., Ltd. HS received grants for research from JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K., Novartis Pharma K.K., AstraZeneca K.K., AbbVie GK., Eisai Co., Ltd., HUYABIO International, CHUGAI PHARMACEUTICAL CO., LTD., PharmaEssentia Japan KK. TI received grants for research from Bristol-Myers Squibb. JKU recieved scolarship grant from Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Eisai Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Company, Limited., Nippon Shinyaku Co., Ltd. AT received scholarship grants from Takeda Pharmaceutical Company, Limited, Nippon Shinyaku Co., Ltd., Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., OHARA Pharmaceutical Co., Ltd., Popuri, Kinshikouraininjin, AbbVie, SHIONOGI & CO., LTD., Asahi Kasei Pharma Corporation., the Japanese Society of Hematology. MH recieved scholarship grants from CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Otsuka Pharmaceutical Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. HS received scholarship grants from Astellas Pharma Inc., TEIJIN PHARMA LIMITED, SHIONOGI & CO., LTD., Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Nippon Shinyaku Co., Ltd. CS received lecture honoraria from Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K., (© 2023 The Author(s).)

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting., (© 2023. Japanese Society of Hematology.)

We retrospectively gathered data of 21 patients (13 male and 8 female; median age 65 years) diagnosed with immunoglobulin M (IgM)-related light-chain (AL) amyloidosis in Japan to investigate characteristics of IgM-AL amyloidosis and its optimal treatment strategy. Median IgM and difference free light chain (FLC) at diagnosis were 1257 mg/dl and 34.3 mg/l, respectively. Organ involvement was observed in the heart in 7 patients (33%), kidneys in 15 (71%), and lymph nodes in 5 (24%). Initial treatments were melphalan/dexamethasone in 7 patients, bortezomib/cyclophosphamide/dexamethasone in 3, autologous stem cell transplantation in 3, rituximab/bendamustine in 1, other in 3, and none in 4. Hematological responses among 15 evaluable patients were as follows: 3 reached complete response (CR), 4 partial response (PR), and 1 very good PR (VGPR), making the overall response rate of PR or better 40%. Median overall survival (OS) was 14.0 months and 1-year OS was 71.4%. Prognosis was significantly poorer in patients with cardiac involvement than those with non-cardiac involvement (1-year OS 27.8% vs. 85.7%, p = 0.0468). The involved FLC value was low in several patients and therapeutic response was difficult to assess. Further study is necessary to determine the optimal treatment for IgM-AL amyloidosis., (© 2023. Japanese Society of Hematology.)

The prognostic impact of patient-related factors, including age, nutritional parameters, and inflammation status, in higher-risk myelodysplastic syndromes (HR-MDS) has been largely unexplored. This multicenter retrospective study aimed to establish a real-world practice-based prognostic model for HR-MDS by considering both disease- and patient-related parameters in 233 patients treated with AZA monotherapy at seven institutions. We found that anemia, presence of circulating blasts in peripheral blood, low absolute lymphocyte count, low total cholesterol (T-cho) and albumin serum levels, complex karyotype, and del(7q) or  - 7 were poor prognostic factors. Therefore, we developed a new prognostic model called the Kyoto Prognostic Scoring System (KPSS) by incorporating the two variables with the highest C-indexes (complex karyotype and serum T-cho level). The KPSS classified patients into the following three groups: good (0 risk factors), intermediate (1), and poor (2). Median overall survival for these groups was 24.4, 11.3, and 6.9, respectively (p < 0.001). The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification., (© 2023. Japanese Society of Hematology.)

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM., (© 2022 Sanofi and the Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Tandem autologous stem cell transplantation (ASCT) has been reconsidered for high-risk patients with myeloma, and the eligibility criteria for up-front ASCT have been updated to include more elderly patients. This study aimed to evaluate the efficacy and tolerability of tandem ASCT in elderly patients with myeloma compared to tandem ASCT in young patients and single ASCT in elderly patients. A retrospective study using the Transplant Registry Unified Management Program database of the Japanese Society for Transplantation and Cellular Therapy, which included 64 elderly and 613 young patients who received tandem ASCT, and 891 elderly patients who received single ASCT, was conducted. The median overall survival (OS) over 38.5 months in the elderly and young patients who received tandem ASCT, and elderly patients who received single ASCT was 78.9, 92.5, and 77.1 months, respectively; no significant difference in the median OS was observed. The cumulative incidence of transplantation-related mortality was similar in the elderly and young patients receiving tandem ASCT. High-risk cytogenetic abnormality was not identified as a poor prognostic factor for OS in elderly patients who received tandem ASCT but in those who received single ASCT. Thus, tandem ASCT was effective and tolerable in elderly patients with myeloma., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β 2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system., (© 2023. The Author(s).)

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab., Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status., Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database., Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database., Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β 2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen., Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p  < 0.001). To confirm this concept, our results will need to be validated in other cohorts., Competing Interests: The authors declare no conflicts of interest except JK received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Sanofi K.K. and Ono Pharma Inc., and is an advisory role in Janssen Pharmaceutical K.K, and Novartis Pharma K.K. TI received honorarium from Bristol-Myers Squibb Co, Takeda Pharmaceutical Co., Ltd. and Sanofi K.K.; and research funding from Bristol-Myers Squibb Co. KI received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Ono Pharma Inc., Novartis Pharma K.K., Kyowa Kirin Co., Ltd., Celgene K.K., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co. Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd. and Meiji Seika Pharma Co. Ltd. SF received honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Sanofi K.K., Bristol-Myers Squibb Co., Ltd., and Celgene K.K. HT received personal fees from Bristol-Myers Squibb Co (Celgene K.K.), personal fees from Novartis Pharma K.K., grants from Kyowa Kirin Co., Ltd. HS reports honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Celgene K.K., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., SymBio Pharmaceuticals Ltd., Eisai Co., Ltd., and Kyowa Kirin Co., Ltd.; and research funding from Pharma Essentia Japan K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Celgene K.K., Novartis Pharma K.K., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., Eisai Co., Ltd., HUYA Bioscience International, LLC., and Chugai Pharmaceutical Co., Ltd.; and scholarship endowment from Astellas Pharma Inc., Teijin Pharma Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., and Nippon Shinyaku Co., Ltd. CS received honoraria from Bristol-Myers Squibb Co., Celgene K.K., Janssen Pharmaceutical K.K., and Sanofi K.K. IM received personal fees from Bristol-Myers Squibb Co. (Celgene K.K.), personal fees from Novartis Pharma K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Pfizer Japan Inc., during the conduct of the study; grants from Ono Pharmaceutical Co., Ltd., personal fees from Janssen Pharmaceutical K.K, grants from Nippon Shinyaku Co., Ltd., grants from Kyowa Kirin Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Shionogi & Co., Ltd., grants from Teijin Pharma Ltd., grants from Boehringer Ingelheim Co., Ltd., grants from Sanofi K.K., grants from Chugai Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from MSD K.K, grants from Asahi Kasei Pharma Corporation, grants and personal fees from Astellas Pharma Inc., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants from Japan Blood Products Organization, grants from Nihon Pharmaceutical Co., Ltd., grants and personal fees from AbbVie GK, grants from Taiho Pharmaceutical Co., Ltd., grants from Mitsubishi Tanabe Pharma Corporation, grants from Nippon Kayaku Co., Ltd., grants from CSL Behring LLC, grants from Mundipharma K.K, grants from Ayumi Pharmaceutical Corporation, grants from Eli Lilly Japan K.K., grants from Actelion Pharmaceuticals Japan Ltd., personal fees from Amgen BioPharma K.K., outside the submitted work. AT-K serves as an advisor for Megakaryon and receives research fundings from Ono Pharmaceutical Co., Ltd., DSK, and Cognano. JK received research funding from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., Bristol-Myers Squibb Co., Sysmex, Dainippon Sumitomo Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., AbbVie GK, Teijin Pharma Ltd. and Otsuka Pharmaceutical Co. Ltd., has received honoraria from Janssen Pharmaceutical K.K, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., SymBio Pharmaceutical Limited, Bristol-Myers Squibb Co., Astellas Pharma Inc., Pfizer Japan Inc., Nippon Shinyaku Co., Ltd., Daiichi Sankyo Co. Ltd., Dainippon Sumitomo Pharma Co., Ltd., AbbVie G.K. and Otsuka Pharmaceutical Co. Ltd., and is a consultant for Janssen Pharmaceutical K.K, and Bristol-Myers Squibb Co., (© The Author(s), 2022.)

Carfilzomib (CFZ) constitutes powerful combinatory therapy for relapsed/refractory multiple myeloma (RRMM); however, cardiovascular adverse events (CVAEs) have been shown as major treatment obstacles with the use of CFZ. Along with our multi-institutional prospective observational study by the Kyoto Clinical Hematology Study Group on the efficacy and safety of CFZ-based treatments (UMIN000025108), we here performed an ad hoc analysis of CFZ-related CVAEs in 50 patients with RRMM. We analyzed the association between CFZ-related CVAEs and pre-planned examinations, including patients' background, electrocardiographic findings, echocardiographic findings, and serum/plasma levels of 18 potential candidate biomarkers. The common CVAEs were hypertension (42%), arrhythmia (14%), and prolongation of QT corrected interval (10%), whereas no serious CVAEs occurred. The pretreatment serum level of interleukin-6 was identified as a significant risk factor for CFZ-related hypertension. This study revealed hypertension as the most frequent CFZ-related CVAE and suggested that baseline serum interleukin-6 is a useful predictor for CFZ-induced hypertension.

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd)., Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database., Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia., Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors received research funding from Ono Pharma. and Celgene (Current Bristol Myers Squibb). JKa, SF, TI, HT, HS, SY, KS, KO, MH, CS, and JKu received speaker’s bureau from Ono Pharma. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, AT-K, and JKu received speaker’s bureau from Celgene (Current Bristol Myers Squibb). SF, TI, TH, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Janssen. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Takeda Pharma. JKa, SF, TI, HT, HS, SY, SK, MH, CS, and JKu received speaker’s bureau from Sanofi. JKa, TI, HT, HS, SY, SK, KO, IM, MH, AT-K, and JKu received speaker’s bureau from Novartis. SK and JKu received speaker’s bureau from Fujimoto Pharma. TI, HS, MH, and JKu received research funding from Celgene (Current Bristol Myers Squibb). HS received research funding from Janssen. IM and JKu received research funding from Takeda Pharma. HS, IM, and JKu received research funding from Sanofi. HS and MH received research funding from Novartis. JKu received research funding from Fujimoto Pharma. JKa received consulting fees from Janssen and Takeda Pharma. MH received scholarship donations from Takeda Pharma. and Ono Pharma. AT-K received scholarship donations from Takeda Pharma. and Sanofi., (© The Author(s), 2022.)

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53-1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46-0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Autologous stem cell transplantation (ASCT) is the standard of care for eligible patients with light-chain (AL) amyloidosis, but little is known about it in Asian populations. To investigate the outcome of and prognostic factors for ASCT, we retrospectively analyzed ASCT cases registered to the Transplant Registry Unified Management Program between December 1999 and December 2015, with extra clinical information collected through a secondary survey. The primary endpoint was overall survival (OS). Hematologic response, organ response, and transplantation-related mortality were analyzed as secondary endpoints. The database search identified 330 patients (median age, 57 years; range, 31 to 74), and the secondary survey provided details for the 110 patients (33.3%) included in the study cohort. Fewer than 3 organs were involved in 56.4% of the patients, with cardiac involvement in 57.3%. Performance status (PS) was 0 to 1 in 83.6%. The conditioning melphalan dose was reduced in 54.6%. Overall hematologic response was a partial response or better in 77.6% of the patients and a complete response in 49.3%. The 5-year OS was 70.1%. A PS of 0 to 1 was associated with a significantly better prognosis in terms of OS. Although survival after ASCT for AL amyloidosis improved over time, poor PS and cardiac involvement had negative impacts on prognosis. The early mortality after ASCT was 6.4%. Poor PS and cardiac involvement led to high early mortality. A brain natriuretic peptide (BNP) level of 400 pg/mL was associated with worse OS. Our study has several limitations inherent to a retrospective analysis using a questionnaire. The depth of response and biomarker responses were significantly limited by the degree of missing data. Nonetheless, our data support the importance of careful patient selection for good outcomes of ASCT in patients with AL amyloidosis. In our cohort, poor PS and cardiac involvement had a negative impact on prognosis, and BNP level was a useful prognostic factor., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting., Aims: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group., Methods and Results: All 50 patients with RRMM enrolled in this study were treated with CFZ-based treatments between 2017 and 2019. KRD and KD were administered to 31 and 19 patients, respectively. The overall response rates (ORRs) were 80.6% with KRD and 73.7% with KD. Two-year progression-free survival (PFS) and overall survival (OS) were 58.5% and 79.7% with KRD, and 23.1% and 52.6% with KD. By multivariate analysis, refractoriness to BTZ and to LEN were identified as independent unfavorable factors for both PFS and OS. The common non-hematologic AEs included hypertension (42.0%), fever (24.0%), fatigue (24.0%), and infection (16.0%). No serious heart failure was observed. This study is registered as UMIN000025108., Conclusion: This study suggests the need of the development of novel CFZ-containing strategy which can overcome the refractoriness to BTZ and/or LEN, while both KRD and KD were shown to be mostly feasible in Asian patients in a daily practice setting., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

New drugs for multiple myeloma (MM) have dramatically improved patients' overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant-eligible MM patients. To investigate whether the post-ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16-77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs' introduction in Japan: group 1 (2007-2010), group 2 (2011-2016), and group 3 (2017-2018). We compared the groups' post-ASCT OS. The 2-year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%-87.4%), 89.1% (88.0%-90.1%), and 92.3% (90.0%-94.2%) (P < .0001) and the 5-year OS (95% CI) rates were 64.9% (62.4%-67.3%), 71.6% (69.7%-73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post-ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post-diagnosis, better treatment response pre-ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post-ASCT. The post-ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high-risk-karyotype patients with ISS stage III remains poor, their treatment requires improvement., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A total of 129 symptomatic patients with multiple myeloma (MM) who underwent high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) were analyzed. The 4-year overall survival (OS) of patients with maintenance ( n  = 82) was 80%, whereas that of patients without maintenance ( n  = 47) was 72% ( p  = 0.426). The 4-year progression-free survival (PFS) of patients with maintenance was 38%, whereas that of patients without maintenance was 27% ( p  = 0.088). Multivariate analysis revealed that an International Staging System score ≥2 was associated with worse PFS (hazard ratio 1.62, p  = 0.043). Among the 129 patients, two were excluded owing to early relapse, 50 patients achieved complete response (CR), and 77 patients failed to achieve CR. Patients who achieved CR showed better 4-year PFS than those who failed to achieve CR (41% vs. 30%, p  = 0.027); however, 4-year OS was not different (76% vs. 82%, p  = 0.971). In patients who achieved CR, 4-year OS with/without maintenance was 74%/81% ( p  = 0.357), 4-year PFS with/without maintenance was 42%/40% ( p  = 0.954). In patients who failed to achieve CR, the 4-year OS with/without maintenance was 97%/91% ( p  = 0.107), and 4-year PFS with/without maintenance was 36%/16% ( p  < 0.001). In patients who failed to achieve CR, maintenance significantly improved the PFS. Maintenance after HDT/ASCT can prolong PFS in patients who fail to achieve CR in real-world settings., Competing Interests: This work was supported by Bristol‐Myers Squibb/Celgene K.K.All authors received research funding from Ono Pharmaceutical Co., Ltd., Fujimoto Pharmaceutical Corporation. HT, HS, AT, IM, JKA, TI, KI, SK, and SY received honoraria from Novartis Pharma K.K. JKU, HT, JKA, AT, HS, IM, SF, TI, KI, MH, SK, and SY received honoraria from Bristol‐Myers Squibb/Celgene K.K. IM, HS, JKU, SF, MH, and SY received honoraria from Janssen Pharmaceutical K.K. SF, JKA, TI, HS, KI, MH, and SK received honoraria from Takeda Pharmaceutical Company, Limited. AT, HS, JKA, KI, MH, and SK received honoraria from Kyowa Kirin Co., Ltd. HS, JKA, KI, MH, and SK received honoraria from Chugai Pharmaceutical Co., Ltd. At, JKA, IM, KI, MH, and SK received honoraria from Astellas Pharma Inc. SF, HS, MH, and SY received honoraria from Sanofi K.K. SF, HS, MH, SK, and SY received honoraria from Ono Pharmaceutical Co., Ltd. JKA, IM, KI, and MH received honoraria from Otsuka Pharmaceutical Co., Ltd. JKA and IM received honoraria from Daiichi Sankyo Company, Limited. IM received honoraria from Pfizer Japan Inc. and Amgen inc. IM and TI received honoraria from AbbVie GK. AT, JKA, and MH received honoraria from MSD K.K. HS received honoraria from AstraZeneca K.K., Sanofi K.K. AT, KI, and MH received honoraria from Nippon Shinyaku Co., Ltd. JKA received honoraria from JCR Pharmaceuticals Co., Ltd. JKU and SK received honoraria from Fujimoto Pharmaceutical Corporation. KI and MH received honoraria from Dainippon Sumitomo Pharma Co., Ltd. MH received honoraria from Pfizer Japan Inc., Japan Blood Products Organization, Mochida Pharmaceutical CO., Ltd., and Mundipharma K.K. MH received honoraria from Eisai Co., Ltd. JKU, AT, HS, and TI received research funding from Bristol‐Myers Squibb. IM, TI, and HS received research funding from AbbVie GK. AT and HS received research funding from Ono Pharmaceutical Co., Ltd. IM, HS, and SY received research funding from Chugai Pharmaceutical Co., Ltd. IM and HS received research funding from Novartis Pharma K.K. IM received research funding from Takeda Pharmaceutical Company, Limited., Pfizer Japan Inc., Eisai Co., Ltd., and Alexion Pharmaceuticals, Inc. HS received research funding from Janssen Pharmaceutical K.K., Sanofi K.K., and AstraZeneca K.K. MH received research funding from Taiho Pharmaceutical Co., Ltd., Teijin Limited, Eisai Co., Ltd., Nihon Pharmaceutical Co., Ltd., and JCR Pharmaceuticals Co., Ltd. AT, IM received scholarship grant from Takeda Pharmaceutical Company, Limited., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Shinyaku Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Shionogi & Co., Ltd., and AbbVie GK. AT, HT, and IM received scholarship grant from Kyowa Kirin Co., Ltd. AT received scholarship grant from Ohara Pharmaceutical Co., Ltd, and Kinshikouraininjin., the Japanese Society of Hematology. IM received scholarship grant from Ono Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Asahi Kasei Pharma Corporation., Taiho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Novartis Pharma K.K., and MSD K.K. JKU received scholarship grant from Fujimoto Pharmaceutical Corporation., (© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The plateau phase emerging during the treatment of multiple myeloma (MM) is known to last steadily for a certain period, even without treatment. Therefore, the treatment started at plateau phase is expected to be associated with a better outcome. In this study, this hypothesis was evaluated retrospectively for previously treated MM patients in Kansai Myeloma Forum database who received lenalidomide (LEN) with or without dexamethasone for the first time. Disease stability index (DSI) was defined as (maximum - minimum values of M protein during the 90 days before the start of LEN) divided by M-protein values at the start of LEN. The patients were classified into three groups: stable (S), DSI ≤ 0.25; increasing (I), DSI > 0.25 with increasing M protein; decreasing (D), DSI > 0.25 with decreasing M protein. In univariate analysis of 352 patients, DSI group "I", non-IgG type, serum albumin<3.5 g/dL, and age≥70 were statistically significant prognostic factors for both progression-free survival and overall survival. In multivariate analysis, the former 3 risk factors were statistically significant for poor overall survival. Thus, DSI is an independent prognostic factor for the treatment with LEN for previously treated MM., (© 2021 John Wiley & Sons Ltd.)

Objectives: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM)., Methods: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database., Result: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type., Conclusion: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Systemic AL amyloidosis is a disease wherein amyloid proteins derived from monoclonal immunoglobulin light chains produced by abnormal plasma cells are deposited in the tissues through the whole body and cause organ failure. The treatment aims to minimize treatment-related toxicity and mortality to achieve a deeper and more persistent hematologic response as early as possible. Stem cell transplantation is preferred; however, only 20% of patients are eligible. Patients are selected as per strict transplant indication criteria. Transplant-ineligible patients receive chemotherapy with high efficacy, such as melphalan/dexamethasone, bortezomib/cyclophosphamide/dexamethasone, and daratumumab/bortezomib/cyclophosphamide/dexamethasone. The prognosis of advanced cardiac amyloidosis remains poor, and delays in diagnosis are fatal. Early diagnosis and early treatment are important to prevent and minimize organ damage.

Extended post-therapy long-term survival of patients with diffuse large B cell lymphoma (DLBCL) may also lead to an increase of late adverse events. We retrospectively investigated the frequency and clinical manifestation of second primary malignancy (SPM) after rituximab-containing immunochemotherapy in patients with DLBCL treated at seven institutes belonging to the Kyoto Clinical Hematology Study Group (KOTOSG) from the perspective of the existence of past or synchronous cancer history. In a median follow-up period of 899 days, 69 SPMs were observed in 58 of 809 patients. The most frequent SPM was gastric cancer, followed by lung cancer and colorectal cancer. The cumulative incidence of SPM increased steadily over time and was not significantly influenced by the presence or absence of past or synchronous cancer history. Our study suggests the need for careful attention to SPM in patients with DLBCL in daily practice.

We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4-93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0-24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.

We retrospectively analyzed the clinical features and outcomes in a real-world cohort of adolescents and the young adult (AYA) patients (age between 16 and 39 years) with symptomatic multiple myeloma (MM) registered with the Kansai Myeloma Forum. 26 patients had been diagnosed as symptomatic MM out of 3284 patients. The prevalence of AYA-MM was 0.8% in this cohort. 81% of the patients was received stem cell transplantation, which may improve outcome. Anemia and hypercalcemia might be prognostic factors, however International Staging System failed to predict overall survival. Five patients developed late-onset adverse events which were serious and life-threatening. The 5-year overall survival was 71.0%. We need to develop the new strategy to overcome AYA-MM.

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

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.

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.

A 50-year-old male was diagnosed with multiple myeloma (MM) and treated by high-dose melphalan followed by autologous stem cell transplantation in April 2014. However, he relapsed and received non-myeloablative bone marrow transplantation from an unrelated HLA-matched donor (UR-BMT) in July 2016. After 100 days of UR-BMT, the disease remained stable disease and the patient was treated with carfilzomib, lenalidomide, and dexamethaonse (KRd) therapy. After 10 cycles of KRd, he obtained stringent complete response without exacerbation of graft-versus-host disease. We concluded that KRd after allogeneic stem cell transplantation is one of the useful treatment regimens for relapsed refractory MM.

A 47-year-old male was admitted to our hospital because of left hypochondrium part pain and was diagnosed with splenomegaly with splenic infarctions in May 2016. His complete blood cell count was almost within normal limits, and a bone marrow biopsy revealed normal cellularity with no fibrosis. In addition, no abnormal uptake was noted on FDG PET/CT. In August 2016, he underwent splenectomy for splenomegaly. The histological examination revealed fibrotic stenosis of the blood vessels in the spleen. After splenectomy, his platelet count elevated and remained at >1,000×10 9 /l 3 months later. Finally, he was diagnosed with latent essential thrombocythemia (ET) because the JAK2V617F mutation was positive. Accordingly, oral hydroxyurea was initiated. Thrombosis could be a complication in myeloproliferative neoplasms (MPN). In our case, ET was masked, perhaps, because of hypersplenism and splenomegaly because of splenic vein thrombosis. Hence, examination of the JAK2V617F mutation in patients with splanchnic vein thrombosis is recommended because of the possibility of latent MPN.

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.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) in the elderly was revised from the category EBV-positive DLBCL not otherwise specified in WHO 2017. The prognosis of this lymphoma is very poor. We report a case of an 82-year-old woman diagnosed with gastric EBV-positive DLBCL (WHO 2008). Gastroduodenoscopy revealed multiple ulcers and fold thickening. She was followed-up without any treatment because of her old age. Repeat endoscopy one year and eight months later revealed a single ulcer with no lymphoma cells found in a biopsy specimen. Two years later, the lesion had spontaneously disappeared.

We retrospectively analyzed twenty-six patients with primary plasma cell leukemia (pPCL) registered from May 2005 until April 2015 by the Kansai Myeloma Forum. Twenty patients received novel agents (bortezomib or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent autologous stem cell transplantation (SCT) was 40 months, those undergoing allogeneic SCT 55 months, and those undergoing both types of SCT (auto-allo) 61 months; whereas for those who did not undergo SCT it was 28 months ( p  = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia.

Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached. The median time to treatment failure (TTF) was 4.4 months. The best response was recorded in 96 patients, with a 31% overall response rate (ORR) and a 79% rate of achieving at least stable disease. Number of pre-POM regimens ≥ 5, non-IgG-type M-protein, and time from initial therapy to POM or POM/DEX therapy < 2 years were associated with shorter TTF and OS. Frequent (> 10%) severe adverse events included neutropenia (55.1%), thrombocytopenia (33.7%), anemia (30.6%), febrile neutropenia (12.2%), fatigue (11.2%), and anorexia (10.2%). In conclusion, POM and POM/DEX showed substantial efficacy against RRMM, but new combination therapies with POM are needed to improve efficacy further without causing hematologic toxicities.

A 61-year-old female was diagnosed with a lymphoid crisis of chronic myeloid leukemia (CML) in February 201X and started chemotherapy combined with dasatinib (DAS). After 1 month of initiating second consolidation therapy, the neutrophils decreased to 1%, bone marrow examination revealed large granular lymphocytes (LGL) at 13%, and complete cytogenetic remission was attained (CCyR). Suspecting DAS-induced agranulocytosis, DAS was discontinued. After 2 weeks, LGL disappeared and neutrophils recovered. In this case, CCyR was attained for the first time when LGL increased. We considered that the expansion of LGL correlated with the clinical efficacy, and agranulocytosis was an off-target effect of DAS.

A 73-year-old male who underwent splenectomy was diagnosed with splenic non-caseating granuloma in May 201X, and sarcoidosis was disregarded from the differential diagnosis. Owing to the persisting inflammation, the patient was carefully followed up with no treatment. Four months post splenectomy, the patient was hospitalized due to progressive dyspnea. Chest computed tomography revealed an encapsulated pleural effusion and lymphocytic infiltration in the left lower lung, with subclavian and mediastinal lymphadenopathy. Although the patient was treated with antibiotics, his condition showed no improvement; therefore, prednisolone 40 mg was administered, resulting in lung lesion improvement. A re-examination of the tissue obtained from the previously removed spleen revealed splenic marginal zone lymphoma (SMZL), a specific low-grade, small B-cell lymphoma. As a result, the patient was treated with rituximab combined with chemotherapy. During the fifth course of the chemotherapy, a subcutaneous abscess appeared in the cervical region, and Mycobacterium shigaense was isolated from the pus discharge, suggesting that the splenic granulomatous lesion formed due to M.shigaense, and dissemination of the Mycobacterium infection occurred following splenectomy and chemotherapy, when the patient was immunosuppressed. Overall, we consider that SMZL developed because of chronic inflammation resulting from a nontuberculous mycobacterial infection.

BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1.7-fold during treatment. The median time to reach maximum values was 17 days. Horn's drug Interaction Probability Scale indicated a possible interaction between lenalidomide and warfarin. These patients exhibited no marked alterations in hepatic function or serum albumin concentrations prior to and following combination chemotherapy and no additional administration of CYP2C9 inhibitors or vitamin K supplements was conducted. In addition, no patient experienced chemotherapy-induced nausea or appetite loss. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Therefore, the combination of warfarin and lenalidomide may cause a pharmacodynamic interaction, more likely by inhibiting the production of interleukin-6. In conclusion, clinically important interactions between warfarin and lenalidomide and low-dose dexamethasone therapy were observed in AL amyloidosis patients, where INR values signi ficantly increased. Therefore, close and regular monitoring of patients during the course of treatment is important, and the dose of warfarin should be reduced if required.

Here we describe the case of a 62-year-old woman diagnosed with multiple myeloma (IgA-κ type) who had a high serum CEA level of 27.7 ng/ml. Upper and lower gastrointestinal endoscopy and PET/CT scan showed no abnormality. After two courses of VAD therapy, the serum CEA level decreased to 5.7 ng/ml, with a decrease in the IgA level, suggesting the diagnosis of CEA-producing myeloma. After 4 years and 1 month, she had a relapse with an increase in the LDH level and myeloma cells in the blood, followed by cognitive loss and convulsion. She died 1 month after the onset of neurological symptoms. Several myeloma cells were detected in the cerebral spinal fluid, which suggested the diagnosis of myelomatous meningitis. Myelomatous meningitis is a rare disease and accounts for 1% of all myelomas. This is the fourth reported case of CEA-producing myeloma.

A 63-year-old male was diagnosed as having chronic phase CML in 2001. He obtained a major molecular response with imatinib (IM). In 2012, amulodipin was started for hypertension. In January 2013, IM was switched to nilotinib (NIL) in a clinical trial, and in February 2015, NIL was discontinued because MR 4.5 had been maintained for two years. One month later, he was admitted to our hospital because of headache and high blood pressure (194/108 mmHg). His urine test showed protein 3+ and occult blood 2+. His eGFR rapidly deteriorated from 45.6 to 28.5 after admission. MR angiography showed left renal artery stenosis. He thus underwent angioplasty of the left renal artery with a stent implantation. His renal function subsequently improved. Cardiovascular events such as PAOD (peripheral artery occlusive disease) during NIL treatment were recently reported. However, to date, only four cases including our present patient with renal artery stenosis associated with NIL have been reported. These observations suggest assessment of risk factors for cardiovascular events at the start of NIL and careful monitoring to be important during tyrosine kinase inhibitor treatment of CML patients.

The aim of the present study was to clarify whether gastric antisecretory drugs affect the clinical efficacy and toxicity of orally administered melphalan in patients with multiple myeloma. A total of 10 patients receiving bortezomib plus oral melphalan and prednisolone (VMP) therapy between December 2011 and November 2014 were analyzed retrospectively. The patients were divided into a control group (seven patients) and a concomitant group (three patients, who were also administered with gastric antisecretory drugs). The gastric antisecretory drugs included rabeprazole sodium (two patients) and famotidine (one patient). No significant differences between the groups were observed in either the characteristics of the patients or the VMP regimen. The levels of monoclonal protein (M protein) in the control group tended to decrease (with a VMP cycle-dependency), although they were primarily stable in the concomitant group. During the second and third VMP cycles, the levels of M protein were markedly lower in the control group compared with the concomitant group. All the patients in the control group achieved a partial response, whereas those in the concomitant group exhibited stable disease. Hematological toxicity levels were revealed to be comparable between the two groups, whereas gastrointestinal toxicity was more prevalent in the control group. In conclusion, the results of the present study suggested that the clinical efficacy of melphalan may be reduced by the co-administration of gastric antisecretory drugs. This interaction may result in decreased toxicity and clinical efficacy of melphalan.

A 64-year-old man with recurrent multiple myeloma (BJP-κ type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug.

We examined the effect of thalidomide and dexamethasone on the migration of multiple myeloma (MM) cell lines, U266, RPMI8226, and NCI-H929, using chemotaxis chamber plates. U266 underwent chemotactic migration in response to stromal-cell derived factor-1 alpha (SDF-1alpha), and other cell lines underwent random migration in response to SDF-1alpha or monocyte chemotactic protein-1 alpha. Following preincubation with 1 mug/ml thalidomide, the cell lines showed reduced migratory capacity in response to SDF-1alpha. Concerning the corresponding receptors, CXC chemokine receptor 4 was detected only on the surface of U266, by flow cytometry, whereas chemokine (C-C motif) receptor 2 was not detected on all three cell lines. Moreover, decreased migration by thalidomide was not accompanied by altered expression of the corresponding receptors of each cell line. This is the first report to show the effects of thalidomide on the migration of MM cell lines. The results suggest that the inhibition of chemotactic migration might be one of the mechanisms of the success of thalidomide in controlling MM.

Background: The molecular mechanism of natural killer (NK) cell cytotoxicity to myeloma cells remains unclear. We investigated whether MHC class I-related chain (MIC), a ligand of NKG2D that is an activating NK cell receptor, is involved in the cytotoxicity of NK cells toward myeloma cells, and examined the effects of various drugs on the cytotoxicity., Methods: Two human myeloma cell lines and fresh myeloma cells from 10 patients were used. MIC expression was examined by flow cytometry and reverse transcription (RT)-PCR. NK cell cytotoxicity was examined using a 51Cr-release assay. The effects of various drugs, including thalidomide, all-trans retinoic acid, dexamethasone, IFN-alpha and incadronate, on the MIC expression and NK cell cytotoxicity were examined., Results: MIC was highly expressed on the human myeloma cell lines U266 and RPMI-8226 and in myeloma cells of one of 10 patients examined. MIC expression on these cells was not changed by various drugs except IFN-alpha, by which MIC expression was down-regulated. Although MIC and HLA class I molecules were similarly expressed at high levels on both cell lines, U266 was sensitive to NK cells whereas RPMI-8226 was not. Furthermore, cytolysis by NK cells was not inhibited by the addition of anti-MIC Ab or decreased expression of MIC caused by IFN-alpha., Discussion: MIC plays a role in the cytolysis by NK cells in multiple myeloma.