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HighlightsThe prevalence of pPCL was 1.2%.Treatment with novel agents and transplantation may yield a better prognosis.Hypercalcemia at diagnosis was suggested to predict worse outcomes.

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Introduction There has been dramatic evolution in multiple myeloma (MM) therapy in the last decade. The novel agents (Thal, Bor, and Len) have been reported to improve natural history of the cases with MM. In order to use optimal drugs for each patient, we should investigate the actual conditions of the clinical practice. However, we could not have the information regarding epidemiology, clinical features, treatment results, prognosis, and so on because there is no large-scale database demonstrating the clinical features of MM-related diseases in Japan. Therefore, we have founded the study group, named as Kansai Myeloma Forum (KMF), for the purpose of registering the cases with MM-related diseases in Kansai area of Japan on November, 2012. In this study, we analyzed the clinical characteristics and outcomes of MM-related diseases registered in KMF and evaluated the treatment strategies in the novel agent era. Patients & Results Among a total of 923 cases initially diagnosed since 2006 and registered to KMF database until March 31, 2013, we analyzed 434 symptomatic MM cases (213 females/221 males), who were treated since 2006. The median age was 69 (range: 32-96), and the OS rates at 3 and 5 years were 68.7% and 45.3%, respectively. The prognosis of the cases treated after 2010 became significantly better than that of the cases treated between 2006 and 2009 (log-rank test: P=0.019). The prognosis of the cases treated with the novel agents was significantly better than without them (p=0.005). Among the non-transplanted 339 cases, the effects of the novel drugs were shown more clearly (p=0.002). The best response during the course differentiated the prognosis; the hazard ratios of CR, VGPR, PR, SD and PD compared to sCR were 2.23, 3.19, 9.54, 16.84 and 432.01, respectively (P<0.001). Ninety-five cases received the high-dose melphalan therapy (HD-MEL) with stem cell support. The OS rate of these 95 cases was significantly better than that of non-transplanted 339 cases (90.1% at 3-year/61.4% at 5-year vs. 61.6%/40.2%, p<0.001). CR/sCR rate after HD-MEL was 50%. Also, 83 out of 95 cases received at least one of the novel agents during their clinical courses, and 51 cases achieved CR/sCR as best response, showing significant better survival than the cases with best response of VGPR or <PR (p=0.008). The superiority of OS in HD-MEL group was also observed even when less than 65 years old patients (74 out of 95 patients) were compared to 55 patients (≤ 65 years) without HD-MEL but receiving novel agents (90.6% at 3-year/71.4% at 5-year vs. 73.6%/47.3%, p=0.036). Next, we analyzed 123 cases with MGUS and 54 with smoldering MM (SMM), who had diagnosed in 2006 or later. The median age at diagnosis was 66.0 (range: 34-88) in 123 MGUS cases (53 females/70 males). The type of paraprotein detected was IgA in 15.4% of the cases and IgG in 69.1 %. With a median follow-up period of 27.2 months, 8 cases (6.5%) received chemotherapies due to the disease evolution. The evolution rates at 1, 3 and 5 years after the diagnosis were 2.1%, 9.0% and 12.0%, respectively (2.4% per year). The 3-year OS after the start of treatments was 75.0%. In 54 SMM cases (29 females/25 males), the median age was 68.2 (range: 40-87), and IgG and IgA types comprised 72.2% and 14.8%, respectively. With a median follow-up period of 22.4 months, 15 cases (27.8%) received chemotherapy due to progression to symptomatic MM. The evolution rates at 1, 3 and 5 years after diagnosis were 15.4%, 36.7% and 62.5%, respectively (12.5% per year). The 3-year OS after the start of treatments was 76.9%. Discussion & Conclusion The current study revealed the significant effects of novel agents on symptomatic MM cases in the practical use. It has been still unknown and controversial whether HD-MEL with auto-PBSCT is necessary or not in the novel agent era. In this analysis, it was shown that HD-MEL could provide significant survival benefit to symptomatic MM cases even in the novel-agent era. However, it is necessary to determine when and how we should perform HD-MEL for MM during therapeutic sequences including novel agents. This study also suggested that it might be unnecessary to generally consider an early chemotherapy to MGUS or SMM cases before the evolution, since the prognosis after the evolution seemed not to be inferior to that of the de-novo symptomatic MM. Thus, KMF database would provide abundant and beneficial information to consider the treatment strategies of the cases with MM-related diseases. Disclosures: Tanaka: celgene: Research Funding. Kosugi:Janssen: Honoraria; celgene: Research Funding. Kida:celgene: Research Funding. Ohta:celgene: Research Funding. Yamamura:celgene: Research Funding. Shibayama:Janssen: Honoraria; celgene: Honoraria, Research Funding. Kohara:celgene: Research Funding. Kaneko:celgene: Research Funding. Fuchida:celgene: Research Funding. Kobayashi:celgene: Research Funding. Miyamoto:celgene: Research Funding. Shindo:celgene: Research Funding. Kuroda:celgene: Research Funding. Uoshima:celgene: Research Funding. Matsumura:celgene: Research Funding. Yoshii:celgene: Research Funding. Kamitsuji:celgene: Research Funding. Boku:celgene: Research Funding. Ishii:celgene: Research Funding. Matsuda:celgene: Research Funding. Takahashi:celgene: Research Funding. Hamada:celgene: Research Funding. Adachi:celgene: Research Funding. Nakatani:celgene: Research Funding. Nomura:celgene: Research Funding. Taniwaki:celgene: Research Funding. Takaori:celgene: Research Funding. Shimazaki:celgene: Research Funding. Tsudo:celgene: Research Funding. Hino:celgene: Research Funding. Matsumura:Janssen: Honoraria, Research Funding; celgene: Research Funding. Kanakura:celgene: Research Funding.

Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted. Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS. Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p<0.0001) (Figure 1). A univariate analysis showed that age >65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) >3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC <4000/µL, amyloidosis, fluid retention, pleural effusion, ascites, serum albumin ≤3.5 g/dL, serum creatinine >1.5 mg/dL, CRP >2.0 mg/dL and sIL-2R >4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG >3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG >3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG >3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p<0.0001) (Figure 2). The survival of patients with both poor risk in our model and high risk in ISSWM were extremely poor (5-year OS: poor and high [n=57], 24.7%; poor and intermediate [n=14], 80.0%; poor and low [n=2], not available; p=0.0031). In contrast, no significant differences were observed for the survival for the ISSWM risk groups in patients with good risk in our model (5-year OS: good and high [n=69], 76.0%; good and intermediate [n=83], 81.6%; good and low [n=42], 89.5%; p=0.2045). Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.