This phase 1, open‐label, dose‐escalation study investigated the tolerated dose (recommended dose), safety, efficacy, and pharmacokinetics of pomalidomide alone or pomalidomide plus low‐dose ...dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Twelve patients were enrolled. Patients received pomalidomide 2 mg (Cohort 1) or 4 mg (Cohort 2) orally on day 1 and days 3–21 of a 28‐day cycle. The tolerated dose of pomalidomide was determined to be 4 mg given on days 1–21 of a 28‐day cycle. Efficacy outcomes with pomalidomide plus low‐dose dexamethasone were consistent with those of previous studies. Responses (partial response or better) were achieved by three patients (25%; 1 17% in Cohort 1 and 2 33% in Cohort 2), and the median time to response was 6.4 months overall (9.0 months for Cohort 1 and 4.2 months for Cohort 2). The median progression‐free survival was 5.5 months overall (5.1 months for Cohort 1 and not reached for Cohort 2). The most frequently occurring grade ≥3 adverse events were neutropenia (67%), anemia (25%), lymphopenia (25%), and pneumonia (25%), consistent with previous studies of pomalidomide plus low‐dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Further investigation of pomalidomide is recommended for Japanese patients with refractory or relapsed and refractory multiple myeloma. This study was registered with ClinicalTrials.gov (NCT01568294).
This phase 1, open‐label, dose‐escalation study in Japanese patients with refractory or relapsed and refractory multiple myeloma investigated the tolerated dose (TD; recommended dose), safety, efficacy, and pharmacokinetics of single‐agent pomalidomide or pomalidomide plus low‐dose dexamethasone. The TD was found to be pomalidomide 4 mg days 1–21 of a 28‐day cycle. Pomalidomide plus low‐dose dexamethasone demonstrated efficacy in this patient population (median progression‐free survival = 5.5 months) and the safety profile was consistent with prior studies of pomalidomide.
We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0 mg/m
2
. We then ...conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0 mg/m
2
was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9 mg/m
2
on days 1–4, and dexamethasone 20 mg orally on days 1–2, 4–5, 8–9 and 11–12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89 % with CR rate of 30 %. The median PFS time was 12.1 months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22 %) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration.
We evaluated the clinical significance of prognostic factors including the International Staging System (ISS) and modified European Group for Blood and Marrow Transplantation response criteria in ...1650 Japanese patients with multiple myeloma (MM) who underwent upfront single autologous stem cell transplantation (ASCT). We categorized patients into two treatment cohorts: pre‐novel agent era (1995–2006) and novel agent era (2008–2011). The combined percentage of pre‐ASCT complete response and very good partial response cases (463 of 988, 47%) significantly increased during the novel agent era compared with the pre‐novel agent era (164 of 527, 31%; P < 0.0001). The 2‐year overall survival (OS) rate of 87% during the novel agent era was a significant improvement relative to that of 82% during the pre‐novel agent era (P = 0.019). Although significant differences in OS were found among ISS stages during the pre‐novel agent era, no significant difference was observed between ISS I and II (P = 0.107) during the novel agent era. The factors independently associated with a superior OS were female gender (P = 0.002), a good performance status (P = 0.024), lower ISS (P < 0.001), pre‐ASCT response at least partial response (P < 0.001) and ASCT during the novel agent era (P = 0.017). These results indicate that the response rate and OS were significantly improved, and the ISS could not clearly stratify the prognoses of Japanese patients with MM who underwent upfront single ASCT during the novel agent era.
We evaluated the clinical significance of the International Staging System (ISS) and modified European Group for Blood and Marrow Transplantation response criteria in 1650 Japanese patients with multiple myeloma who underwent upfront single autologous stem cell transplantation (ASCT). The factors that were independently associated with superior OS were female gender (P = 0.002), a good performance status (P = 0.024), lower ISS (P < 0.001), pre‐ASCT response at least partial response (PR) (P < 0.001), and ASCT during the novel agent era (P = 0.017). No significant differences in OS were found between the ISS I and II (P = 0.107) during the novel agent era.
Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard ...international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.
A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell ...transplantation (HSCT). Adult patients (
n
= 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (
n
= 52), or fluconazole 400 mg (
n
= 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, −5.4 to +17.4%;
P
= 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (
P
= 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.
To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with ...newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15–60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.
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.
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.
Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood ...stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one‐third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.
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