Changing trends in prognostic factors for patients with multiple myeloma after autologous stem cell transplantation during the immunomodulator drug/proteasome inhibitor era

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.     

PAD序贯自体造血干细胞移植治疗难治多发性骨髓瘤(附22例)

目的:多发性骨髓瘤(multiple myeloma,MM)至今仍不可治愈,几乎所有病人均会出现复发或难治,本文初步探讨硼替佐米应用于难治性MM患者PAD化疗并序贯自体外周血造血干细胞移植(autologous pe-ripheral blood stem cell t ransplantation,APBSCT)的可行性和疗效。方法:采用PAD(硼替佐米+阿霉素+地塞米松)方案治疗复发或难治性MM。结果:22例中3例难治MM患者给予PAD方案化疗4-6个疗程后,2例达到接近完全缓解(nCR),1例达到部分缓解(VGPR),并随后行APBSCT,动员方案PAD+CTX(PAD,环磷酰胺1.5g/m2,d15)联合G-CSF。预处理方案为马法兰140mg/m2。移植后采用沙利度胺100mg/天。所有患者在移植前均达到CR或VGPR,干细胞采集充分,安全有效,移植后造血功能均快速顺利重建。无1例死亡。移植后采用沙利度胺维持,随访3-12个月,病情稳定。结论:PAD用于难治MM患者的治疗达CR后,继续序贯进行APBSCT不仅可行,而且PAD不影响正常造血干细胞动员,故采用PAD和序贯用PAD+CTX动员方案的APBSCT的治疗手段,为难治MM患者的治疗提供新的治疗手段。但对长期生存的改善作用需进一步研究。     

PAD序贯自体造血干细胞移植治疗难治多发性骨髓瘤（附22例）

目的：多发性骨髓瘤（multiple myeloma,MM）至今仍不可治愈,几乎所有病人均会出现复发或难治,本文初步探讨硼替佐米应用于难治性MM患者PAD化疗并序贯自体外周血造血干细胞移植（autologous pe-ripheral blood stem cell t ransplantation,APBSCT）的可行性和疗效。方法：采用PAD（硼替佐米＋阿霉素＋地塞米松）方案治疗复发或难治性MM。结果：22例中3例难治MM患者给予PAD方案化疗4-6个疗程后,2例达到接近完全缓解（nCR）,1例达到部分缓解（VGPR）,并随后行APBSCT,动员方案PAD＋CTX（PAD,环磷酰胺1.5g/m2,d15）联合G-CSF。预处理方案为马法兰140mg/m2。移植后采用沙利度胺100mg/天。所有患者在移植前均达到CR或VGPR,干细胞采集充分,安全有效,移植后造血功能均快速顺利重建。无1例死亡。移植后采用沙利度胺维持,随访3-12个月,病情稳定。结论：PAD用于难治MM患者的治疗达CR后,继续序贯进行APBSCT不仅可行,而且PAD不影响正常造血干细胞动员,故采用PAD和序贯用PAD＋CTX动员方案的APBSCT的治疗手段,为难治MM患者的治疗提供新的治疗手段。但对长期生存的改善作用需进一步研究。     

高危多发性骨髓瘤的现状挑战与思考

多发性骨髓瘤(multiple myeloma,MM)是一种常见的血液系统恶性肿瘤,其发病率居血液系统恶性肿瘤第2位,目前仍不可治愈.不同MM患者生存时间跨度大,短至数月,长至15年以上,这说明MM患者间存在着非常大的生物学异质性,因此根据细胞遗传学异常、临床特征、基因表达谱等因素将MM进行危险度分层,对判断该病的疾病...     

Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of weekly bortezomib in the treatment of patients with recurrent/refractory multiple myeloma. METHODS: A total of 40 patients with multiple myeloma who had received either 1 or 2 previous treatment regimens were treated with bortezomib at a dose of 1.6 mg/m(2) intravenously for 4 consecutive weeks, followed by 1 week without treatment. Responses were measured using International Myeloma Working Group criteria. RESULTS: Twenty-two patients (55%; 95% confidence interval, 40%-70%) achieved objective responses to treatment, with a median response duration of 16 months. The median progression-free survival for all patients was 9.6 months, with a 1-year progression-free survival rate of 39%. The 1-year and 2-year overall survival rates were 75% and 51%, respectively. Weekly bortezomib was generally well tolerated; grade 3/4 (using the National Cancer Institute Common Toxicity Criteria [version 3.0]) neutropenia (13%), thrombocytopenia (20%), fatigue (15%), diarrhea (13%), and neuropathy (10%) were experienced by a minority of patients. CONCLUSIONS: In the current study, a schedule of weekly bortezomib was found to be effective and well tolerated in patients with previously treated multiple myeloma. Although the response rate and duration appear comparable to those achieved with twice-weekly bortezomib, the relative efficacy of these 2 schedules cannot be determined definitively on the basis of this phase 2 study. A weekly schedule of bortezomib is a reasonable option for patients who have logistic difficulties receiving a twice-weekly schedule, and is an attractive schedule for incorporation into combination regimens.     

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array

Bortezomib‐ and thalidomide‐based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment‐induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome‐wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest‐ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.     

HLA genotyping in Japanese patients with multiple myeloma receiving bortezomib: An exploratory biomarker study of JCOG1105 (JCOG1105A1)

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.     

Novel agents-based regimens as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials

To investigate the effect of novel agents like bortezomib, lenalidomide and thalidomide as part of induction treatment prior to autologous stem-cell transplantation (ASCT) for previously untreated patients with multiple myeloma, we performed a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched for RCTs of novel agents as part of induction therapy before ASCT. Three RCTs of bortezomib, two RCTs of thalidomide and no RCT of lenalidomide were identified, covering a total of 2,316 subjects. Due to different mechanisms of action, we performed a subgroup analysis by type of agent (thalidomide or bortezomib). The weighted risk ratios of a complete response (CR) were 4.25 [95% CI: 2.44-7.41] (p < 0.001) for bortezomib and 1.66 [95% CI: 1.15-2.38] (p = 0.007) for thalidomide, respectively. The summary hazard ratios for progression-free survival (PFS) were 0.73 [95% CI: 0.59-0.89] (p = 0.002) for bortezomib and 0.68 [95% CI: 0.59-0.79] (p < 0.001) for thalidomide, respectively. The corresponding ratios for overall survival (OS) were 0.87 [95% CI: 0.64-1.18] (p = 0.37) and 0.88 [95% CI: 0.73-1.05] (p = 0.14), respectively. Additionally, there was a statistically significant heterogeneity between subgroups (thalidomide and bortezomib) for CR (p = 0.005) but nonsignificant for PFS (p = 0.64) and OS (p = 0.97). In conclusion, our analysis showed novel agents as induction treatment prior to ASCT improved CR and PFS but not OS.     

Reduced survival after autologous stem cell transplantation in myeloma and lymphoma patients with low vitamin D serum levels

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is applied for consolidation in myeloma and relapsing lymphoma patients. Vitamin D (VitD) exerts effects during hematopoietic stem cell proliferation, differentiation and interactions with the immune system. VitD deficiency is frequent in patients with hematological malignancies, but its prognostic relevance after ASCT remains unclear. We investigated the effect of VitD serum levels in patients with lymphomas and myeloma at ASCT on progression-free (PFS) and overall survival (OS). The cohort (n = 183) was divided into two groups: 81 (44%) had VitD levels >52 nmol/L and 102 (56%) ≤52 nmol/L at ASCT. VitD levels >52 nmol/L were associated with better PFS (P = 0.0194) and OS (P = 0.011). Similarly, when evaluating myeloma patients alone, patients with lower VitD levels (≤52 nmol/L) had inferior PFS (P = 0.0412) and OS (P = 0.049). Finally, the multivariate analysis was consistent that varying VitD levels were significantly associated with OS (P = 0.0167), also when stratifying patients in groups with VitD levels > versus ≤52 nmol/L (P = 0.0421). Our data suggest that reduced serum VitD levels in myeloma and lymphoma patients undergoing HDCT/ASCT are associated with inferior outcome. Optimizing VitD levels before ASCT may be warranted.     

Immunologic approaches for the treatment of multiple myeloma

The FDA approval of two monoclonal antibodies in 2015 has heralded a new era of targeted immunotherapies for multiple myeloma (MM). In this review we discuss the recent approaches using different immunological components to treat MM. In particular, we review current monoclonal antibody based therapies, engineered T- and NK cell products, ‘off-target’ immunomodulation, and strategies utilizing allogeneic cell transplantation in MM. We discuss how an immunologic approach offers promise for the treatment of this genetically heterogeneous disease, and how patients with acquired drug resistance may particularly benefit from these therapies. We also describe some of the limitations of the current strategies and speculate on the future of personalized immunotherapies for MM.     

T - VAD 方案联合自体外周血造血干细胞移植治疗多发性骨髓瘤的疗效观察

目的：观察 T - VAD 方案联合自体外周血造血干细胞移植（ autologous peripheral blood hematopoietic stem cells,APBSC）治疗多发性骨髓瘤（multiple myeloma,MM）的临床疗效及不良反应。方法：选取2010年1月-2014年12月采用 T - VAD 方案联合自体外周血造血干细胞移植治疗的30例多发性骨髓瘤患者的临床资料进行回顾性研究。T - VAD 方案：沙利度胺起始剂量为50mg/晚,每周增加50～100mg/晚,最大剂量200mg/晚,若无明显不适,持续服用。长春新碱0.4mg/ d,静脉滴注,第1～4d;多柔比星10mg/（m2·d）,静脉滴注,第1～4d;地塞米松40mg/ d,静脉滴注,第1～4d,第9～12d,28d 为一个疗程,共4个疗程。T - VAD 方案4个疗程诱导治疗后给予自体外周血造血干细胞采集、移植术。结果：患者移植术后,造血功能均顺利重建,无移植相关的死亡发生。30例患者在移植后3个月,完全缓解10例（33.3%）,高质量缓解（非常好的部分反应,VGPR）16例（53.3%）,部分反应2例（6.6%）,无变化2例（6.6%）。不良反应主要有不同程度的恶心、呕吐、脱发及骨髓抑制等。结论：T - VAD 联合自体外周血造血干细胞移植治疗多发性骨髓瘤疗效明显,患者耐受性好。     

Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials

We performed analyses of the randomized phase 3 ASPIRE and ENDEAVOR trials to investigate the efficacy of carfilzomib among subgroups of relapsed or refractory multiple myeloma patients who had early or late disease relapse following initiation of the immediately prior therapy. In ASPIRE and ENDEAVOR, patients had received 1 to 3 prior lines of therapy. Patients in ASPIRE received carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide and dexamethasone (Rd), and patients in ENDEAVOR received carfilzomib and dexamethasone (Kd) or bortezomib and dexamethasone (Vd). Patients with relapse ≤1 year after initiating the most recent prior line of therapy were categorized as early relapsers, and patients with relapse after >1 year were categorized as late relapsers. The median progression‐free survival (PFS) in ASPIRE for early relapsers was 21.4 months for KRd vs 10.7 months for Rd (hazard ratio [HR]: 0.714; 95% confidence interval [CI]: 0.508–1.004; P = 0.0257), and for late relapsers was 29.7 months for KRd vs 18.2 months for Rd (HR: 0.675; 95% CI: 0.533–0.854; P = 0.0005). The overall response rate (ORR) for early relapsers was 83.2% for KRd vs 54.8% for Rd, and for late relapsers was 89.0% for KRd vs 69.7% for Rd. The median PFS in ENDEAVOR (Kd vs Vd) for early relapsers was 13.9 months vs 5.7 months (HR: 0.598; 95% CI: 0.423–0.846; P = 0.0017), and for late relapsers was 22.2 months vs 10.2 months (HR: 0.486; 95% CI: 0.382–0.620; P < 0.0001). The ORR (Kd vs Vd) for early relapsers was 63.4% vs 49.1% and for late relapsers was 81.8% vs 66.8%. In conclusion, patients with relapsed or refractory multiple myeloma who received carfilzomib‐containing regimens had improved PFS and ORR compared with control groups, regardless of whether they had an early or late relapse following the most recent prior therapy.     

Paclitaxel‐releasing mesenchymal stromal cells inhibit the growth of multiple myeloma cells in a dynamic 3D culture system

Multiple myeloma is an aggressive tumour able to suppress osteoblastogenesis probably mediated by bone marrow mesenchymal stromal cells (BM‐MSCs) that can also support plasma cell growth/survival. The use of MSCs for multiple myeloma therapy is a controversial topic because of the contradictory results on the capacity of MSCs to inhibit or to promote cancer growth. Our previous studies demonstrated that MSCs could be loaded with Paclitaxel (PTX) and used to deliver the drug in situ in amount affecting tumour growth (in vitro and in vivo). Therefore, independently on the discussed action of MSCs in myeloma, MSCs could represent a ‘trojan horse’ to vehicle and deliver anti‐tumour agents into bone marrow. This study confirms, by an in vitro 3D dynamic culture system, that PTX loaded BM‐MSCs (PTXr‐MSCs) are active on the proliferation of RPMI 8226, a human myeloma cell line. Our results demonstrated a dramatic suppression of myeloma cell growth by PTXr‐MSCs, suggesting that drug loaded MSCs could be a tool to deliver drug into the bone marrow. Drug releasing MSCs provide a therapeutic approach to potentiate the existing treatments against a very aggressive malignancy as multiple myeloma. Copyright © 2016 John Wiley & Sons, Ltd.     

Prognostic relevance of CD56 expression in multiple myeloma: a study including 107 cases treated with high-dose melphalan-based chemotherapy and autologous stem cell transplant

CD56 is a neural adhesion molecule and expressed in 70-80% cases of multiple myeloma (MM). Lack of CD56 expression has shown to be a poor prognosis in MM patients treated with conventional chemotherapy, but its prognostic relevance in MM treated with high dose chemotherapy and autologous stem cell transplant (ASCT) is not known. CD56 expression was evaluated by immunohistochemistry on bone marrow paraffin embed specimens from 107 MM cases undergoing Melphalan-based high dose therapy and ASCT. CD56 was expressed by the myeloma cells in 71% of the patients. CD56 negative myeloma was associated with bone lesions ( p = 0.032), but there was no association with any other biological or genetic risk factors including deletions 13q, p53 and IgH translocations, as evaluated by fluorescence in situ hybridization (FISH). There was no significant difference between CD56 positive and CD56 negative myeloma for progression free or overall survival ( p = 0.28 and p = 0.67, respectively). In contrast to reports of CD56 in myeloma treated with conventional chemotherapy, CD56 negativity was not found to confer a poor prognosis in these patients, suggesting Melphalan-based high-dose chemotherapy and ASCT may overcome the adverse influence of CD56 negative myeloma.     

Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation

Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean +/- SD: 67 +/- 54 ng/mL vs. 38 +/- 13 ng/mL; p = 0.006) and controls (31 +/- 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 +/- 63 vs. 40 +/- 13; p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 +/- 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma.     

Successful treatment with a modified bortezomib schedule of weekly and longer intervals for patients with refractory/resistance multiple myeloma

Bortezomib is a potent agent for multiple myeloma (MM); however, severe treatment-related toxicities such as peripheral neuropathy have been observed in conjunction with its use. In this study, we present the cases of 9 patients with refractory MM whose administration schedule was modified from twice weekly to an interval of once weekly or longer mainly due to adverse events. The average duration from diagnosis to the time of bortezomib induction was 56 months. The schedule was changed to the modified administration according to the physician's discretion. The average duration of modified treatment was 16 months. Six patients with IgG or IgA subtype showed more than a minor response. One patient with BJP had stable disease for 3 years, and the other BJP-type patient with extramedullary plasmacytomas showed remarkable tumor regression. The treatment-related toxicities of this strategy were mild and tolerable. To our knowledge, this is the first report of the administration of bortezomib at intervals longer than once weekly.