Bortezomib Maintenance Therapy as a Standard of Care Provides Favorable Outcomes in Newly Diagnosed Myeloma Patients: A Multisite Real-Life Study

BackgroundLenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM.Patients and MethodsA retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m²) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy.ResultsA total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P < .001) and OS (P < .001) among transplant-ineligible but not transplant-eligible patients.ConclusionAnalysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease.     

多发性骨髓瘤患者血清血管生成素水平的测定及意义

目的研究血管生成素（Angs）与多发性骨髓瘤（MM）的关系并探讨其临床意义。方法用双抗体夹心酶联免疫吸附测定法检测60例MM患者不同时期的Angs血清浓度,观察其与MM临床分期、肿瘤量分级和治疗效果的关系。结果MM患者血清中Ang-2较正常对照组明显升高;血清Ang-1含量与正常对照组差异无统计学意义。MM患者Ⅱ期的Ang-2血清水平显著低于Ⅲ期。不同肿瘤量分级的MM患者血清Ang-2含量差异有统计学意义。MM治疗有效者,血清Ang-2水平比治疗前明显降低,血清Ang-1水平与治疗前差异无统计学意义;治疗无效者,其血清Ang-1、Ang-2含量与治疗前比较差异均无统计学意义。结论MM患者血清Ang-2水平测定对MM的发病机制研究、病情评价、疗效监测、预后预测有一定意义。     

Deep Sequencing Reveals Myeloma Cells in Peripheral Blood in Majority of Multiple Myeloma Patients

IntroductionThe evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease–detection methods.Materials and MethodsWe developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points.ResultsUsing this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R² = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results.ConclusionThis study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages.     

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies

IntroductionTreatment for multiple myeloma (MM) has continued to evolve with second generation immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). This study aims to evaluate the epidemiology and risks of infection in patients with MM managed with these therapies.Patients and MethodsClinical and microbiological records were reviewed to capture patient demographics, disease characteristics, treatment received, episodes of infection, and outcomes. Infections were classified as microbiologically defined (MDI), clinically defined (CDI), and fever of unknown focus (FUF). Univariate and multivariate analyses were performed to determine risk factors for infection, with a P value < .05 considered statistically significant.ResultsA total of 148 patients with MM with 345 infection episodes were identified. Of these, 29.0% (100/345), 58.0% (200/345), and 13.0% (45/345) were defined as MDI, CDI, and FUF, respectively. Of 100 MDIs, 50.0% were owing to viruses, whereas 45.0% were owing to bacterial infection. The most common infection site was the respiratory tract (56.8%). Hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. On multivariate regression, receipt of a PI (odds ratio [OR], 16.80; 95% confidence interval [CI], 2.47-114.52), combination of IMiD and PI (OR, 13.44; 95% CI, 2.39-75.76), mAb-combination (OR, 10.44; 95% CI, 1.99-54.51), and lines of therapy (> 4) (OR, 7.72; 95% CI, 1.25-47.81) were associated with increased risk of infection (all P < .05).ConclusionViral infections now constitute the majority of infections in patients with MM treated with newer agents. Receipt of a PI and lines of therapy (> 4) were associated with higher risk for infection.     

New Agents in Multiple Myeloma: An Examination of Safety Profiles

Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib. Cardiac toxicity was observed with thalidomide and may occur with proteasome inhibition. Thromboembolic complications occur with thalidomide and its derivatives, but are less common with bortezomib. Peripheral neuropathy (PN), an important complication of MM, may be exacerbated by bortezomib and thalidomide, and was also observed with lenalidomide. In contrast, PN is rarely observed with carfilzomib and pomalidomide. Renal impairment reduces the clearance of lenalidomide but does not seem to affect substantially the pharmacokinetics of pomalidomide, carfilzomib, or bortezomib. Several therapies have recently been approved, such as the oral proteasome inhibitor ixazomib, the HDAC inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Others are still in clinical development, including the HDAC inhibitors romidepsin and vorinostat, with safety data continuing to emerge. Therapy decisions should consider safety profiles in association with pre-existing comorbidities and toxicities from previous therapeutic regimens. Optimal treatment selection and the management of toxicities will result in fewer patients requiring dose reductions and treatment discontinuations, ultimately leading to improved outcomes.     

唑来膦酸联合89 S r治疗恶性肿瘤晚期多发骨转移的疗效观察

目的 探讨恶性肿瘤晚期多发骨转移患者采用唑来膦酸联合89 Sr治疗的临床疗效.方法 将90例恶性肿瘤晚期多发骨转移患者,按照随机抛硬币法将其分组为对照组(唑来膦酸静脉滴注)与观察组(唑来膦酸静脉滴注联合89 Sr静脉注射),各45例.采用疼痛视觉模拟法(VAS)评价两组患者治疗前、后疼痛情况,通过问卷调查表调查两组患者治疗前、后生活质量改善情况,统计两组临床疗效及不良反应.结果 治疗后,两组患者VAS评分及生活质量各项指标均较治疗前明显改善,而观察组各项指标改善程度优于对照组,P<0.05.观察组治疗临床有效率为84.4%,明显高于对照组(66.7%),P<0.05;两组患者不良反应率比较,P>0.05.结论 唑来膦酸联合89 Sr治疗恶性肿瘤晚期多发骨转移可缓解患者疼痛,提高临床治疗效果,改善其生活质量,同时不会增加治疗期间所产生的不良反应,因此值得深入研究以利于其推广应用.     

Survival Benefit of Zoledronic Acid in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors

Purpose

A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors.

Methods

Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines.

Results

The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99).

Conclusion

Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.     

异基因造血干细胞移植在年轻多发性骨髓瘤患者治疗中的应用

目的探讨异基因造血干细胞移植在年轻多发性骨髓瘤治疗中的疗效及安全性。方法回顾性分析我科2003年4月至2012年6月行清髓异基因造血干细胞移植(allo-SCT）的22例多发性骨髓瘤患者,中位年龄为44.5岁（30～54岁）。所有患者随访至2012年10月。中位随访时间11月（0.9～92月）。结果22例患者移植前完全缓解率为13.6%,移植后完全缓解率达63.6%。100天内移植相关死亡率（TRM）为9.1%。1年内TRM为22.7%。1年内的复发率为13.6%。随访期内总生存率为68.2%,无进展生存率为50%。多因素分析未显示年龄、性别、移植前缓解状态及诊断至移植时长是影响总生存期的独立危险因素。结论清髓的异基因造血干细胞移植用于年轻多发性骨髓瘤患者具有较好的疗效及安全性,且一年内复发率较低。     

唑来膦酸联合靶向及免疫调节药物的抗肿瘤研究进展

唑来膦酸是第三代含氮双磷酸盐,在临床中广泛用于治疗骨疾病。既往研究发现唑来膦酸在体内外对多种肿瘤细胞均有抗肿瘤作用,同时可以协同增加化疗、内分泌治疗、放疗等抗肿瘤疗效。最近研究发现,唑来膦酸亦可以协同增加靶向及免疫调节药物的抗肿瘤疗效,其抗肿瘤作用机制与抑制甲羟戊酸代谢途径、影响肿瘤信号通路、调节免疫反应、抗血管生成等有关。本文综述了唑来膦酸联合靶向及免疫调节药物在抗肿瘤治疗方面的研究进展。     

Clinical Characteristics and Prognosis of MAF Deletion in Chinese Patients With Multiple Myeloma

BackgroundIn this study, we analyzed the frequency, clinical characteristics, and prognosis of MAF deletion in Chinese patients with multiple myeloma (MM).Patients and MethodsTwo hundred consecutive patients with newly diagnosed MM were analyzed. Patient samples were evaluated using a fluorescence in situ hybridization probe set, including 13q deletion, 17p deletion, and 1q21 gain, as well as immunoglobulin heavy chain gene (IgH) rearrangement, IgH/cyclin D1, IgH/fibroblast growth factor receptor 3 (FGFR3), and IgH/MAF. The frequency of MAF deletion and the clinical characteristics and overall survival of patients with MAF deletion were analyzed.ResultsThe incidence rate of MAF deletion was 15.0% (30/200) in newly diagnosed patients and all of them were monoallelic of MAF deletion. MAF deletion was associated with sex (P = .008), lactate dehydrogenase level (P = .026), 13q deletion (P = .028), FGFR3 deletion (P = .006), and IgH deletion (P = .018). Additionally, in an analysis of the overall survival rates of patients with MAF deletion who received a bortezomib-based regimen treatment, no significant differences were found in overall survival between positive and negative groups (P = .365).ConclusionMAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.     

Representation of Minorities and Elderly Patients in Multiple Myeloma Clinical Trials

Multiple myeloma (MM) occurs in all races, but the incidence in non‐Hispanic black patients (NHBs) is two to three times higher than in non‐Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p < .0001) and Hispanic patients (EF 0.04%, p < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients.     

唑来膦酸联合放疗治疗骨转移癌临床研究

目的观察唑来膦酸联合放疗治疗骨转移癌的疗效。方法将60例骨转移癌患者随机分为观察组（30例）和对照组（30例）。观察组静脉点滴唑来膦酸4mg加局部放疗30Gy/10f/2w，对照组则单纯行放疗。结果观察组与对照组疼痛总缓解率分别为93.3%和73.3%，有显著性差异（P〈0.05）。观察组和对照组KPS评分改善有效率分别为90.0%和66.7%，两组差异有显著性差异（P〈0.05）。结论唑来膦酸联合放疗治疗骨转移癌疼痛疗效优于单纯放疗，明显提高患者生存质量。     

Single-center Experience in Treating Patients With t(4;14) Multiple Myeloma With and Without Planned Frontline Autologous Stem Cell Transplantation

Background

Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib.

Feasibility and Efficacy of Local Radiotherapy With Concurrent Novel Agents in Patients With Multiple Myeloma

IntroductionThis study evaluated the safety and efficacy of radiotherapy (RT) with concurrent novel agents (NAs), cytotoxic therapy (CTx), or both in the management of osteolytic bone lesions in multiple myeloma (MM).Patients and MethodsA total of 39 patients with MM received RT to 64 different bone sites during the 2007-2012 period, with a dose of 8 to 37.5 Gy (mean, 26.8 Gy) delivered in 1 to 15 fractions (median, 10 fractions). Of these patients, 21 also received concurrent NAs or CTx. Pain response, M protein and κ light chain response, and adverse events were evaluated.ResultsRT was completed in 35 of 39 patients (89.7%) in this study. Pain relief was observed in 30 of 31 patients (96.7%). Hematologic toxicity (grade 3 or 4 by the Radiation Therapy Oncology Group system) was seen in 43.2% of treated patients, and NA therapy was stopped in 2 patients owing to grade 4 toxicity. RT adverse effects resolved at 4 to 6 weeks posttreatment. Changes in pre- and posttreatment levels of M protein trended toward significance in patients treated with RT + systemic therapy (ST) versus. RT alone (ΔM Protein_RT+ST = 5.6 g/L; ΔM Protein_RT = 0 g/L; P = .089).ConclusionTreating MM with RT concurrently with CTx including NAs was safe and well tolerated in the majority of patients (14 of 16 [87.5%] for those taking NAs and 19 of 21 [90.5%] for all patients). Excellent clinical pain response (> 95%) was also seen in patients regardless if they were treated with RT + ST or RT alone.     

The Myeloma Landscape in Australia and New Zealand: The First 8 Years of the Myeloma and Related Diseases Registry (MRDR)

BackgroundReal-world multiple myeloma (MM) data are scarce, with most data originating from clinical trials. The Myeloma and Related Diseases Registry (MRDR) is a prospective clinical-quality registry of newly diagnosed cases of plasma cell disorders established in 2012 and operating at 44 sites in Australia and New Zealand as of April 2020.MethodsWe reviewed all patients enrolled onto the MRDR between June 2012 and April 2020. Baseline characteristics, treatment, and outcome data were reviewed for MM patients with comparisons made by chi-square tests (categorical variables) and rank sum tests (continuous variables). Kaplan-Meier analysis was used to estimate progression-free survival and overall survival (OS).ResultsAs of April 2020, a total of 2405 MM patients were enrolled (median age, 67 years, with 40% aged > 70 years). High-risk features were present in 13% to 31% of patients: fluorescence in-situ hybridization (FISH) ≥ 1 of t(4;14), t(14;16), or del(17p) 18%, International Staging System (ISS)-3 31%, and Revised ISS (R-ISS)-3 13%. Cytogenetic/FISH analyses were performed in 50% and 68% of patients, respectively, with an abnormal karyotype result in 34%. Bortezomib-containing therapy was the most common first-line therapy (79.3%, n = 1706). Patients not receiving bortezomib were older (median age, 76 vs 65 years, P < .001) with inferior performance status (Eastern Cooperative Oncology Group performance status ≥ 2, 41% vs 18%, P < .001). Median progression-free survival and OS were 30.8 and 65.8 months, respectively. Younger patients had superior OS (76.3 vs 46.7 months, P < .001, < 70 and ≥ 70 years, respectively). R-ISS score was available in 50.7% (n = 1220) of patients, and higher R-ISS was associated with inferior OS (R-ISS-1 vs R-ISS-2 vs R-ISS-3: not reached vs 68.1 months vs 33.2 months, respectively, P < .001).ConclusionClinical registries provide a more complete picture of MM diagnosis and treatment, and highlight the challenges of adhering to best practices in a real-world context.     

Determination of IL6, IL1, and IL4 in the Plasma of Patients with Multiple Myeloma

Interleukin 6 (IL6) plasma levels were measured in 63 patients with multiple myeloma and 8 individuals with benign monoclonal gammopathy. 15 of these 71 samples showed by an enzyme linked immunosorbent assay (ELISA) detectable levels that ranged from 5 to 107 pg of IL6/ml. The IL6 levels of patients with multiple myeloma did not differ significantly from those of normal individuals (N = 25, range 5-27 pg IL6/m1) (Student's t-test, p = 0.295). The samples were negative for IL4; 3 were found positive for IL1β. A correlation between IL6, IL4 and IL1β levels and disease status was not observed for this group of patients.     

The Burden in Caregivers of Multiple Myeloma Patients Undergoing Outpatient Autologous Stem-Cell Transplantation Compared to Inpatient Transplantation

BackgroundThe application of different models of autologous stem-cell transplantation (ASCT) in multiple myeloma has demonstrated the feasibility and safety of outpatient-based programs of care. Although several systematic reviews have evaluated the burden of caregivers, only a few studies have included outpatient ASCT.Patients and MethodsThe feelings of lack of family support, daily activities, and general health were compared between caregivers of 2 groups of patients with multiple myeloma who underwent inpatient (n = 71) or outpatient (n = 25) ASCT.ResultsThe 3 features did not significantly differ between the 2 study groups at baseline, before, and 3 months after ASCT. Multivariate modeling showed that the baseline values were significantly related to the changes in study outcomes independent of patient and caregiver characteristics. Other correlates were caregivers’ work and patient age for impact on daily activities and disease burden across time for impact on general health (all P < .05).ConclusionThe outpatient model neither improves nor impairs global caregivers’ burden compared to standard ASCT care. Further research is needed to confirm this observation and to better assess the burden and quality of life of caregivers and their influence on patient outcomes and quality of life.