染色体1q21扩增对硼替佐米或沙利度胺治疗初治多发性骨髓瘤疗效的影响

目的 探讨1q21扩增与接受硼替佐米或沙利度胺治疗的初治骨髓瘤患者疗效的关系.方法 应用FISH技术对108名接受硼替佐米和(或)沙利度胺治疗的初治骨髓瘤患者进行1q21扩增的检测,并分析其与患者临床特征及疗效间的关系.结果 完成检测的108例患者中,有29例(26.9％)1q21扩增阳性.伴有1q21扩增的患者与不伴1q21扩增的患者中位年龄分别为62岁与58岁(P=0.029),血红蛋白均值分别为81.39 g/L与97.58 g/L(P=0.002),其余临床特征如肌酐、血钙、白蛋白、β2微球蛋白及骨髓浆细胞比例两组间差异均无统计学意义.伴有1q21扩增的患者比不伴有1q21扩增的患者合并IgH易位及13q缺失的比例更高(79.3％ vs.48.1％,P=0.004和58.6％ vs.31.6％,P=0.011).可评估疗效的95例患者中,总有效率为73.7％(70/95),伴1q21扩增患者有效率低于不伴1q21扩增患者(50％ vs.80.8％,P=0.007).剔除12例硼替佐米与沙利度胺联合治疗的患者,按治疗方案不同将剩余83例分为硼替佐米组和沙利度胺组,结果显示硼替佐米组伴有1q21扩增患者与不伴有1q21扩增患者治疗有效率差异无统计学意义(70％ vs.80％,P=0.789),而沙利度胺组伴有1q21扩增患者治疗有效率较不伴有1q21扩增患者差(20％ vs.78.3％,P=0.005).多因素分析显示纳入因素中仅1q21扩增是疗效的独立影响因素,其优势比(OR值)=0.231(95％CI:0.078～0.684,P=0.008).结论 1q21扩增是影响多发性骨髓瘤预后的重要因素,伴1q21扩增的患者接受沙利度胺治疗疗效较不伴1q21扩增患者差,但接受硼替佐米治疗疗效与未扩增者无差异.     

Prognostic Value of 1q21 Gain in Multiple Myeloma

Background

Multiple myeloma (MM) is a heterogeneous disease characterized by chromosomal translocation, deletion, and amplification in plasma cells, resulting in a huge heterogeneity in its outcomes. In the era of novel agents such as bortezomib, thalidomide, and the cycles of treatment, risk stratification by chromosomal aberrations may enable a more rational risk-stratification selection of therapeutic approaches in patients with MM.

Indatuximab Ravtansine (BT062) Monotherapy in Patients With Relapsed and/or Refractory Multiple Myeloma

BackgroundIndatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138, which is overexpressed on multiple myeloma (MM) cells.Patients and MethodsWe report from 2 clinical studies of patients with relapsed and/or refractory MM previously treated with an immunomodulatory drug and a proteasome inhibitor. Single- and multi-dosing schedules were investigated to define dose-limiting toxicities, maximum tolerated dose (MTD), recommended phase II dose, and to describe safety, efficacy, and pharmacokinetics.ResultsIn the first-in-human study, indatuximab ravtansine was administered to 32 patients on day 1 of each 21-day cycle. The MTD was 160 mg/m². In the phase I/IIa study, indatuximab ravtansine was administered to 35 patients on days 1, 8, and 15 of each 28-day cycle, and the MTD/recommended phase II dose was 140 mg/m². Most (88%) adverse events were grade 1 or 2, the most common being diarrhea and fatigue. There was rapid clearance of indatuximab ravtansine and no relevant accumulation. Over 75% of heavily pretreated patients achieved stable disease or better. With the multi-dose schedule, minor and partial responses occurred in 14.7% of patients, the median time to progression was 3 months, and the median overall survival was 26.7 months.ConclusionOur data support further investigation of indatuximab ravtansine as part of a combination regimen for relapsed and/or refractory MM.     

Analysis of the Efficacy of Thalidomide Plus Dexamethasone-Based Regimens in Patients With Relapsed/Refractory Multiple Myeloma Who Received Prior Chemotherapy,Including Bortezomib and Lenalidomide: KMM-166 Study

BackgroundFor patients with multiple myeloma (MM) that relapsed after treatment with bortezomib- and lenalidomide-based regimens, there were no other treatment options in Korea until 2016. We aimed to determine the efficacy of thalidomide plus dexamethasone-based regimens in patients with relapsed/refractory MM (RRMM).Patients and MethodsWe conducted a multicenter retrospective analysis in Korea for patients with RRMM treated with thalidomide-based regimens who previously received bortezomib and immunomodulatory agents (IMiDs), including thalidomide and lenalidomide.ResultsIn 47 patients with RRMM, the median age was 64 years and the median number of previous treatment lines, including bortezomib and IMiDs, was 3. Primary resistance to bortezomib and lenalidomide was observed in 12 (26%) and 8 (17%) patients, respectively. The most common regimen was a combination of thalidomide, cyclophosphamide, and dexamethasone. The overall response rate was 38%; 2 patients (4%) experienced a complete response, and 2 patients (4%) experienced a very good partial response. The overall response rate of patients previously exposed to thalidomide was 53%. The median progression-free survival was 5.9 months, and overall survival was 9.2 months. Patients with disease that responded to the thalidomide-based regimen had better progression-free survival compared to those who did not (median, 8.8 vs. 2.5 months; P = .008). The most common adverse events were anemia (51%) for hematologic toxicities and peripheral neuropathy (30%) for nonhematologic toxicities.ConclusionThalidomide-based regimens are potential salvage treatment options for patients with RRMM, even those with disease with prior resistance to IMiDs.     

Weekly Bortezomib,Pegylated Liposomal Doxorubicin,and Dexamethasone Is a Safe and Effective Therapy for Elderly Patients With Relapsed/Refractory Multiple Myeloma

BackgroundThe synergic, additive effect of bortezomib and pegylated liposomal doxorubicin (PLD) has never been tested in an elderly group of patients with relapsed/refractory multiple myeloma (MM).Patients and Methods:In this study, 25 patients with a median age of 75 years were treated with bortezomib at usual doses of 1.3 mg/m² every 21 days. After 2 cycles, bortezomib was given intravenously (I.V.) weekly every 32 days. Pegylated liposomal doxorubicin 30 mg/m² I.V. was given on day 4 for 2 cycles and then was given on day 8. Dexamethasone 40 mg I.V. was given on days 1-4 for 2 cycles and then 20 mg weekly.Results:Bortezomib/PLD/dexamethasone therapy resulted in 20 of 25 objective responses for an overall response rate of 80% (complete remission + very good partial remission, 66%). Median overall survival was not reached. Median duration of response (progression-free survival) was 8 months. Eleven of 16 patients (68%) with ≥ VGPR still maintain a response at a median of 12 months versus 4 months for patients with < VGPR (PFS, overall survival; P = .0001). Grade 3/4 toxicities were mild in most of the patients.ConclusionBortezomib/PLD/dexamethasone combination is safe and effective in elderly patients with resistant-relapsing MM.     

Daratumumab,Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study

BackgroundDaratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m² subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).ResultsA total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10^–5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.ConclusionThese data support the use of D-Vd in Chinese patients with RRMM.     

Socioeconomic Status Is an Independent Prognostic Factor for Overall Survival in Patients With Multiple Myeloma: Real-World Data From a Cohort of 223 Patients

IntroductionSocioeconomic status (SES) has been shown to be a prognostic factor for overall survival in a variety of hematologic malignancies, especially for patients who require continuous care such as those with multiple myeloma (MM).Patients and MethodsWe retrospectively collected data from 223 patients with symptomatic MM diagnosed and treated in our department from January 2005 to December 2019. The modified Kuppuswamy scale, slightly modified, was used for the SES assessment. The Kaplan-Meier estimator of survival and Cox regression analysis were used.ResultsIn our cohort of 223 patients with MM, low SES was an independent poor prognostic factor for overall survival (OS), in addition to higher International Staging System stage and high-risk cytogenetics (hazard ratio for low SES on Cox regression analysis, 2.092; 95% confidence interval [CI], 1.36-3.2; log-rank P = .000). Patients with low SES had inferior survival compared with the whole patient cohort (median OS: low SES, 28 months; 95% CI, 18-37.9; high SES, 68 months; 95% CI, 55.6-80.4; log-rank P = .000). The low SES effect on OS was more evident for the elderly patients who were not transplant eligible and in those with a diagnosis of MM International Staging System stage I. The effect of low SES on OS was attenuated by time, and ethnic origin had no effect on OS.ConclusionsThe results of the present study have shown that low SES is an independent poor prognostic factor for survival of patients with MM.     

High Red Cell Distribution Width is an Adverse Predictive and Prognostic Factor in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemoimmunotherapy

IntroductionThe red blood cell distribution width (RDW) is an easy-to-obtain laboratory value that has emerged as a potential prognostic factor in solid and hematologic malignancies.Patients and MethodsWe evaluated 121 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with standard chemoimmunotherapy at our institution between 2010 and 2012. We categorized patients with high RDW (> 14.6%) and normal RDW (11.6%-14.6%). We fitted multivariate regression models for complete response (CR) and overall survival (OS).ResultsPatients with high RDW were less likely to achieve CR to chemoimmunotherapy than patients with normal RDW (48% vs. 83%; P < .001). The 5-year OS rate for patients with high RDW was lower than in patients with normal RDW (51% vs. 79%; P = .001). In multivariate regression models, high RDW was independently associated with lower odds of achieving CR (odds ratio, 0.32; 95% confidence interval [CI], 0.12-0.83; P = .02) and with higher risk of death from any cause (hazard ratio [HR], 2.04; 95% CI, 1.03-4.02; P = .04) than normal RDW in patients with DLBCL treated with chemoimmunotherapy. High RDW remained an independent adverse factor for OS after adjustment for the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index scores with HR 2.20 (95% CI, 1.12-4.31; P = .02) and HR 2.67 (95% CI 1.28-5.59; P = .009), respectively.ConclusionHigh RDW appears to be an adverse predictive and prognostic factor in patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).     

Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States

Background

In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival.

The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21)

The MLL gene at chromosome 11q23 is frequently rearranged in acute leukemia. Here we report the identification of a new MLL fusion partner in the case of an infant with AML-M4 and a t(11;17)(q23;q21) translocation. Fluorescence in situ hybridization (FISH) and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 or MSF. Rapid amplification of cDNA ends (RACE) revealed an in-frame fusion of MLL to LASP1, a gene that is amplified and overexpressed in breast cancer. Retroviral transduction of myeloid progenitors demonstrated that MLL/LASP1 is the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, thus establishing a potential subgroup among the MLL fusion proteins.     

EMA Review of Belantamab Mafodotin (Blenrep) for the Treatment of Adult Patients with Relapsed/Refractory Multiple Myeloma

On August 25, 2020, a marketing authorization valid through the European Union was issued for belantamab mafodotin monotherapy for the treatment of multiple myeloma (MM) in adult patients who have received at least four prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and an anti‐CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy. Belantamab mafodotin is an antibody‐drug conjugate that combines a mAb, which binds specifically to B‐cell maturation antigen, with maleimidocaproyl monomethyl auristatin F, which is a cytotoxic agent. It was evaluated in Study 205678 (DREAMM‐2), an open‐label, two arm, phase II, multicenter study in patients with MM who had relapsed following treatment with at least three prior therapies, who were refractory to an IMiD, a PI, and an anti‐CD38 mAb alone or in combination. Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belantamab mafodotin by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Belantamab mafodotin achieved an overall response rate (ORR) of 32% (97.5% confidence interval [CI]: 22–44) with a median duration of response (DoR) of 11 months (95% CI: 4.2 to not reached). The most frequently (≥20%) reported adverse reactions grades 3–4 with belantamab mafodotin were keratopathy (31%), thrombocytopenia (22%), and anemia (21%). With regard to the corneal risks associated with belantamab mafodotin, patients would need to undergo specific ophthalmic examinations so that any findings can be promptly and adequately managed. The scientific review concluded that a 32% ORR and a median DoR of 11 months observed with belantamab mafodotin was considered clinically meaningful. Given the manageable toxicity profile and considering that belantamab mafodotin has a mechanism of action that is different from that of authorized treatments in this group of highly pretreated patients whose disease is refractory to three classes of agents, the benefit risk for belantamab mafodotin monotherapy was considered positive, although the efficacy and safety evidence were not as comprehensive as normally required.Implications for PracticeBelantamab mafodotin (Blenrep, GlaxoSmithKline, St. Louis, MO, U.S.A) was approved in the European Union as monotherapy for the treatment of adult patients with refractory/relapsed multiple myeloma. Belantamab mafodotin resulted in durable response in highly pretreated patients whose disease is refractory to three classes of agents. Belantamab mafodotin is a monoclonal antibody against B‐cell maturation antigen conjugated with the potent antimitotic agent maleimidocaproyl monomethyl auristatin. This is the first monoclonal antibody to target this antigen in multiple myeloma, which represents a true novelty from a pharmacological point of view.     

dup(1)(q21q32) as a sole cytogenetic event is associated to a leukemic transformation in myelodysplastic syndromes

Duplication of the long arm of chromosome 1 (1q) has been detected accompanied with other chromosome abnormalities in Myelodysplastic Syndromes (MDS). However, as a sole karyotypic change, it is rarely observed. We present here two patients affected of a MDS that showed a dup(1)(q21q32) as a sole cytogenetic change in their bone marrow cells. Complementary methodologies confirmed the duplication of chromosome 1q and, did not show additional cryptic chromosome abnormalities. One patient acquired a secondary trisomy 8 and the other one progressed toward an acute leukemia with no additional cytogenetic alterations.     

An Open-Label Single-Arm Pilot Phase II Study (PX-171-003-A0) of Low-Dose,Single-Agent Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma

BackgroundCarfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after ≥ 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry.MethodsPatients received carfilzomib 20 mg/m² intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria.ResultsThe primary endpoint of best ORR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent.ConclusionThis pilot study was the first phase II single-agent trial conducted with carfilzomib. Based on these findings, the study was amended to test a higher carfilzomib dose in an additional 250 patients (PX-171-003-A1).