Oral idarubicin, dexamethasone and vincristine in the treatment of multiple myeloma: final analysis of a phase II trial

This prospective phase II study evaluated a regimen with vincristine, oral idarubicin and dexamethasone (VID) in 74 patients with multiple myeloma. A partial response was achieved in 57% (16/28) of patients with previously untreated disease and in 35% (16/46) with refractory diseases. VID chemotherapy is an effective and tolerable oral alternative in an outpatient setting for these patients.     

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.     

Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC-IE): a novel, intensive induction chemotherapy regimen for patients with high-risk multiple myeloma

We evaluated toxicities and responses to a novel, dose intensive and time sequenced, chemotherapy programme (DC-IE) in 45 patients with high-risk myeloma. DC-IE consisted of: dexamethasone (days 1–4); cyclophosphamide (day 5); idarubicin and etoposide (days 8–10). Complete response (CR) was achieved in four patients, six patients achieved near complete responses (nCR) and 21 patients achieved a partial remission (PR). Overall response rate was 76% (CI 56–94%) for newly diagnosed patients ( n  =21) and 62% (CI 36–81%) for relapsed/refractory patients ( n  =24). Toxicities were limited to myelosupression; two patients died of sepsis during neutropenia (4%). DC-IE is active and tolerable for high-risk multiple myeloma, including patients with relapsed or refractory disease to anthracycline containing regimens.     

Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma

Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age > or =65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34-40% vs. 13-19%), including complete response rate (5-8% vs. 0-1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged > or =65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma.     

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.     

CCNU (lomustine), idarubicin and dexamethasone (CIDEX): an effective oral regimen for the treatment of refractory or relapsed myeloma

We report the results of a non-randomized pilot study of an oral regimen comprising CCNU (lomustine; 25 or 50 mg/m2 on day 1), idarubicin (4-demethoxydaunorubicin) (10 mg/m2 on days 1-3) and dexamethasone (10 mg b.d. on days 1-4) in patients with relapsed or refractory myeloma. Treatment was given every 28 d for a maximum of six courses. Sixty patients were entered of whom 57 were evaluable. Overall response rate (partial or minor response) was 49% with 30% of patients achieving a partial response (50% tumour reduction). Response rates were higher in patients with untested relapse than in those with refractory disease (overall response rates 56% vs. 31%). The major toxicity was neutropenia and the regimen was otherwise well tolerated. The median survival from entry of all patients was 15 months, with 30% of patients alive at 2 years. This regimen represents a useful addition to available treatment options.     

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study

The clinical efficacy and safety of a four-drug combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone was assessed for patients with relapsed or refractory multiple myeloma. Seventy patients received at least two cycles of treatment with bortezomib 1.3 mg/m² intravenously on days 1, 4, 8, and 11; cyclophosphamide 150 mg/m² orally on days 1–4; thalidomide 50 mg/day orally every day; and dexamethasone 20 mg/m² intravenously on days 1, 4, 8, and 11. The overall best response rate was 88%, with 46% complete response, 9% very good partial response, and 33% partial response. After a median follow-up of 12.6 months, the median progression-free survival (PFS) was 14.6 months with a 3-year PFS of 14% and the median overall survival (OS) was 31.6 months with a 3-year OS of 47%. Grade 3 or 4 adverse events included thrombocytopenia (12%), neutropenia (4%), peripheral sensory neuropathy (3%), with thrombosis being very rare (<1%). Bortezomib combined with cyclophosphamide, thalidomide, and dexamethasone is a highly effective salvage therapy with manageable toxicity for patients with relapsed or refractory multiple myeloma.     

A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide

In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma (MM; N = 3846), the overall incidence rate (IR, events per 100 patient-years) of second primary malignancies (SPMs) was 3.62. IR of invasive (hematologic and solid tumor) SPMs was 2.08, consistent with the background incidence of developing cancer. In a separate analysis of pooled data from pivotal phase 3 trials of relapsed or refractory MM (N = 703), the overall IR of SPMs was 3.98 (95% confidence interval [CI], 2.51-6.31) with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) with placebo/dexamethasone; IRs of nonmelanoma skin cancers were 2.40 (95% CI, 1.33-4.33) and 0.91 (95% CI, 0.23-3.66), respectively; IRs of invasive SPMs were 1.71 (95% CI, 0.86-3.43) and 0.91 (95% CI, 0.23-3.66), respectively. The risk of SPMs must be taken into account before initiating lenalidomide treatment. In the context of the observed survival benefit in relapsed or refractory MM patients, the benefit/risk profile of lenalidomide/dexamethasone remains positive.     

Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.     

Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study

The purpose of this single arm phase II study was to test a modified version of the three drug combination vincristine, adriamycin and dexamethasone (m-VAD), in which intravenous vincristine (0.4 mg/d) and adriamycin (9 mg/m2 per day) infusions are administered for only 2 h on days 1-4 of each 28 d cycle, in patients with refractory multiple myeloma. In addition, only two 4 d courses of dexamethasone 40 mg/d was given during each cycle. The entry criteria for 44 patients included plasma cell myeloma and a measurable monoclonal peak, either refractory to initial treatment with melphalan and prednisone, or resistant to melphalan and prednisone after initially responding (resistant relapsed disease, 27 patients). Patients treated previously with chemotherapy other than melphalan and prednisone were excluded. There were no complete responses. Of the 41 evaluable patients who completed at least one course of therapy 11 had a partial response (27%, 95% C.I. 14-40%). The response rates were 19% for primary refractory disease patients, and 32% for those with resistant relapsed disease. The median duration of response was 4 months. The median survival for all 44 patients was 7.6 months (5.5 months for primary refractory patients, and 10 months for relapsed resistant disease patients). Episodes of documented bacterial infection occurred in 12 patients, and 10 patients had minor viral infection. The dexamethasone dose was reduced in 12 patients. The median neutrophil nadir was 1.2 x 10(9)/l, and median platelet nadir was 147 x 10(9)/l. Five deaths were judged as treatment related and occurred during marrow cytopenia. The results of this modified form of VAD are inferior to that reported previously for 4 d continuous infusions of vincristine and doxorubicin. This could be related to either patient selection factors, or to a reduction of the efficacy of the drug combination produced by either the shortened intravenous infusions and/or omission of one 4 d course of dexamethasone.     

A phase 2, randomized,double‐blind,placebo‐controlled study of siltuximab (anti‐IL‐6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma

We compared the safety and efficacy of siltuximab (S), an anti‐interleukin‐6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high‐dose dexamethasone could be added to S/plc. Response and progression‐free survival (PFS) were analyzed pre‐dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C‐reactive protein, a marker reflective of inhibition of interleukin‐6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all‐grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma. © 2014 Wiley Periodicals, Inc. Am. J. Hematol. 90:42–49, 2015. © 2014 Wiley Periodicals, Inc.     

The use of novel Therakos™ Cellex® for extracorporeal photopheresis in treatment of graft‐versus‐host disease in paediatric patients

Interleukin‐6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid‐induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti‐IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥2 prior lines of therapy, one of which had to be bortezomib‐based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone‐containing regimen. Suppression of serum C‐reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone‐refractory disease. The median time to progression, progression‐free survival and overall survival for combination therapy was 4·4, 3·7 and 20·4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination‐treated patients, including ≥grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid‐containing myeloma regimens is warranted, with special attention to infection‐related toxicity.     

CTD方案治疗难治或复发多发性骨髓瘤

目的应用环磷酰胺、沙立度胺及地塞米松(CTD)方案治疗难治或复发多发性骨髓瘤(MM)。方法20例难治或复发MM患者接受沙立度胺,100~200mg/d,口服持续应用;环磷酰胺,200~300mg.m-2.d-1,1~4d,静脉注射;地塞米松,20~40mg/d,1~4d,口服。4周为1个疗程。3个疗程后,若出现疗效或病情稳定则再连续应用3个疗程;若病情进展,则停止治疗。结果3个疗程后,13例(65%)患者显示治疗反应,其中9例患者获部分缓解,4例患者获微小缓解。而5例患者病情稳定,2例进展。对病情未进展的18例患者继续治疗3个疗程后再次评价,则部分缓解13例(65%),获微小缓解5例。结论CTD是一个具有较好治疗前景的方案。     

酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤疗效观察

目的:评价酞胺哌啶酮(商品名:反应停)联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤(MM)的疗效和不良反应。方法:12例难治复发性MM患者口服酞胺哌啶酮350-400 mg／d,环磷酰胺50 mg／d,地塞米松40 mg／d(第1个月第1-4天,第9-12天,第17-20天,第2个月第1-4天,第9-12天;以后每月服第1-4天)。观察有效率、效应发挥时间、生存时间及不良反应。结果:完全缓解2例,部分缓解3例,进步1例,无效6例,有效率50．0％;效应时间为2-6个月,平均3．5个月;生存时间为8-34个月。不良反应多能耐受,末梢神经炎发生率100％(12／12),窦性心动过缓发生率为50．0％(6／12),便秘为66．7％(8／12),肺栓塞8．3％(1／12),粒细胞减少16．7％(2／12),感染16．7％(2／12)。结论:酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性MM有效,安全,平台期时间长,不良反应较轻。     

Lenalidomide in combination with dexamethasone improves survival and time-to-progression in patients ≥65 years old with relapsed or refractory multiple myeloma

Two pivotal, phase III, randomised, placebo-controlled, registration trials (MM-009 and MM-010) showed that lenalidomide plus dexamethasone was more effective than placebo plus dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma. This pooled, retrospective subanalysis of MM-009 and MM-010 analysed outcomes according to patient age. A total of 704 patients (390 aged <65?years, 232 aged 65-74?years, and 82 aged ≥75?years) received lenalidomide or placebo, both in combination with dexamethasone. The overall response rate (ORR) was significantly higher in patients treated with lenalidomide plus dexamethasone versus placebo plus dexamethasone in all age groups (P?相似文献   

An international,multicenter, prospective,observational study of neutropenia in patients being treated with lenalidomide + dexamethasone for relapsed or relapsed/refractory multiple myeloma (RR‐MM)

Neutropenia is a well‐known dose‐limiting toxicity associated with lenalidomide plus dexamethasone treatment in patients with multiple myeloma; however, little is known about its management and associated outcomes in the real world setting. The present prospective, multicenter, observational study evaluated the incidence, management, and outcomes of grade 3/4 neutropenia in patients with relapsed or relapsed/refractory multiple myeloma who initiated treatment with lenalidomide plus dexamethasone. Of 198 patients, 62 (31%, 95% CI: 25, 38) experienced grade 3/4 neutropenia, and half of these patients experienced 3 or more events during the 12‐month observational period. Grade 3/4 neutropenia occurred throughout lenalidomide treatment, with a median time to first event of 8.8 weeks (Q1, Q3: 5.9, 17.3). In a multivariate analysis, diagnosis of relapsed and refractory disease was associated with grade 3/4 neutropenia. Lenalidomide exposure reduction, use of G‐CSF, unplanned hospitalization, and outpatient clinic visits were more common in patients who experienced grade 3/4 neutropenia than in those who did not. In conclusion, grade 3/4 neutropenia is a common toxicity and patients are at continued risk throughout treatment with lenalidomide and dexamethasone. Further efforts should be made to improve the recommendations for neutropenia management in this population. Am. J. Hematol. 91:806–811, 2016. © 2016 Wiley Periodicals, Inc.     

Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.     

Lenalidomide: an update on evidence from clinical trials

Lenalidomide is a novel immunomodulatory agent with a unique dual mechanism of action: its tumoricidal effect leads to direct tumor cell death, and its immunomodulatory effect keeps the tumor in remission. Phase III clinical trials have demonstrated that in patients with relapsed/refractory multiple myeloma (MM), lenalidomide in combination with dexamethasone offers high clinical response rates and improved time to disease progression, progression-free survival (PFS), and overall survival (OS) compared with dexamethasone alone. In patients with newly diagnosed MM, the combination of lenalidomide and low-dose dexamethasone prolonged survival compared with lenalidomide and standard high-dose dexamethasone. The benefits of lenalidomide-based treatment regimens can be optimized by initiating treatment early in the disease course, either as a frontline treatment or at first relapse. Lenalidomide is generally well tolerated; the primary adverse events are myelosuppression and venous thromboembolic complications. These adverse events emerge early in the course of treatment and can be managed using standard interventions such as granulocyte colony-stimulating factor, dose reduction, and thromboprophylaxis. The combination of lenalidomide and dexamethasone is effective and generally well tolerated in patients with renal impairment provided that creatinine clearance level and adverse events are carefully monitored and the starting dose of lenalidomide is adjusted appropriately. Early results from phase III trials indicate that in patients with newly diagnosed MM, continuous lenalidomide therapy is well tolerated and associated with significant improvements in PFS, offering a new treatment option for patients with MM - although no OS benefit has yet been seen in this setting. Lenalidomide-based treatment is effective across the spectrum of MM disease phases, allowing for the long-term management of myeloma.     

The combination of cyclophosphamide, velcade and dexamethasone induces high response rates with comparable toxicity to velcade alone and velcade plus dexamethasone

The combination of bortezomib (velcade), pulsed dexamethasone and weekly cyclophosphamide (CVD) in relapsed/refractory myeloma patients induces high overall (75%) and complete (31%) response rates compared to velcade/dexamethasone (overall 47%, CR 5%) and velcade alone (overall 27%, CR 0%). The toxicity profiles including thrombocytopenia, neutropenia, and neuropathy were comparable between the groups.