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.     

硼替佐米节律性化疗对老年多发性骨髓瘤的疗效研究

目的探讨硼替佐米节律性化疗对老年多发性骨髓瘤（MM）的疗效研究。方法对8例初治伴严重并发症老年MM患者均给予节律性化疗：硼替佐米1mg／m^2·qw＋地塞米松10mg／qw,4周为1个疗程（VD）,休息1个月,重复上述方案,共化疗6个疗程。结果8例患者中有效率为100％。1～2个疗程后完全缓解6例,完全缓解率为75％,另2例患者化疗1～2个疗程后获得部分缓解,但分别于化疗后6个月一1年死于感染和出血。结论硼替佐米节律性化疗对伴有严重并发症的MM患者,疗效显著,且患者耐受性好,不良反应少。节律性化疗在MM中的作用机制与抑制新生血管的生成是否有关,有待进一步研究探讨。     

Emerging trends in the clinical use of bortezomib in multiple myeloma

Consolidation with high-dose therapy followed by single or double autologous stem cell transplantation has improved response and survival of patients with multiple myeloma (MM), but the disease remains incurable. The emergence of novel agents offer potentially significant advances in the treatment of MM. Bortezomib, a selective inhibitor of the proteasome, has proven to be safe and effective in patients with relapsed and/or refractory MM as monotherapy in phase II/III clinical trials and has produced promising activity in combination regimens with cytotoxic agents. Bortezomib-based combination regimens have also exhibited clinical benefits with manageable toxicities and may ultimately lead to improvement in the duration of response and survival of patients in the first-line setting. High complete and near-complete response rates after 2-4 cycles of bortezomib-based induction therapy may improve outcome in autologous stem cell transplantation recipients. Bortezomib also appears to overcome the adverse prognostic impact of high b2-microglobulin levels and chromosome 13 deletion, as these patients at high risk have shown responses and improved survival with bortezomib therapy. Of interest, patients whose disease previously responded to bortezomib appear to retain sensitivity to the drug, and bortezomib is being explored in maintenance regimens. The use of bortezomib in MM therapy, including ongoing randomized phase III trials, is reviewed herein.     

硼替佐米联合地塞米松治疗24例多发性骨髓瘤的疗效分析

背景及目的:硼替佐米(bortezomib)是一种有效、可逆性的蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在骨髓瘤患者的治疗中发挥持久的疗效。本研究旨在观察硼替佐米联合地塞米松治疗初治、难治/复发多发性骨髓瘤(multiple myeloma,MM)患者的疗效和毒副作用,及该方案在肾功能不全患者中应用的安全性。方法:24例MM患者接受硼替佐米联合地塞米松方案治疗,每3周为一个疗程。所有患者共接受中位3个疗程(1～8个疗程)的化疗。采用EBMT疗效评价标准评价疗效,按国立癌症研究所的常规毒性判定标准评价不良反应。结果:全组中位随访4个月,总有效率79.2%(19/24)。轻链型患者CR率57.1%(4/7),明显高于非轻链型患者5.9%(1/17),差异有统计学意义(P=0.014)。7例合并肾功能不全的患者与肾功能正常患者的疗效相近,差异无统计学意义(P=0.272)。Ⅲ～Ⅳ级不良反应包括白细胞减少(2/24,8.3%)、血小板减少(8/24,33.3%)、腹泻(2/24,8.3%)和乏力(1/24,4.2%),经对症治疗或推迟化疗后均可恢复。结论:硼替佐米联合地塞米松方案治疗MM患者有明显疗效,在轻链型患者疗效更加显著。副作用可以耐受,在合并肾功能不全的患者可安全应用。     

硼替佐米联合毛喉素诱导硼替佐米耐药骨髓瘤细胞凋亡的实验研究

背景与目的：硼替佐米作为蛋白酶体抑制剂已成为新诊断和复发多发性骨髓瘤患者临床治疗的主要药物,但仍有部分患者对硼替佐米产生耐药而影响其长期生存。近年来研究发现,提高细胞内环腺苷酸浓度可以诱导骨髓瘤细胞凋亡并延缓其生长,成为骨髓瘤治疗新途径。该研究通过观察硼替佐米联合腺苷酸环化酶激动剂毛喉素(forskolin)对硼替佐米耐药骨髓瘤细胞的作用,探究克服骨髓瘤耐药的可能途径及其机制。方法：以硼替佐米耐药骨髓瘤细胞株H929-R和原代细胞为模型,通过观察细胞生长、形态、凋亡相关基因的改变来研究硼替佐米、毛喉素单独或联合处理对硼替佐米耐药细胞增殖及凋亡的影响;并应用Rh123/PI双染法检测药物处理前后细胞内线粒体跨膜电位的变化;同时采用实时荧光定量聚合酶链反应(real-time lfuorescent quantitative polymerase chain reaction,RTFQ-PCR)和蛋白[质]印迹法(Western blot)检测线粒体凋亡相关基因转录水平及抗凋亡基因Bcl-2和Mcl-1的蛋白水平的改变。结果：硼替佐米(20 nmol/L)与毛喉素(50 nmol/L)能够协同诱导硼替佐米耐药细胞凋亡。进一步研究发现,毛喉素可协同硼替佐米促使耐药细胞内线粒体跨膜电位下降并下调其Bcl-2和Mcl-1蛋白的表达。结论：毛喉素联合硼替佐米能够诱导硼替佐米耐药骨髓瘤细胞凋亡。     

Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment

BackgroundRenal impairment is a common complication of multiple myeloma (MM) and is related to shorter overall survival and increased rates of early death. Bortezomib is a new agent for the treatment of patients with myeloma, with high response rates and controllable side effects. In this study, we will evaluate the efficacy and safety of bortezomib and dexamethasone in patients with newly diagnosed MM complicated by renal impairment.Patients and MethodsThis is a prospective study of the general characteristics, reversibility of renal impairment, response of myeloma, and side effects of 18 consecutive newly diagnosed patients with MM and renal impairment who received ≥ 2 cycles of bortezomib and dexamethasone.ResultsOf 18 patients newly diagnosed with MM, the median age was 60 years, and the median serum creatinine was 5.3 mg/dL. Patients received a median of 4 cycles of bortezomib and dexamethasone. Reversal of renal impairment was documented in 38.9% of the patients, and the median time to reversal was 16 days. Moreover, 33.3% of the patients achieved renal response (a 50% decrease in serum creatinine). The overall response rate of MM was 83.3%, including a 33.3% complete response (CR) rate, a 16.7% near-CR rate, a 16.7% very good partial response (PR) rate, and a 16.7% PR rate. Grade 3/4 adverse events consisted of infection (n = 3), peripheral neuropathy (n = 3), and ileus (n = 1). After a median follow-up of 15.7 months, the median progression-free survival for all patients was 12.6 months.ConclusionBortezomib plus dexamethasone is a safe and effective regimen for newly diagnosed patients with MM complicated by renal impairment.     

An observational, retrospective analysis of retreatment with bortezomib for multiple myeloma

PurposeThe aim of this retrospective chart review of patients with multiple myeloma (MM) was to describe patterns of retreatment with bortezomib-based therapy and responses to retreatment in a community-based setting.Patients and MethodsData were retrospectively extracted from the medical records of patients treated in US Oncology—affiliated community oncology clinics who received 2 separate treatments with bortezomib-based therapy. Eligible patients had ≥ 60 days between treatments and ≥ 4 bortezomib doses during initial treatment. Responses were determined primarily by laboratory values. Response categories included (1) very good partial response (VGPR), ≥ 90% M-protein decrease; (2) partial response (PR), 50%–89% decrease; and (3) less than PR (< PR), < 50% decrease, excluding progressive disease (PD).ResultsRetreatment response data were available for 82 patients; 5 (6%) had VGPR, 12 (15%) had PR, 52 (63%) had < PR, 5 (6%) had PD, and 8 (10%) died. Among 62 patients with response assessments for initial treatment and retreatment, VGPR/PR rates to retreatment were 44%, 23%, and 13% among patients with VGPR, PR, and < PR to initial treatment, respectively. Median time between bortezomib treatments was 9.7 months; 29% of patients received non-bortezomib therapy between treatments. The most common treatment pattern (58% of patients) was single-agent bortezomib at initial treatment and retreatment. Toxicity contributed to discontinuation in 38% of patients during initial treatment and 22% during retreatment; rates of neuropathy contributing to discontinuation were 18% and 6%, respectively.ConclusionRetreatment with bortezomib-based therapy is feasible, with predictable toxicities. This observational analysis supports bortezomib alone or in combination as a retreatment option after initial bortezomib treatment in patients with relapsed MM.     

Treatment of Multiple Myeloma: A Comprehensive Review

Multiple myeloma (MM) is a neoplastic plasma cell disorder that results in end-organ damage (hypercalcemia, renal insufficiency, anemia, or skeletal lesions). Patients should not be treated unless they have symptomatic (end-organ damage) MM. They should be classified as having high-risk or standard-risk disease. Patients are classified as high risk in the presence of hypodiploidy or deletion of chromosome 13 (del[13]) with conventional cytogenetics, the presence of t(4:14), t(14;16), t(14;20) translocations or del(17p) with fluorescence in situ hybridization. High-risk disease accounts for about 25% of patients with symptomatic MM. If the patient is deemed eligible for an autologous stem cell transplantation (ASCT), 3 or 4 cycles of lenalidomide and low-dose dexamethasone, or bortezomib and dexamethasone, or thalidomide and dexamethasone are reasonable choices. Stem cells should then be collected and one may proceed with an ASCT. If the patient has a complete response or a very good partial response (VGPR), the patient may be followed without maintenance therapy. If the patient has a less than VGPR, a second ASCT is encouraged. If the patient is in the high-risk group, a bortezomib-containing regimen to maximum response followed by 2 additional cycles of therapy is a reasonable approach. Lenalidomide and lowdose dexamethasone is another option for maintenance until progression. If the patient is considered ineligible for an ASCT, then melphalan, prednisone, and thalidomide is suggested for the standard-risk patient, and melphalan, prednisone, and bortezomib (MPV) for the high-risk patient. Treatment of relapsed or refractory MM is covered. The novel therapies—thalidomide, bortezomib, and lenalidomide—have resulted in improved survival rates. The complications of MM are also described. Multiple myeloma is a plasma cell neoplasm that is characterized by a single clone of plasma cells producing a monoclonal protein (M-protein). The malignant proliferation of plasma cells produces skeletal destruction that leads to bone pain and pathologic fractures. The M-protein might lead to renal failure, hyperviscosity syndrome, or through the suppression of uninvolved immunoglobulins, recurrent infections. Anemia and hypercalcemia are common complications.     

Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function

BACKGROUND: Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS: Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS: Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS: Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.     

Repeated complete responses with bortezomib in a heavily pretreated primary refractory patient with light chain multiple myeloma

Multiple myeloma (MM) remains largely incurable despite continued intensive research. Recent advances, especially in the area of myeloma biology, have led to better understanding of the disease process and the introduction of new therapeutic agents. Bortezomib, a first-in-class proteasome inhibitor, has demonstrated significant activity in patients with MM, including in patients with advanced-stage relapsed/refractory disease. Only limited data from prospective clinical trials are available to assess the activity of retreatment or maintenance therapy with bortezomib. The following case report presents the disease profile of a 54-year-old woman with heavily pretreated, refractory, advanced MM who exhibited repeated complete responses to bortezomib retreatment, highlighting the remarkable activity and feasibility of bortezomib as repeat therapy for this disease.     

硼替佐米对多发性骨髓瘤CLC-3表达的影响

目的:研究接受硼替佐米化疗的多发性骨髓瘤（MM）患者在化疗前后CLC-3蛋白表达的变化,探讨硼替佐米对MM患者CLC-3的影响及疗效的变化。方法:流式细胞技术分离12例初发、及复发难治的多发性骨髓瘤患者的浆（瘤）细胞,检测其CLC-3蛋白表达情况。然后所有观察病例均予以硼替佐米为主的化疗方案治疗至少4（4-6）个疗程,检测其CLC-3蛋白表达的水平,了解该指标与临床疗效的关系。结果:12例MM患者治疗前的CLC-3均存在高表达。经硼替佐米为主的化疗方案治疗后,其表达水平呈下降趋势。6例完全缓解（CR）及4例非常好的部分缓解（VGPR）的患者,CLC-3表达水平恢复接近正常。结论:硼替佐米可以对多发性骨髓瘤患者的CLC-3的表达情况产生影响,CLC-3表达水平与硼替佐米疗效呈负相关性。硼替佐米直接能否下调CLC-3水平,以及氯通道可否作为治疗该病的新靶点值得进一步研究。     

Bortezomib in combination with dexamethasone and subsequent thalidomide for newly-diagnosed multiple myeloma: A Chinese experience

ObjectiveBortezomib–dexamethasone–thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology 2007;12(3):235–9), but this regimen has not been tested in the Chinese patients. We report here our results testing with this combination in the Chinese population and to investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM.MethodsBetween June 2006 and March 2008, 20 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m² IV on days 1, 4, 8 and 11 and dexamethasone at 20 mg/m² IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Fourteen patients were male and 6 were female. Median age was 59 years (range 43–86 years). 11 patients were stage 2 according to the International Staging System, 8 were stage 3, only 1 patient was stage 1. All patients received a median of two cycles of therapy (range 1–6). The EBMT criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3.Results16 out of 20 patients (80%) achieved PR and 3 (15%) achieved CR; therefore the overall response rate was 95%. With a median follow-up duration of 7.8 months (4–22 months), no patients died. Grade 3–4 toxicities included fatigue (3/20), thrombocytopenia (10/20) diarrhea (5/20) and orthostatic hypotension (3/20) Grade 2 neuropathy occurred in four out of 20 patients and herpes zoster occurred in four out of 20 patients. Routine anticoagulation or anti-thrombosis was not used. Only 1 patient suffered from DVT/PE.ConclusionsOur preliminary experience in Chinese patients indicated that bortezomib–dexamethasone–thalidomide is highly effective in newly-diagnosed MM. Grade three and 4 toxicities are rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in the Chinese patients with MM are being cautiously observed.     

Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.     

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

BACKGROUND: Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated. METHODS: Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned. RESULTS: There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration. CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.     

A practical update on the use of bortezomib in the management of multiple myeloma

Despite intensive therapy, multiple myeloma (MM) remains an incurable disease, and novel treatment approaches are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory or relapsed MM following the failure of at least two prior lines of therapy. Recently, it also received approval from the FDA for use as a second-line agent. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to review clinical data and experience in the treatment of MM with bortezomib, including bortezomib-based combination therapy. The conclusions of this expert panel, together with updated clinical data from the American Society of Hematology 46th Annual Meeting, provide a practical update on the use of bortezomib in MM. Bortezomib has demonstrated significant antitumor activity as a single agent in refractory and/or relapsed MM, with a significantly longer survival than with dexamethasone (1-year overall survival rate of 80% vs. 66%) and a 78% longer median time to progression. In combination therapy, patient responses suggest the possibility of chemosensitization and synergy. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem cell therapy. Bortezomib is well tolerated; most side effects are only mild to moderate and are manageable. Information is given on the practical management of the most common adverse events, including peripheral neuropathy and thrombocytopenia, and the use of bortezomib in renal and hepatic impairment.     

Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party

BackgroundThe best therapeutic approach for primary plasma cell leukemia (PPCL) remains unknown so far. In very limited studies, the poor clinical outcome of this aggressive variant of multiple myeloma seemed to be ameliorated by the use of the proteasome inhibitor bortezomib. Aiming to provide more consolidated data, this multicenter retrospective survey focused on unselected and previously untreated PPCL patients who had received bortezomib as frontline therapy.Patients and methodsTwenty-nine patients with PPCL were collected. Bortezomib was given at standard doses and schedules, in various combinations with dexamethasone, thalidomide, doxorubicin, melphalan, prednisone, vincristine, and cyclophosphamide.ResultsAn overall response rate of 79% was observed, with 38% of at least very good partial remission. Grade 3–4 hematological, neurological, infectious, and renal toxic effects occurred in 20%, 21%, 16%, and 4% of patients, respectively. After a median follow-up of 24 months, 16 patients were alive (55%), 12 of whom were in remission phase and 4 relapsed. The best long-term results were achieved in patients who received stem-cell transplantation after bortezomib induction.ConclusionBortezomib, used as initial therapy, is able to increase the percentage and the quality of responses in PPCL patients, producing a significant improvement of survival.     

A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303)

BACKGROUND:

Bortezomib, an inhibitor of the 26S proteasome and NF‐κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin.

METHODS:

Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0‐2, and ejection fraction within normal limits. Patients with stable disease for ≥9 months were excluded. Patients received bortezomib 1.3 mg/m² by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m² IV on Days 1 and 8 was added at the time of progression.

RESULTS:

Twenty‐five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single‐agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression‐free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3‐4 neutropenia (n = 3) and grade 3 anorexia (n = 2).

CONCLUSIONS:

Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. Cancer 2011. © 2011 American Cancer Society.     

Bortezomib,melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

BACKGROUND:

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event‐free survival compared with MP alone.

METHODS:

In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose‐intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m² on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28‐day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.

RESULTS:

After a median follow‐up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.

CONCLUSIONS:

A weekly infusion of bortezomib associated with lower dose‐intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.     

OPP-EBV-CAD Regimen as Salvage Treatment in Advanced Refractory or Resistant Multiple Myeloma

With the aim of developing an effective therapy for heavily pretreated refractory MM outpatients, we evaluated the OPPEBVCAD regimen, a Hodgkin's disease-derived protocol that includes many drugs effective in MM administered in a sequential schedule. Twenty-two pts aged 42-72 years, with symptomatic highly-pretreated refractory (18 cases), or primary resistant MM (four cases, including two pts with plasma cell leukemia-PCL) received this therapy every 28 days (2-4 cycles, followed by a maintenance program). Therapeutic response (Chronic Leukemia-Myeloma Task Force criteria) and performance status (PS) and pain (W.H.O.) were evaluated. All of the pts were evaluable for response. There were 9 (40%) objective responses (OR: stabilization of blood counts and bone lesions, serum calcium normalization, 50% or more reduction in the concentration of serum monoclonal component (MC), 90% reduction in Bence-Jones proteinuria), 8 (36%) partial responses (PR: 25-50% reduction in serum MC), 1 no response or stable disease (NR), and 4 (18%) cases of progressive disease (PD). OR plus PR were 77%. Of the 4 primary resistant tumors (2 PCL and 2 MM), 2 achieved PR, 1 OR (a PCL case) and 1 progressed. Median survival was 15 months for responding pts (OR plus PR) and 4.5 months for non-responders (NR plus PD). PS and pain improved in 15 pts and did not change in 9. The most frequent side effects were cytopenias, with one drug related infective death. The OPPEBVCAD regimen proved to be an effective therapy for refractory relapsing or primary resistant MM: in responders (two-thirds of the pts), survival was prolonged by about 10 months. Its efficacy in anthracycline-treated pts, as well as the feasibility of using it on an outpatient basis without any continuous drug infusions, make this regimen a promising third line salvage therapy.