Bortezomib in treatment of extramedullary plasmacytoma of the pancreas

BACKGROUND:Extramedullary pancreatic plasmacy- toma treated with bortezomib is rarely reported. METHODS:We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months,then an asymptomatic swelling of the pancreas was found.A biopsy on the mass and a fine needle aspiration of the pancreas were performed.The diagnosis of extramedullary plasmacytoma(EMP)was made.The patient was initially treated with combination chemotherapy consisting of vincristine,doxorubicin and dex...     

A phase II study of bortezomib in patients with MALT lymphoma

We have performed a phase II study to evaluate bortezomib in patients with MALT-lymphoma. Sixteen patients entered the trial, 4 had gastric MALT-lymphoma, 7 of the ocular adnexa, one of the colon, and 2 of the parotid, and one patient each the lung and the breast. Bortezomib was given at 1.5 mg/m² days 1, 4, 8 and 11; repeated every 21 days. The overall response rate was 80% (13/16); 7 patients achieved complete remission (43%), 6 partial response (37%) and 3 stable disease. After a median follow-up of 23 months (range; 8–26), all patients are alive and 4 have relapsed. Fifteen patients required dose reductions due to either neuropathy (7 patients) or diarrhea (8 patients). Bortezomib appears to be active in patients with MALT-lymphoma. However, an unexpectedly high rate of toxicities was seen, warranting assessment of combination schedules with bortezomib at a lower dose than given in our study (ClinicalTrials.govIdentifier: NCT 00373906).     

Natural polyphenols antagonize the antimyeloma activity of proteasome inhibitor bortezomib by direct chemical interaction

Bortezomib is a therapeutic proteasome inhibitor with antimyeloma activity and polyphenols are well known compounds that exert antiproliferative effects against tumuors. We attempted to co-treat myeloma cells with bortezomib and polyphenols, anticipating a synergistic effect. However, the anticancer activity of bortezomib was blocked by the polyphenols. The structural features of the polyphenols correlated strikingly with their antagonistic effect; in particular, the presence or absence of a vicinal diol moiety was the key element for effective blockage of the anticancer function of bortezomib. We speculated that the vicinal diols in the polyphenols interact with the boronic acid of bortezomib and convert the active triangular boronic acid of bortezomib to an inactive tetrahedral boronate, thus abolishing the antimyeloma activity of bortezomib. We confirmed this hypothesis by ¹¹B nuclear magnetic resonance spectroscopy and an in vitro assay on multiple myeloma (MM) cell lines and primary myeloma cells from patients. Based on these findings, restriction of the intake of natural polyphenols in foods or vitamin supplements during bortezomib treatment in MM patients should be considered.     

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).     

Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma

Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m² on days 1–3, bortezomib 1·3 mg/m² on days 1, 4, 8, 11, with rituximab 375 mg/m² on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4–30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.     

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.     

Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen

Subcutaneous (sc) rather than intravenous administration of bortezomib (Bor) is becoming more common for treating multiple myeloma (MM) because scBor results in lower incidence and severity of peripheral neuropathy and has equivalent efficacy. Bor is an irritant cytotoxic agent when it leaks out; therefore, it is recommended that injections of scBor should be rotated among eight different sites on the abdomen and thigh. However, detailed information about injection site reaction (ISR) has not been sufficiently documented. We retrospectively analyzed the incidence and severity of ISR following scBor administration in 15 Japanese patients with MM. Grade 1 ISR occurred following 40 of 158 (25.3%) scBor injections in ten patients, whereas grade 2 ISRs occurred following seven injections (4.4%) in five patients. Five patients did not develop ISR. Of note, grade 2 ISR was documented in 6 of 65 (9.2%) thigh injections but only in 1 of 93 (1.1%) abdominal injections. These data show that grade 2 ISRs were more common in the thigh compared with the abdomen possibly because the thigh contains lesser adipose tissue than the abdomen. Grade 2 ISRs resolved without any sequela within a median of 7 d. scBor administration on the abdomen instead of the thigh should be considered, especially for emaciated patients, because ISR rapidly resolves within the interval before the next injection even if it occurs.     

硼替佐米对多发性骨髓瘤干细胞的作用研究

目的:探讨硼替佐米对多发性骨髓瘤干细胞的作用?方法:本实验采用人多发性骨髓瘤细胞系KMS-11及OCI-MY5常规体外培养,随机设定空白组和硼替佐米干预处理后的实验组,通过流式细胞仪利用肿瘤干细胞外排Hoechst33342染料的特性来分析比较侧群细胞的比例?结果:硼替佐米作用后侧群细胞比例明显上升(P < 0.05)?结论:硼替佐米主要的作用靶点是非侧群细胞,为硼替佐米的序贯治疗提供了客观依据?     

How to treat patients with relapsed/refractory multiple myeloma: evidence-based information and opinions

Introduction: Relapsed/refractory multiple myeloma (rrMM) remains a difficult condition to treat despite the availability of new drugs. This review aims to provide evidence to guide physicians in the choice of salvage therapy in certain subgroups of patients.

Areas covered: The review attempts to present evidence-based information and suggest possible approaches based on data on previous therapies, previous remission duration and toxicity of previous treatments, patient's co-morbidities and disease characteristics at relapse. Unfortunately, little evidence is available; there are no large and/or randomized trials, direct comparisons of drugs or combinations for rrMM patients to draw any definite conclusion.

Expert opinion: Almost all the studies presented here suggest that depth of response is a key factor also for patients with rrMM. Identifying the best approach between combinations and sequential therapies remains controversial. Several studies favor the former approach in early relapse as it leads to a higher complete response rate, regardless of previous therapies. However, in both strategies, achieving maximal response should always remain a main goal. Consolidation/maintenance therapy is beneficial both in combination and sequential therapies also in rrMM. Second generation new drugs, such as pomalidomide, carfilzomib, bendamustine and HDAC inhibitors, will probably expand the rescue possibilities also in this setting.     

New generation pharmacotherapy in elderly multiple myeloma patients

Background: Observational databases have demonstrated that the overall prognosis of multiple myeloma patients has markedly improved over the past decade, yet the greatest strides have been attained in younger rather than older patients. Objective: To review recent clinical trials that include new generation agents (thalidomide, lenalidomide and bortezomib) and autologous stem cell transplantation in older multiple myeloma patients. Results: Conventional regimens such as melphalan plus prednisone can be improved with the addition of thalidomide or bortezomib: more patients attain complete and near-complete remission, and progression-free survival rates are nearly doubled. In addition, autologous hematopoietic stem cell transplantation studies show that this treatment approach can be used successfully in selected older myeloma patients in whom the toxicity profile of autotransplant and resulting overall survival may be similar to that obtained in the younger patient group. Conclusions: In the advanced-age population, implementation of new therapies results in significant benefits in older as well as younger patients.