Bortezomib Therapy For Multiple Myeloma Research Articles

Impact of CD34/CD309 expression in circulating endothelial progenitor cells on prognosis and response to bortezomib therapy in multiple myeloma

ABSTRACT Multiple myeloma (MM) is a prevalent yet incurable hematologic malignancy. Despite the proven efficacy of proteasome inhibitors in treating MM, resistance to Bortezomib-based treatments persists in a subset of patients. This case control study explores the potential of circulating endothelial progenitor cells (EPCs) as biomarkers for predicting response to Proteasome Inhibitor based therapy combined with Dexamethasone in MM patients. This study was conducted on 105 MM patients receiving bortezomib plus dexamethasone therapy and 90 healthy individuals as a control group. Utilizing 8-color multi-parameter flow cytometry, we assessed the levels of circulating EPCs, identified through CD34 FITC and CD309 PE markers at diagnosis and after one treatment cycle (4 weeks). Our findings revealed that patients exhibiting poor response to therapy showed significantly higher CD34/CD309 values than those with a good response (p < 0.001). The delineation of response based on CD34/CD309 expression was established with a cutoff ≤ 0.9 for percentage (yielding 100% sensitivity and 94.1% specificity) and ≤ 12.5 for absolute value (also with 100% sensitivity and 94.1% specificity). These results underscore the potential of EPC population levels, as quantified by CD34/CD309, to serve as a predictive biomarker for immunomodulatory treatment in MM patients undergoing Proteasome Inhibitor and Dexamethasone therapy.

ORAL AMYLOIDOSIS ASSOCIATED WITH MULTIPLE MYELOMA - A CASE REPORT

A 54-year-old black female patient undergoing dexamethasone and bortezomib therapy for multiple myeloma presented with asymptomatic papules and nodules on the border of the tongue. The lesions were firm in consistency, with light yellowish color and ranging in size from 0.2 to 0.6 cm. A biopsy was performed, and the histopathologic examination with hematoxylin and eosin showed an extracellular deposition of eosinophilic material within the connective tissue. Congo red stain confirmed the diagnosis of amyloidosis. Amyloid deposition associated with multiple myeloma is progressive and can involve any organ. Currently, there is no treatment for this condition. Therefore, the patient has been kept under clinical follow-up showing involvement of the tongue, floor of the mouth, and lower and upper lip, which present with reduced tissue elasticity. A 54-year-old black female patient undergoing dexamethasone and bortezomib therapy for multiple myeloma presented with asymptomatic papules and nodules on the border of the tongue. The lesions were firm in consistency, with light yellowish color and ranging in size from 0.2 to 0.6 cm. A biopsy was performed, and the histopathologic examination with hematoxylin and eosin showed an extracellular deposition of eosinophilic material within the connective tissue. Congo red stain confirmed the diagnosis of amyloidosis. Amyloid deposition associated with multiple myeloma is progressive and can involve any organ. Currently, there is no treatment for this condition. Therefore, the patient has been kept under clinical follow-up showing involvement of the tongue, floor of the mouth, and lower and upper lip, which present with reduced tissue elasticity.

Two Secondary Primary Malignancies after Bortezomib Therapy for Multiple Myeloma: A Single-center Experience.

Two Secondary Primary Malignancies after Bortezomib Therapy for Multiple Myeloma: A Single-center Experience.

Rare occurrence of bortezomib-induced Sweet′s syndrome in multiple myeloma

Sweet's syndrome (SS) (acute neutrophilic dermatosis) has already been described in cases of acute leukemia. It has been rarely reported in patients receiving bortezomib therapy for multiple myeloma (MM). A 65-year-old male, who was diagnosed as a case of MM 3 years back, initially received lenalidomide- and dexamethasone-based regimen, followed by lenalidomide maintenance, but subsequently had progressive disease with increasing monoclonal M-spike on serum protein electrophoresis, so shifted to bortezomib and dexamethasone along with monthly zoledronic acid-based treatment. He developed itching over face and neck with darkening and thickening of the skin. Examination revealed hyperpigmentation of face along with excoriation and erosions with involvement of V of neck with relative sparing of upper eyelid, postauricular area, and nasolabial folds. Histopathological examination of skin biopsy revealed neutrophilic infiltration of dermis suggestive of SS. A wide variety of cutaneous complications has been described in 10-20% of patients receiving bortezomib. However, SS has rarely been described in such patients with only a few case reports reported so far. Our patient developed features of SS while on bortezomib therapy and had shown dramatic response to bortezomib withdrawal and treatment with oral and topical steroids showing temporal association of this rare syndrome with bortezomib therapy.

Ocular Complications of Bortezomib Therapy in Multiple Myeloma

Introduction:Bortezomib (Velcade¨; V), a proteasome inhibitor, is currently FDA (Food and Drug Administration) approved for the treatment of multiple myeloma (MM) and relapsed mantle cell lymphoma. Common side effects reported with its use include thrombocytopenia, fatigue, peripheral neuropathy and neutropenia. Ocular complications associated with bortezomib are less well described. We describe 6 patients with multiple myeloma who developed meibomitis, multiple chalazions and blepharitis after treatment with bortezomib containing regimens, resulting in delay and in some cases termination of the therapy.Methods:We reviewed the charts of forty patients who received induction chemotherapy for multiple myeloma between June 2013-June 2014 at Montefiore Medical Center, New York. Charts were reviewed for data pertaining to demographics, chemotherapy regimen and schedule as well as follow up of ocular symptoms.Results:Six of these forty (15%) patients complained about bilateral eye soreness, itching and redness. They did not have any evidence of viral or upper respiratory infections. Ophthalmology evaluation showed blepharitis, meibomitis and multiple chalazion. Majority of the patients were 60 years or greater, with 50% African-Americans. Half of the cases had stage 3 MM with a median duration of chemotherapy 8 weeks prior to onset of ocular symptoms. 4 of these 6 patients received VCD regimen (Bortezomib via subcutaneous route and Cyclophosphamide/ Dexamethasone as tablets) while the remaining 2 patients received VD and VCD-R (addition of Lenalidomide) via intravenous and subcutaneous route respectively. Ocular symptoms led to a 1-3 week delay in the next cycle of chemotherapy. These symptoms promptly responded to withdrawal of chemotherapy and other conservative measures. Chemotherapy was resumed in 4 out of 6 patients, with recurrence of chalazion in two patients within 3 weeks of starting Bortezomib.Conclusions:Ocular symptoms are commonly seen but rarely reported with bortezomib therapy. They can adversely affect patient’s quality of life as well as lead to interruption in chemotherapy. Although these symptoms respond well to withdrawal of chemotherapy and conservative measures, the rate of recurrence is high once bortezomib is resumed. Awareness of these complications and early intervention can potentially avoid treatment delay. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chalazia Associated with Bortezomib Therapy for Multiple Myeloma

Chalazia Associated with Bortezomib Therapy for Multiple Myeloma

Bortezomib-associated fatal liver failure in a haemodialysis patient with multiple myeloma

Context. Bortezomib is a proteasome inhibitor with excellent antimyeloma activity. The most frequent toxic side effects are gastrointestinal, neuropathy and thrombocytopenia. The liver was not considered an important target organ for toxicity until one case of bortezomib-induced severe hepatitis was reported in a patient with multiple myeloma. Case report. We describe a patient developing acute cholestatic and parenchymal hepatitis complicated by fatal liver failure after bortezomib therapy for multiple myeloma. Discussion: The importance of being aware of this potential fatal complication is emphasized considering that this drug is increasingly prescribed and in order to discontinue this drug if liver adverse reaction is suspected.

多発性骨髄腫に対する Bortezomib 療法の適正使用

多発性骨髄腫に対する Bortezomib 療法の適正使用

Monitoring bortezomib therapy in multiple myeloma: screening of cyclin D1, D2, and D3 via reliable real-time polymerase chain reaction and association with clinico-pathological features and outcome

Cyclins D1, D2, and D3 (CCND1, 2, 3) are regulated by proteasomal degradation. Their overexpression in multiple myeloma (MM) has prognostic value. We performed this pilot study to analyze a possible association between CCND1–3 overexpression and response to treatment with the proteasome inhibitor bortezomib, since a specific prognostic marker for bortezomib response has not been reported, but would be ideal to predict who benefits most from bortezomib in times of several potentially efficient therapeutic options. Bone marrow (BM) specimens of 20/47 consecutive patients were available for reliable CCND1–3 analyses by real-time PCR. With CCND1 overexpression in 9/20 patients, the risk for progression after bortezomib treatment was significantly decreased (HR 0.102, 95% CI 0.021–0.498, p = 0.0048) and progression-free survival substantially prolonged (p = 0.0011). Our study is the first to suggest that overexpressed CCND1 in MM is an independent prognostic marker associated with a more durable response to bortezomib. These preliminary results warrant a larger study.

Multiple Significant Bortezomib-Related Toxicities in One Patient: Case Report and Literature Review

Bortezomib has shown significant efficacy in the treatment of patients with relapsed multiple myeloma (MM) and is generally well tolerated. We report a 65-year-old male patient undergoing bortezomib therapy for MM who, with the addition of liposomal doxorubicin, presented with severe paralytic ileus, peripheral neuropathy, pruritic rash, and testicular pain. Each of these toxicities was temporally related to the bortezomib-based therapy and the administration of concomitant liposomal doxorubicin. Herein, we discuss the patient's course and briefly review the literature on these bortezomib combination—related toxicities.

Marked improvement of platelet transfusion refractoriness after bortezomib therapy in multiple myeloma

We report a patient with refractory multiple myeloma (MM) who developed platelet transfusion refractoriness (PTR). A 61-year-old woman was diagnosed with MM in July 2003. She underwent high-dose chemotherapy followed by autologous stem cell transplantation, and achieved a very good partial response. However, she relapsed in June 2006, and was referred to our hospital in October of the same year. Laboratory examinations showed pancytopenia and increased plasma cells in the peripheral blood. Platelet transfusions from random donors became ineffective, and anti-HLA class I antibody (83.8% positive) was detected in the serum by flow cytometry assay (Flow PRA). Therefore, she was considered to have developed PTR due to anti-HLA class I antibody caused by the previous blood transfusions. She was transfused with HLA-matched platelets, and then treated with bortezomib plus dexamethasone (BD) for refractory MM. The serum IgG level decreased from 7,451 to 1,735 mg/dL, and HLA class I antibody was markedly decreased to 1.9%. In addition, platelet transfusion from random donors showed clinical effects after BD therapy. This case suggests that bortezomib might be effective in different types of immune disease by inhibiting allo-reactive antibody.

Monitoring bortezomib therapy in multiple myeloma: Screening of cyclin D1 overexpression as a potential prognostic marker for response to treatment

8614 Background: Cyclin D1 (CCND1), 2 (CCND2) and 3 (CCND3) are overexpressed in almost all MM and their deregulation has prognostic value. As cyclins are substrates of the proteasome, proteasome i...

Response to Bortezomib Therapy for Multiple Myeloma (MM) in Actual Clinical Practice: Preliminary Effectiveness Findings of an International Observational Study.

Background: Bortezomib (VELCADE®) is indicated for the treatment of MM in patients (pts) who have received at least 1 prior therapy. The electronic VELCADE Observational Study (eVOBS) is designed to evaluate the clinical and outcomes benefits of bortezomib in actual clinical practice. The study is open for enrollment between October 2006 and December 2008 in Belgium, France, Greece, Russia, Spain, Sweden, and Turkey with 3-year follow up. This report includes preliminary outcomes in pts with at least 4 months of data as of July 2007.Methods: Adults were eligible for study if they were scheduled to initiate bortezomib within the approved indication. All bortezomib dosages and concomitant treatments were permitted, except investigational therapies. Data on concomitant therapies, treatment response, and safety were collected prospectively during bortezomib therapy. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria could include M-protein, EBMT, SWOG, or others as defined by the investigator.Results: A total of 86 pts with at least 4 months of data were included in this analysis. Median age was 61 yrs, and 50 (58%) pts were male. Median interval since diagnosis was 3 yrs. The number of previous therapies for MM was 1, 2–3, and ≥4 for 38%, 44%, and 11% of pts, respectively. Demographic and clinical characteristics of the initial participants were similar to those of the participants in the prospective controlled phase 3 APEX trial (Richardson, N Engl J Med , 2005: 352; 2487–98). Most pts (61%) received bortezomib with dexamethasone. Adverse events (AEs) were reported in 61 (71%) pts, including Grade ≥3 AEs in 38% and Grade ≥4 AEs in 9%. AEs were treatment-related in 45% of patients and treatment-limiting in 9%. Presently, 72 of 86 pts have been evaluated for response, of whom 54 completed 4 or more cycles. Response rates are shown in the table. Updated data will be presented at the meeting.Best Response(n = 72)Complete response (CR)5 (7)Near complete response (nCR)9 (13)Partial response (PR)30 (42)Minimal response (MR)9 (13)Stable disease (SD)6 (8)Progressive disease (PD)13 (18)Overall response (≥PR)44 (61)Overall response (≥MR)53 (74)Conclusions: In this preliminary analysis of data from a prospective, observational study of actual clinical practice, most pts received bortezomib in combination with 1 or more other therapies for MM. Overall response in actual clinical practice was at least as common as previously reported with bortezomib monotherapy. Response rates and safety data from actual clinical practice demonstrate that bortezomib-containing regimens are effective and well-tolerated in the treatment of MM.

Neurotoxicity of bortezomib therapy in multiple myeloma: A single‐center experience and review of the literature

Bortezomib is active in heavily pretreated multiple myeloma patients; the dose-limiting toxicity is peripheral neuropathy (PN). The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33-80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2-36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1-19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. The risk of bortezomib-related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation.

Radiation Recall Dermatitis after Bortezomib Therapy.

Introduction: Radiation recall dermatitis (RRD) is an inflammatory skin reaction at a site of previous radiation therapy after the administration of a medication, usually a chemotherapeutic agent. A radiation recall reaction has not been previously reported with bortezomib.Case Report: A seventy-year-old man with stage III IgD multiple myeloma was treated with bortezomib after previous treatments with pulse decadron and cyclophosphamide. The patient was treated ten years earlier for a chest wall sarcoma with a local resection and radiation therapy to the tumor bed. After receiving bortezomib therapy for multiple myeloma, the patient developed erythema, desquamation, and ulceration only at the site of radiation therapy ten years prior. The patient received a dose reduced second infusion, causing a similar reaction.Discussion: RRD is an inflammatory skin reaction that develops in a previously irradiated area after administration of certain promoting agents, most often with chemotherapy. Unlike radiation enhancement, there may be a long interval between the eruption and the administration of the causative agent. A number of drugs have been associated with this phenomenon, particularly the anthracyclines. Bortezomib has not been previously described as a causative agent for RRD. Erythema is the most common sign, which may be painful. Vesiculation, desquamation, and ulceration have also been reported. Histologically, the involved areas reveal epidermal dysplasia, necrotic keratinocytes, mixed inflammatory reaction, and sometimes psoriasiform dermatitis. Dose reduction, and the use of corticosteroids have been used to prevent recurrence of RRD, although rechallenge with the same agent may not lead to RRD again. The pathogenesis of this local phenomenon is not well understood, although an idiosyncratic drug hypersensitivity reaction has been proposed.

Bortezomib Therapy for Multiple Myeloma in Relapse after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RICT).

Multiple myeloma (MM) remains incurable and specially of poor prognosis in case of refractory or relapsed disease. However, recent therapeutic advances including the use of new drugs are promising. Although, Bortezomib, new proteasome inhibitor, has proven its efficacy in patients with refractory or relapsed MM, it has not been sufficiently evaluated in the setting of allogeneic hematopoietic stem cell transplantation. Here, we report four cases of MM patients, very heavily pre-treated and all previously transplanted, who received bortezomib associated to dexamethasone for relapse after allogeneic RICT (median time from diagnosis: 68 months, median time from RICT: 41 months). We studied the feasibility, efficacy and safety of bortezomib: two patients achieved a complete remission, one patient a very good partial response, and one had no response. The tolerance was excellent with only one patient who developed a reversible grade 3 hematological toxicity. No GVHD recrudescence was observed. All patients relapsed after completion of bortezomib treatment. This questions about the potential benefit of maintenance therapy with bortezomib. Given the feasibility and the high efficacy of bortezomib combined with dexamethasone in relapsed MM after RICT, our results argue in favour of an immune-modulatory activity of bortezomib. New strategies combining RICT and bortezomib are warranted to increase and maintain an adequate response. Combination RICT and bortezomib regimen are anticipated to further extend survival in relapsed MM.