Bortezomib Initiation Research Articles

Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome.

Currently, there is no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). This study aimed to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs. A pre- and post-intervention study was conducted from February 2017 through June 2019 at Siriraj Hospital (Bangkok, Thailand). Five patients were invited to receive once-weekly BTZ (1.3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/d) for 4 months. The primary outcomes were the difference in antibody level at 8 and 48 weeks compared with baseline and the incidence of serious adverse events (AEs). The secondary outcome was the occurrence of opportunistic infections (OIs) during the 72 weeks after starting BTZ. The median patient age was 46 years (range, 34-53). All patients had 3-5 OIs prior to enrollment. All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment. There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.73 ± 0.72) or 48 weeks (3.74 ± 0.53) compared with baseline (3.84 ± 0.49; P = .336 and P = .555, respectively). However, after serum dilution, the antibody titer nonsignificantly decreased 8-16 weeks after BTZ initiation (P = .345). Ten OIs were observed 24-72 weeks after BTZ initiation. Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and 10 OIs were observed during 24-72 weeks of BTZ treatment. No serious AEs were observed. Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells. Clinical Trials Registration. NCT03103555.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Effect of Dosing Bortezomib According to Adjusted Body Surface Area in Multiple Myeloma

Introduction:Multiple myeloma (MM) is the second most common hematologic malignancy in the U.S., accounting for 15% of hematologic malignancies. MM five-year survival rates have improved from 25.8% in 1980 to their current rate of 49.6% (SEER Stat Fact Sheets: Myeloma). Grade 2 or higher peripheral neuropathy (PN) has been reportedin up to 39% of patients on bortezomib, with 31% of patients requiring a dose reduction and 9% requiring discontinuation (Velcade [bortezomib] injection prescribing information; Blood 2008 112:1593-99). Although dosing recommendations are available to help limit PN in patients at high risk of developingPN, there is limited evidenceon how these dose adjustments relate toobese patients receiving bortezomib therapy. The American Society of Clinical Oncology (ASCO) guidelines recommend avoiding unnecessary dose reductions in obese patients, especially when the goal of treatment is cure (J Clin Oncol 30: 1553-61). To date, no studies have evaluated dosing bortezomib according to an adjusted body surface area (BSA) in MM, a difficult-to-cure disease, mainly affecting older people with other co-morbidities.Objectives:To evaluate the effect of an adjusted bortezomib dosing scheme utilized at the University of Iowa in MM patients post-autologous hematopoietic stem cell transplant (HSCT). The primary objectivewas the incidence of neuropathy requiring MM therapy dosage adjustment or discontinuation including the following: adjustment in bortezomib therapy due to neuropathy, adjustment in any MM regimen due to neuropathy, discontinuation of thalidomide, and discontinuation of thalidomide due to neuropathy. Secondary objectives included the percentage of patients with disease progression while on bortezomib therapy and percentage of patients deceased due to MM at data collection.Methods:This is a single-center, retrospective chart review of MM patients with a BSA >2.0 and/or weight >60 kg treated with bortezomib post-autologous HSCT between 01/01/14 and 01/31/16. Two dosing schemes were evaluated, a dose-adjusted and a non-adjusted version (referred to as protocol vs. non-protocol dosing, respectively). Protocol dosing was defined as bortezomib 1 mg/m2 intravenously on days 1, 4, 15 and 18 q 4 weeks with a maximum dose of 2 mg or BSA capped at 2.0 m2 while using an adjusted body weight when weight is >60 kg. Patients that received non-protocol dosing received bortezomib 1 mg/m2 intravenously. Statistical analysis of baseline characteristics was performed using Fisher's exact test for nominal data and T-test for continuous data. Primary and secondary objectives were evaluated using a multiple regression analysis.Results:71 patients were identified, of which 33 received non-protocol dosing, 31 received protocol dosing, and 7 were excluded due to the inability to verify outside infusion center dosing. Baseline characteristics between the non-protocol and protocol dosing group were well matched and no statistically significant difference was seen in age at bortezomib initiation, mean BSA, gender, current enrollment in a HCCC clinical trial, time of bortezomib therapy, or HSCT history. No statistically significant difference was seen between patients receiving non-protocol versus protocol dosing in primary or secondary study objectives, including the following outcomes: change in bortezomib therapy due to neuropathy (18.2% vs. 12.9%, p>0.05), change in regimen due to neuropathy (33.3% vs. 32.3%, p>0.05), discontinuation of thalidomide (36.4% vs. 35.5%, p>0.05), discontinuation of thalidomide due to neuropathy (21.2% vs. 22.6%, p>0.05), disease progression while on bortezomib (12.1% vs. 6.5%, p>0.05), deceased due to MM at data collection and disease progression while on bortezomib therapy or death at data collection (21.2% vs. 16.1%, p>0.05).Conclusion:The use of a weight adjusted dosing protocol for bortezomib in obese patients did not appear to decrease the incidence of neuropathy, specifically neuropathy leading to alterations in MM therapy. Although this was a relatively small study and further evaluation would be beneficial, the percentage of patients with disease progression or death while on bortezomib therapy was not found to be affected by the weight adjusted protocol. These results are in line with the 2012 ASCO statement that recommends avoiding unnecessary dose reductions while treating obese patients with cancer. DisclosuresNo relevant conflicts of interest to declare.

A case of bortezomib-associated thrombotic microangiopathy in a multiple myeloma patient

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma. We present a case of a 70-year-old woman with multiple myeloma, who presented thrombotic microangiopathy with multi-organ involvement thrombotic microangiopathy (ocular, cardiac, and renal) after bortezomib initiation. A kidney biopsy confirmed the diagnosis of thrombotic microangiopathy. A temporal relation between bortezomib exposure and thrombotic microangiopathy onset was seen in the absence of other concurrent medication or disease known to cause thrombotic microangiopathy, and thrombotic microangiopathy was only resolved after drug discontinuation. The exact pathophysiological mechanism remains unknown. To our knowledge, this is the second biopsy-proven published case of bortezomib-associated thrombotic microangiopathy. Since bortezomib is extensively used for treating patients with multiple myeloma, prescribing clinicians should maintain a high index of suspicion of this potentially fatal complication.

1617 Colon Ischemia as Initial Presentation of Amyloidosis: A Rare and Challenging Diagnosis

INTRODUCTION: Amyloidosis is a systemic disease rarely involving gastrointestinal tract (GIT) and requires a high index of suspicion to diagnose. GI presentations including abdominal pain, bleeding, malabsorption or protein losing enteropathy. Predisposing conditions are plasma cell dyscrasia, chronic inflammatory conditions or hemodialysis. We present case of Amyloidosis involving entire GIT presented with severe colon ischemia required total colectomy. CASE DESCRIPTION/METHODS: A 59-year-old man with 6 months history of abdominal pain, bloating and constipation. He tried laxatives with partial relief. A colonoscopy revealed ulcerations in the sigmoid colon with biopsies consistent with ischemic colitis. CT angiography of the abdomen showed patent vessels with no findings to explain ischemic changes. A colonoscopy repeated 3 months later showed persistent inflammation in the sigmoid colon. He, subsequently, was diagnosed with multiple myeloma and initiated on bortezomib and dexamethasone. A few weeks after initiating this treatment, he presented to ED with significantly worsened abdominal pain, distension and nausea. CT A/P revealed thickening from the rectum to the descending colon with proximal dilation, concerning for pneumatosis and ischemic colitis. He was taken emergently for a total colectomy with end ileostomy. Pathology revealed that he, in fact, had extensive amyloidosis (transmural, interstitial, and vascular involvement) with hemorrhage and necrosis throughout the removed colon as well as the removed portion of the ileum with positive margins. There have been prior reports of colonic ischemia after initiation of bortezomib however this does not appear to be culprit in this case given the patient’s findings on initial colonoscopy prior to starting the medication. DISCUSSION: Amyloid deposition infiltrates multiple organs. GIT involvement is common, rectal biopsy can confirm diagnosis. However, severe colon ischemia is uncommon presentation. Our patient presented with severe ischemic colitis and pneumatosis on CT scan. Prior to this, he had 2 colonoscopies, EGD, and abdominal fat biopsy all was non-diagnostic. He subsequently, had total colectomy, pathology revealed Amyloidosis. Duodenal biopsies confirmed small intestine amyloidosis. Colon ischemia due to Amyloidosis is rare. Diagnosis is challenging but can lead to detrimental consequences when it is delayed. Early diagnosis is critical in preventing progressive disease and potentially fatal complications.

Bortezomib retreatment for relapsed and refractory multiple myeloma in real-world clinical practice.

AimsStudies have shown that bortezomib retreatment is effective in relapsed/refractory multiple myeloma (MM). The observational, prospective electronic VELCADE® OBservational Study (eVOBS) study assessed bortezomib‐based therapies for patients with MM in everyday practice. Here, we report on those patients receiving retreatment with bortezomib.MethodsConsenting adults scheduled to receive bortezomib for MM were enrolled at 162 sites across Europe, Canada, Brazil, Russia, and Turkey between 2006 and 2010. Retrospective data on prior therapies and prospective observational data after bortezomib initiation were captured electronically at baseline, after every bortezomib cycle, and every 12 weeks after discontinuation or progression. Investigator‐assessed responses and adverse events (AEs) were evaluated.ResultsNinety‐six of 873 patients enrolled to eVOBS received bortezomib as first retreatment for progressive disease during the prospective observation period. Median age was 62 years, 53% were male, and median number of prior therapies at retreatment was 4. Overall, 41% of patients initiated bortezomib retreatment in combination with dexamethasone, 16% in combination with lenalidomide, and 21% received monotherapy. Rate of partial response or better (≥PR) was 75% at initial bortezomib therapy, including 44% complete response (CR)/near CR (nCR); at retreatment, ≥PR rate was 46%, including 15% CR/nCR. Median progression‐free survival was 11.4 months (95% confidence interval [CI]: 9.1‐12.7) from start of initial bortezomib treatment and 6.4 months (95% CI: 4.4‐7.2) from start of retreatment. Median overall survival from start of retreatment was 17.6 months (95% CI: 14.4‐23.5). Of the 96 patients retreated with bortezomib, 77% reported an AE. Peripheral neuropathy during bortezomib retreatment occurred in 49% of patients, including 10% grade 3/4.ConclusionThese data suggest that retreatment with bortezomib is a feasible option for patients with relapsed/refractory MM.

Efficacy of Novel Agents on Soft-tissue Plasmacytomas in Patients with Relapsed Multiple Myeloma

Introduction: the frequency of soft-tissue plasmacytomas (EMPs) is high in patients with relapsed multiple myeloma (MM). There are two types of plasmacytomas: 1) paraskeletal: originating from focal bone involvement (vertebrae, ribs, sternum, skull) and 2) extramedullary: originating from hematogenous spread (skin, liver, CNS). The reported incidence in relapsed patients is 3-34% for paraskeletal and 3-10% for extramedullary plasmacytomas. The presence of soft-tissue masses is associated with poor prognosis and the efficacy of novel agents is not well established. There are some reports about the lack of efficacy of thalidomide (Blade et al, Br J Haematol 2001; 113: 422-24) while some efficacy has been reported with bortezomib (Rosinol et al, Eur J Haematol 2006;76:405-08) and pomalidomide (Detweiler et al, Leukemia 2011, 25; 906-908). Aim: to analyze the effectiveness of novel drugs (thalidomide, bortezomib, lenalidomide, pomalidomide, carfilzomib) in patients with relapsed MM and EMPs. Patients and Methods: patients with EMPs (paraskeletal or extramedullary) at the time of first or subsequent relapses from our database from Hospital Clinic of Barcelona who were treated with novel agents were analyzed. Only patients receiving the novel drugs in monotherapy or in combination with corticosteroids were included in the analysis. Patients receiving combination therapy including two novel drugs (i.e. VTD, VRD) were excluded. Results: 29 patients (median age 61, M 17/F 12) with relapsed myeloma and EMPs were treated with bortezomib. The median number of previous therapies was one. 22 patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles received was 4. The serological response rate was: 4% CR, 27% PR, 7% MR, 24% SD, 17% PD, 7% early death, 14% non evaluable. The response of the plasmacytomas were: 14% CR, 17% PR, 10% SD, 41% PD, 4% early death, 14% non evaluable. The median PFS from the initiation of bortezomib was 3.9 months. Sixteen patients (median age 49 years, M 6/F 10) were treated with lenalidomide. 13 patients had paraskeletal and 3 extramedullary plasmacytomas. The median number of previous therapies was two. The median number of cycles was 5.5. Serological response was: 38% PR, 12% MR, 19% SD, 19% PD, 12% non evaluable. The plasmacytoma response was: 25% PR, 19% SD, 44% PD, 12% non evaluable. The median PFS from initiantion of lenalidomide was 8.4 months. Nine patients (median age 61 years, 3M/6F) were treated with pomalidomide at relapse. The median number of previous therapies was 4. Two patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles was 2. Serological response rate was: 44% PR, 11% SD, 23% PD, 11% non evaluable. However, none of the patients showed response of the plasmacytomas (11% SD, 77% PD, 11% early death). The median PFS was 1.3 months. 8 patients (median age 49 years, 6M/2F) were treated with thalidomide at relapse. The median number of previous therapies was one. Six patients had paraskeletal and 2 extramedullary plasmacytomas. The median number of cycles of thalidomide received was one. None of the patients showed serological response (25% stable disease (SD), 50% progressive disease (PD), 25% early death) or reduction in the size of the plasmacytomas (50% SD, 50% PD). The median progressive free survival (PFS) from initiation of treatment with thalidomide was 1.6 months. Four patients (median age 62, 2M, 2F) were treated with carfilzomib. The median number of previous therapies was 3. The EMPs type was paraskeletal (1) and extramedullary (3). The median number of cycles administered was one. None patient responded to carfilzomib: serological response rate: 75% SD, 25% PD; plasmacytomas response: 100% PD. The median PFS was 0.7 months. The median survival in the overall series of patients with soft tissues masses at relapse treated with novel agents was 15.2 months. Conclusions: The efficacy of novel drugs in the treatment of EMPs is limited, being the most effective bortezomib and lenalidomide. None of the patients treated with thalidomide, pomalidomide or carfilzomib showed any response of the soft-tissue involvement (paraskeletal or extramedullary). Finally, the presence of plasmacytomas at relapse is associated with poor OS even in the era of novel agents. However, the efficacy of these novel agents as part of front-line therapy is unknown. Disclosures No relevant conflicts of interest to declare.

Efficacy of Novel Agents on Soft-Tissue Plasmacytomas in Patients with Relapsed Multiple Myeloma

Introduction: the frequency of soft-tissue plasmacytomas (EMPs) is high in patients with relapsed multiple myeloma (MM). There are two types of plasmacytomas: 1) paraskeletal: originating from focal bone involvement (vertebrae, ribs, sternum, skull) and 2) extramedullary: originating from hematogenous spread (skin, liver, CNS). The reported incidence in relapsed patients is 3-34% for paraskeletal and 3-10% for extramedullary plasmacytomas. The presence of soft-tissue masses is associated with poor prognosis and the efficacy of novel agents is not well established. There are some reports about the lack of efficacy of thalidomide (Bladé et al, Br J Haematol 2001; 113: 422-24) while some efficacy has been reported with bortezomib (Rosiñol et al, Eur J Haematol 2006;76:405-08) and pomalidomide (Detweiler et al, Leukemia 2011, 25; 906-908).Aim: to analyze the effectiveness of novel drugs (thalidomide, bortezomib, lenalidomide, pomalidomide, carfilzomib) in patients with relapsed MM and EMPs.Patients and Methods: patients with EMPs (paraskeletal or extramedullary) at the time of first or subsequent relapses from our database from Hospital Clínic of Barcelona who were treated with novel agents were analyzed. Only patients receiving the novel drugs in monotherapy or in combination with corticosteroids were included in the analysis. Patients receiving combination therapy including two novel drugs (i.e. VTD, VRD) were excluded.Results: 29 patients (median age 61, M 17/F 12) with relapsed myeloma and EMPs were treated with bortezomib. The median number of previous therapies was one. 22 patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles received was 4. The serological response rate was: 4% CR, 27% PR, 7% MR, 24% SD, 17% PD, 7% early death, 14% non evaluable. The response of the plasmacytomas were: 14% CR, 17% PR, 10% SD, 41% PD, 4% early death, 14% non evaluable. The median PFS from the initiation of bortezomib was 3.9 months. Sixteen patients (median age 49 years, M 6/F 10) were treated with lenalidomide. 13 patients had paraskeletal and 3 extramedullary plasmacytomas. The median number of previous therapies was two. The median number of cycles was 5.5. Serological response was: 38% PR, 12% MR, 19% SD, 19% PD, 12% non evaluable. The plasmacytoma response was: 25% PR, 19% SD, 44% PD, 12% non evaluable. The median PFS from initiantion of lenalidomide was 8.4 months. Nine patients (median age 61 years, 3M/6F) were treated with pomalidomide at relapse. The median number of previous therapies was 4. Two patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles was 2. Serological response rate was: 44% PR, 11% SD, 23% PD, 11% non evaluable. However, none of the patients showed response of the plasmacytomas (11% SD, 77% PD, 11% early death). The median PFS was 1.3 months. 8 patients (median age 49 years, 6M/2F) were treated with thalidomide at relapse. The median number of previous therapies was one. Six patients had paraskeletal and 2 extramedullary plasmacytomas. The median number of cycles of thalidomide received was one. None of the patients showed serological response (25% stable disease (SD), 50% progressive disease (PD), 25% early death) or reduction in the size of the plasmacytomas (50% SD, 50% PD). The median progressive free survival (PFS) from initiation of treatment with thalidomide was 1.6 months.Four patients (median age 62, 2M, 2F) were treated with carfilzomib. The median number of previous therapies was 3. The EMPs type was paraskeletal (1) and extramedullary (3). The median number of cycles administered was one. None patient responded to carfilzomib: serological response rate: 75% SD, 25% PD; plasmacytomas response: 100% PD. The median PFS was 0.7 months. The median survival in the overall series of patients with soft tissues masses at relapse treated with novel agents was 15.2 months.Conclusions: The efficacy of novel drugs in the treatment of EMPs is limited, being the most effective bortezomib and lenalidomide. None of the patients treated with thalidomide, pomalidomide or carfilzomib showed any response of the soft-tissue involvement (paraskeletal or extramedullary). Finally, the presence of plasmacytomas at relapse is associated with poor OS even in the era of novel agents. However, the efficacy of these novel agents as part of front-line therapy is unknown. DisclosuresNo relevant conflicts of interest to declare.

Severe Diffuse Alveolar Hemorrhage Associated with Bortezomib Administration in Patients with Multiple Myeloma

Background: Bortezomib, a proteasome inhibitor, is frequently used in treatment of patients with multiple myeloma (MM). Bortezomib is generally well tolerated with gastrointestinal symptoms and peripheral neuropathy being the most common adverse effects. Here we report cases of severe diffuse alveolar hemorrhage (DAH) associated with bortezomib administration.Methods and Results: We identified 3 cases of severe DAH that were associated with bortezomib administration in MM patients treated at our institution between 2010 and 2014 (Table 1). All 3 patients presented with fever and worsening hypoxia shortly after initiation of bortezomib therapy and later developed progressive respiratory failure due to DAH. None of 3 patients had any respiratory symptoms or preexisting pulmonary conditions prior to bortezomib initiation. In one patient respiratory symptoms developed after 4 doses of bortezomib, improved off therapy, however rapidly progressed to a respiratory failure with a subsequent bortezomib treatment. Imaging studies showed diffuse areas of ground-glass opacities, apparent prominence of segmental and subsegmental bronchi and interlobular septal thickening. Infectious workup, which included bronchoscopy with bronchoalveolar lavage and respiratory viral studies, was completely negative in all 3 patients. All patients received supportive care, empiric broad-spectrum antimicrobial therapy and high-dose glucocorticoids, which were started within 4 days of hospital admission. Two patients died from complications of DAH and 1 patient recovered without pulmonary sequelae.Conclusion: Bortezomib-associated DAH is a rare, but serious and potentially fatal adverse event. Pathogenesis remains unclear and is likely related to impaired regulation of the inflammatory response. Early recognition of bortezomib associated DAH is essential for immediate discontinuation of the drug and prompt initiation of high dose steroids. More reports are needed to provide further insights about the pathogenesis and most optimal management of bortezomib induced DAH.Abstract 5761. Table 1:Patients who developed DAH after bortezomib administrationPtAge/ Gender/RaceSmokerSxBor doseBor schedule# of Bor dosesTime of onset after last bor dose (days)Platelet count at the onset (103/mm3)Imaging/BAL findingsTime to initiation of high dose steroidsOutcome167/M/CNeverSOB, fever1.3 mg/m2IV/2Xwk85157Bilateral infiltrates and GGO/DAH2Death272/M/CYesFever, cough1.3 mg/m2IV/2Xwk23108Bilateral infiltrates/DAH4Recovery355/M/CYesFever, chills1.5 mg/m2IV/2Xwk12144Bilateral diffuse airspace disease/DAH4DeathAbbreviations: Pt, patient; M, male; C, Caucasian; Sx, symptoms; Bor, bortezomib; BAL, broncho-alveolar lavage; GGO, ground-glass opacities. DisclosuresNo relevant conflicts of interest to declare.

Increasing Bone Sclerosis During Bortezomib Therapy in Multiple Myeloma Patients: Results of a Reduced-Dose Whole-Body MDCT Study

The objective of our study was to assess the frequency, location, extent, and patterns of bone sclerosis occurring in patients with multiple myeloma (MM) during bortezomib-based therapy. From June 2003 through December 2011, 593 whole-body reduced-dose MDCT studies were performed of 79 consecutive patients receiving bortezomib. The median surveillance time was 21 months (range, 3-67 months). Baseline studies were compared with follow-up studies during therapy (follow-up 1), at the end of therapy (follow-up 2), and 12 months after cessation of bortezomib therapy (follow-up 3). We recorded any sclerotic change occurring inside or along the margins of the osteolytic lesions, in the cancellous bone, or inside preexistent medullary or extramedullary lesions. The time point of occurrence of bone sclerosis was correlated with the best hematologic response category. Fourteen (17.7%) patients developed focal (n = 11) or diffuse (n = 3) bone sclerosis. The time window from bortezomib initiation to radiographic detection of bone sclerosis was 8 months (SD, 7 months). Sclerosis occurred at multiple sites (n = 7) or at an isolated site (n = 7). On subsequent whole-body reduced-dose MDCT studies, sclerosis further increased in seven (50%) patients. Hematologic best response during bortezomib treatment was complete response (n = 1), very good partial response (n = 2), partial response (n = 8), and stable disease (n = 3). Radiologic response at the time of sclerosis detection was partial response (n = 8), stable disease (n = 2), and progressive disease (n = 4). Bone remineralization may occur during bortezomib-based therapy for MM in a substantial proportion of patients. The extent, location, and patterns of sclerosis differ among patients and are unpredictable. Sclerosis was documented even in patients showing suboptimal hematologic response.

Real-life patterns of use and effectiveness of bortezomib: the VESUVE cohort study

In response to a regulatory request for real-life data on patterns of use and survival outcomes, 793 patients initiating bortezomib for multiple myeloma in France (May 2004–April 2006) were included in this observational study. Data were collected from medical files and patients were followed for 2 years, with vital status collected after 3 years. In total 779 patients were analyzed: 83.1% had immunoglobulin G (IgG) or IgA M-component, mean age was 65.7 years and 46.5% were female. Bortezomib was initiated as third-or-later line in 82.0%. For 75.9%, the starting dose was 1.3 mg/m2; 42.6% had bortezomib alone, 54.0% with dexamethasone. The mean number of bortezomib cycles was 5.0. Three-year overall survival from bortezomib initiation was 31.4% (95% confidence interval, CI [28.1; 34.7]) and median overall survival was 19.6 months. Two-year progression-free survival was 12.0% (95% CI [9.8; 14.4]), and median progression-free survival was 7.2 months. Overall best response was 44.0%. Survival outcomes during real-life use of bortezomib were within the range of those reported in clinical trials.

Relapse Pattern After Bortezomib Based Salvage Therapy in Patients with Multiple Myeloma

AbstractAbstract 1869 Backgrounds & Aims:More intensive and novel therapy options in multiple myeloma (MM) improve the treatment outcome. However, disease evolution, induced with long disease duration and extensive pretreatment, has resulted in changes in the biological behavior of MM and unusual relapse emergence. Therefore, we studied the relapse pattern after bortezomib based salvage treatment in patients with MM and also we analyzed the prognostic significance according to relapse pattern. Methods:We have retrospectively analyzed the relapse pattern. Eligibility criteria included primary refractory or relapsed MM patients who must have received previous chemotherapy and they also received at least 2 cycles of bortezomib based salvage treatment. Immunoglobulin M type of MM, primary amyloidosis and plasma cell leukemia were excluded in this study. For evaluation of disease response, International Myeloma Working Group (IMWG) uniform response criteria were used. Results:Between November 2004 and August 2011, 132 patients received bortezomib based salvage chemotherapy. In 132 patients, 91 (68.9%) patients showed the disease relapse. The pattern of relapse after bortezomib salvage treatment was heterogeneous, the 14/91 (15.4%) patients relapsed as a novel manifestation comparison with the initiation of bortezomib (plasmacytoma: 7 patients, light chain escape pattern: 4 patients and, plasma cell leukemia: 2 patients). There was no statistical difference in the duration from diagnosis to bortezomib treatment according to novel (group A) vs isoform (group B) relapse. In the group B, the median overall survival after relapse was 16.1 months (95% CI: 11.4–20.8) and the group A was 2.5 months (95% CI: 0.0–5.7)(p=0.000). The 27 out of 132 patients received the retreatment of bortezomib and 23 out of 27 patients showed the disease progression. The 4/24 (16.7%) patients relapsed as a novel manifestation (plasmacytoma: 2 patients, light chain escape pattern: 1 patients and intact immunoglobulin secretion from plasmacytoma type: 1 patient). In patients received retreatment of bortezomib, novel relapsed group showed the trend of poor survival without statistical significance (2.2 months vs 10.0 months) (p=0.30). Conclusion:Our report suggests that bortezomib treatment contribute as a selective pressure and it has culminated in novel relapse manifestation. The relapsed patients as novel pattern after bortezomib treatment show the extreme poor prognosis. These findings suggest that these patients may be worth consideration for intensive treatment or early clinical trials. Disclosures:No relevant conflicts of interest to declare.

The Clinical Spectrum of Bortezomib-Induced Peripheral Neuropathy (P06.140)

Objective: We sought to investigate the incidence, risk factors for development and phenotype of peripheral neuropathy in patient9s treated with bortezomib. Background Bortezomib (Velcade®) is the first member of a new class of chemotherapeutic agents that inhibit the proteasome-ubiquitination pathway. It is FDA-approved for use in multiple myeloma and mantle cell lymphoma. Bortezomib causes a painful axonal sensory-predominant length-dependent peripheral neuropathy in 30-40% of patients. A small subgroup of patients treated with bortezomib develop a severe neuropathy soon after commencing bortezomib, the mechanism of which is unclear. Design/Methods: We searched the Mayo Clinic Hematology Chemotherapy database for patients treated with bortezomib. We reviewed the clinical information to determine if neuropathy occurred in relation to the initiation of bortezomib. We reviewed the clinical and electrophysiological features and long-term followup of patients evaluated by a neurologist. Subjects were included if they received bortezomib and had follow-up for at least one cycle of chemotherapy. Results: 589 patients were identified. 378 patients met inclusion criteria. 138 (36.5%) were determined to have treatment-emergent peripheral neuropathy. The typical pattern was a painful, sensory-predominant peripheral neuropathy involving the hands and feet. Three patients had evidence of a plexopathy or polyradiculoneuropathy. Two patients had nerve biopsies suggesting microvasculitis. A prior history of peripheral neuropathy was more common in patients with treatment-emergent peripheral neuropathy (22% vs 14%, p Conclusions: In our series the incidence of bortezomib-induced peripheral neuropathy is 36.5%, similar to previous reports. A prior history of peripheral neuropathy appears to be a risk factor for the development of bortezomib-induced peripheral neuropathy. The pattern is most commonly a painful, sensory-predominant length-dependent neuropathy. An inflammatory neuropathy or polyradiculoneuropathy can occur with bortezomib with biopsy features suggesting microvasculitis. Disclosure: Dr. Mauermann has nothing to disclose. Dr. Dispenzieri has received research support from Millennium. Dr. Staff has nothing to disclose.

Myocardial scarring following chemotherapy for multiple myeloma detected using late gadolinium hyperenhancement cardiovascular magnetic resonance

We present the case of a 60-year-old lady who was treated with chemotherapy for myeloma. Following initiation of bortezomib, she developed heart failure which was associated with a reduction in left ventricular systolic function. A gadolinium enhanced cardiovascular magnetic resonance scan demonstrated midwall hyperenhancement consistent with midwall fibrosis.

Decrease in CD4+ T-Cell Counts in Patients With Multiple Myeloma Treated With Bortezomib

Bortezomib is highly effective in multiple myeloma and is widely used in this disease. Recently, an increased incidence of varicella zoster virus (VZV) reactivation was reported in patients with myeloma undergoing bortezomib treatment. We investigated the influence of bortezomib on T-cell subpopulations in 53 patients with myeloma before initiation of bortezomib and during therapy. A decrease of CD4+ T cells was seen in 41 of 53 patients (77%). The median CD3+/CD4+ lymphocyte counts declined from 494/microL (range, 130-2187/microL) to 274/microL (range, 41-1404/microL) during bortezomib treatment (P < .001). In the majority of patients (40 of 53 patients, 75%), CD4+ lymphocytes dropped to < 400/microL during bortezomib treatment, and in 18 of 53 patients (33.9%) the CD4+ T cells fell below 200/microL. The minimum CD4S+ cell count was observed at a median of 6 weeks (range, 2-22 weeks) after initiation of treatment. The incidence of herpes zoster reactivation was 5.7% in the whole population of patients with myeloma receiving bortezomib. Nineteen of 53 patients received acyclovir at a dose of 400 mg daily as prophylaxis against VZV reactivation. In this group, none of the patients developed herpes zoster. The incidence of VZV reactivation in patients not receiving acyclovir was 3 of 34 (8.8%). Importantly, occurrence of herpes zoster was associated with reduced CD4+ T-cell subpopulation: all patients who developed herpes zoster had CD4+ lymphocytes < 400/microL. Our results show that bortezomib leads to a transient decrease in CD4+ lymphocytes, accompanied by an increased incidence of VZV infections. The antiviral prophylaxis with acyclovir is effective in patients with myeloma treated with bortezomib.

The risk factors for herpes zoster in bortezomib treatment in patients with multiple myeloma

BackgroundBortezomib has significant activity in treating multiple myeloma (MM). The risk of herpes zoster (HZ) has been reported to increase significantly with bortezomib treatment, but the predisposing factors for HZ are not clear. This study is a retrospective analysis of the relevant risk factors for HZ in Korean MM patients treated with bortezomib.MethodsSixty-six patients with refractory or relapsed MM who underwent chemotherapy with bortezomib were included in the study. Prophylactic antiviral drugs were not used for treatment. The following parameters were reviewed: age, gender, stage and type of MM, extent of previous treatment, history of HZ, duration from the time of diagnosis to the time of bortezomib treatment initiation, and absolute lymphocyte counts (ALC) at the time of bortezomib treatment initiation.ResultsThe incidence of HZ was 16.7%. There were no intergroup differences between the HZ-positive and the HZ-negative groups with regard to a history of HZ, number of previous treatments, and exposure to steroids before bortezomib treatment. The median duration from the time of MM diagnosis to the time of bortezomib treatment initiation in the HZ-positive group was significantly shorter than that in the HZ-negative group. The median ALC at the time of bortezomib initiation in the HZ-positive group was significantly lower than that in the HZ-negative group.ConclusionBortezomib itself might act as a risk factor for HZ by inhibiting cell-mediated immunity, and patients with low ALC at the time of bortezomib treatment initiation were at greater risk of HZ during bortezomib treatment.

Bortezomib and the Increased Incidence of Herpes Zoster in Patients with Multiple Myeloma

BackgroundBortezomib has significantly advanced the treatment of patients with multiple myeloma (MM). However, considering that most patients with MM are elderly, bortezomib-related morbidity should be thoroughly studied to ensure the safe use of this drug. Herpes zoster has been reported as a possible adverse event associated with bortezomib because a major target of bortezomib, nuclear factor—κB, is known to be involved with T-cell immunity. Patients and MethodsWe performed a retrospective analysis of the incidence of herpes zoster among 282 patients treated with a bortezomib-containing regimen. ResultsDuring the patients' pre-bortezomib treatment (median, 2.14 years), the incidence of herpes zoster was 11% (31 of 282 patients). However, after the patients were treated with bortezomib, the incidence increased to 22.3% (63 of 282 patients), of which almost all occurrences were within the first 3 cycles (median duration, 41 days). The time interval from diagnosis to bortezomib initiation date was shorter in herpes zoster—positive patients than in herpes zoster—negative patients (2.14 ± 1.87 years vs. 3.38 ± 2.95 years; P = .002). Disease duration, previous herpes zoster infection, disease stage and type of myeloma, and the type and intensity of previous treatments failed to show any relationship with herpes zoster. These findings suggest that longer history of disease and treatments did not affect the occurrence of herpes zoster, nor did the type of bortezomib regimens or their toxicities. ConclusionBortezomib can increase the incidence of herpes zoster regardless of disease duration, previous treatments, and concomitantly administered drugs. Thus, the occurrence of herpes zoster should be monitored during bortezomib treatment.

Features and Risk Factors of Peripheral Neuropathy During Treatment with Bortezomib for Advanced Multiple Myeloma

BackgroundBortezomib is a first-in-class proteasome inhibitor with remarkable antitumor activity that is approved for the treatment of patients with multiple myeloma. Peripheral neuropathy (PN) is a frequent adverse event reported with bortezomib use. Patients and MethodsThe aim of this retrospective, single-center study was to determine the characteristics of bortezomib-associated PN in 100 patients with advanced myeloma. Peripheral neuropathy was evaluated by investigator's assessment. ResultsWith a median follow-up of 8 months (range, 0.1–32 months) from bortezomib initiation, bortezomib-associated PN was observed in 38 patients (38%; 95% CI, 28%–47%), with grade 3 and 4 PN occurring in 5 patients and 1 patient, respectively. Median time to onset of bortezomib-associated PN was 53 days (range, 11–182 days). Of the 38 patients with bortezomib-associated PN, resolution or improvement occurred in 20 patients (53%) at a median of 3 months (range, 1–8 months). In multivariate analysis, the total number of cycles of bortezomib (< 4 cycles or > 4 cycles; P = .03; odds ratio [OR], 2.6; 95% CI, 1.1–6.1) and a previous history of thalidomide therapy (P = .02; OR, 3.9; 95% CI, 1.2–12.6) were significantly associated with an increased incidence of bortezomib-associated PN. ConclusionWe conclude that, though relatively frequent, bortezomib-associated PN is reversible in a majority of patients. However, bortezomib-associated PN seems to be dependent on previous therapy with thalidomide, suggesting that bortezomib followed by thalidomide could be an optimal sequence of administration of these drugs in the salvage setting.

High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma

We describe the results of 37 myeloma patients who received bortezomib following reduced intensity allogeneic stem cell transplantation (RIC-allo-SCT). Grade 1-2 peripheral neuropathy (35%), mild thrombocytopenia (24%) and fatigue (19%) were the most frequent adverse events, while there was no worsening of graft-vs-host disease symptoms. Twenty-seven patients (73%; 95% CI, 59-87%) achieved an objective response. With a median follow-up of 9 months from bortezomib initiation, the estimate of overall survival was 65% at 18 months while this was significantly higher (p=0.002) in the 27 patients achieving an objective response, suggesting that bortezomib is a safe and efficient option for myeloma patients after RIC-allo-SCT.

Bortezomib as an Alternative in the Treatment of Patients With Malignant Gammopathy

ObjectiveTo describe the use of bortezomib in a district hospital as an alternative in the treatment of malignant gammopathy. MethodsA retrospective analysis was carried out on patients treated with bortezomib in our hospital between November 2005 and October 2007. The patients’ medical histories were used to obtain data regarding diagnosis, treatments prior to bortezomib, date of the last disease progression, number of bortezomib courses, response to bortezomib, overall and event free survival, complications, and side effects. ResultsForty-seven percent of the patients studied were male (5/12). The median age was 67, (range, 40-81). The main diagnosis was multiple myeloma on its own or associated with plasmocytoma. Bortezomib initiation coincided with the last disease progression in 83% of patients (10/12). Fifty percent of the patients completed 7-8 courses of bortezomib. Response was seen in 58% of the patients (7/12), partial response in 33% of them (4/12), and complete response in 25% (3/12). The most common adverse reactions were neuropathy and gastrointestinal toxicity which required treatment to be discontinued in 50% of cases. ConclusionsAccording to the results obtained, bortezomib is a good alternative in the treatment of malignant gammopathy, above all in the case of plasmocytomas.