Bortezomib Therapy Research Articles

Association Of Large Granular Lymphocytic Leukemia (LGL) With B-Cell Lymphoproliferative Disorders

IntroductionLarge granular lymphocytic (LGL) leukemia is an uncommon disease, characterized by a clonal proliferation of mature, post-thymic T-cells, typically CD3+, CD4-, CD8+, CD16+, CD57+ phenotype, representing constitutively active T-cells Less commonly, LGL leukemia is derived from CD3-, CD56+ natural killer (NK) cells. Clonal T-LGLs escape apoptosis by failure to respond to the Fas/Fas ligand (FasL) pathway. Activating mutations in the STAT3gene occur frequently in LGL leukemia, and may play a role in pathogenesis. Autoimmune disorders are frequently associated with LGL leukemia (∼1/3 present with rheumatoid arthritis).The association between LGL leukemia and B-cell lymphoproliferative disorders has been reported, often with low-grade histologies, but is deemed uncommon and the pathogenesis is not well established. We have analyzed a series of patients (pts) diagnosed with both LGL leukemia or expansion and clonal B-cell disorders. Patients and methodsPts with NK or T-LGL leukemia or expansion who were evaluated at Fox Chase Cancer Center or the Cleveland Clinic Taussig Cancer Institute were reviewed, after Institutional Review Board approval. Inclusion criteria were age ≥ 18 yrs and diagnosis of both LGL and B-cell lymphoproliferative disorder. ResultsOne hundred and twenty six pts with a diagnosis of T-LGL leukemia, NK-LGL leukemia or T-LGL expansion were identified. Of these, 44 (34.9%) pts were diagnosed with a clonal B-cell disorder. Twenty-six pts (20.6%) were diagnosed with a clonal B-cell disorder concomitantly with or shortly after the LGL diagnosis, 15 of whom presented with monoclonal gammopathy of unknown significance (MGUS) as their B-cell disorder, 9 with monoclonal B-cell lymphocytosis (MBL), 5 of whom also had monoclonal gammopathy. Eighteen pts (14.2%) had a previous diagnosis of clonal B-cell disorder, including diffuse large B cell lymphoma (DLBCL) (N= 6), CLL (N = 3), mantle cell lymphoma (N=3), multiple myeloma (N = 2), Hodgkin lymphoma (N = 2), Burkitt lymphoma (N = 1) and hairy cell leukemia (N = 1). Fifteen pts (11.9%) received treatment prior to the diagnosis of LGL, 10 of them (7.9%) with regimens including rituximab. The median time from completion of last treatment with rituximab to diagnosis of LGL disorder was 33 months. An additional patient with prior DLBCL was diagnosed with LGL shortly after receiving an oral SYK inhibitor.Two illustrative patients had unexpectedly prolonged remissions of their B cell disorder. A 66 years old man with multiple myeloma who achieved complete remission (CR) after 8 months of bortezomib therapy was then diagnosed with T-LGL, and his myeloma is in ongoing remission now 5 years after T-LGL diagnosis without further therapy. A 66 years old woman with relapsed DLBCL treated with 2ndline immunochemotherapy (R-ICE) for 3 cycles developed lymphocytosis and was diagnosed with T-LGL. With no further therapy, DLBCL is in ongoing remission now 5 years after diagnosis of T-LGL. DiscussionWe report a large series of patients with both clonal B-cell disorders and LGL. Where diagnosis of B-cell disorder and LGL are concurrent, we hypothesize an underlying immune dysregulation leading to both B-cell and T-cell proliferations. Where B-cell disorder precedes LGL, we hypothesize that the underlying disease and/or its treatment creates the environment for LGL, either directly allowing LGL expansion or permitting persistence of antigens that drive LGL expansion. Most pts with antecedent B lymphoma received rituximab (R), with a median time from R-treatment to LGL diagnosis of 33 months. Late onset neutropenia (LON) has been linked to bone marrow expansion of LGL in patients treated with rituximab, suggesting a possible pathogenetic role in our cases as well. Further, in some pts primary B-cell malignancies unexpectedly entered prolonged remission after T-LGL developed, suggesting a possible anti-B cell immune component of LGL. Further studies are warranted. Disclosures:No relevant conflicts of interest to declare.

Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value

Chromosome 1q21 aberrations have not been yet been made part of routine clinical tests and their effect in multiple myeloma is still under investigation. The prognostic value of copy number variation and percentage of plasma cells involved have remained unclear. In the present study, we analyzed the prognostic value of 1q21 in a series of 290 cases of newly diagnosed multiple myeloma treated in a prospective, non-randomized clinical trial (BDH 2008/02). We found that incidence of 1q21 aberration increased at relapse, but its copy numbers and proportion of cells involved did not change. Gains of 1q21 had no impact on survival in patients receiving thalidomide-based treatment but conferred a significantly inferior prognosis in patients under bortezomib-based chemotherapy and was an independent adverse prognostic factor for progression free survival (HR 3.831; 95%CI: 2.125-6.907; P<0.001) and overall survival (HR 3.245; 95%CI: 1.555-6.773; P=0.002). Strikingly, our results showed that the copy number variation and clone size harboring 1q21 gains carried no additional prognostic value and patients with 1q21 gains did not benefit significantly from regimens incorporating bortezomib. Our results indicate that three copies of 1q21 and 20% of plasma cells with this abnormality were enough to confer bortezomib resistance. Therefore, chromosome 1q21 gains should be considered a high-risk feature in multiple myeloma receiving bortezomib therapy.

Comparable outcome of stem cell transplant versus bortezomib-based consolidation in myeloma patients after major response to induction

High-dose therapy with autologous stem cell transplant (ASCT) has been established as standard treatment for eligible patients with myeloma. However, whether this approach is still beneficial with new therapy is yet to be determined. Consolidation of effective therapy may be an alternative to ASCT following major response to initial induction. This retrospective case-series analysis included a total of 48 patients with newly diagnosed myeloma. All these patients achieved complete response or very good partial response to bortezomib-based induction and were eligible for ASCT; 24 of these patients proceeded with ASCT, and other 24 patients opted out of ASCT and received two additional cycles of bortezomib therapy as consolidation. With a median follow-up of 28.5 months in ASCT group and 29 months in non-ASCT group, no significant difference was seen in progression-free survival, 39 versus 32 months, P = 0.82. Median overall survival had not been reached, and the estimated 3-year overall survival rates were 87.5 and 67.5% in ASCT and non-ASCT, respectively, P = 0.97. This study provides an initial assessment of survival outcome of ASCT in comparison with non-ASCT consolidation. The additional study is required to establish the efficacy of non-ASCT consolidation.

Bortezomib-Induced Hepatitis B Reactivation

Introduction: It has recently been reported that hepatitis B (HBV) reactivation in patients with lymphoma who are hepatitis B surface antigen (HBsAg)-negative during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation. However, clinical data on HBV reactivation in multiple myeloma (MM) patients has not been extensively reported. Bortezomib, a selective proteasome inhibitor, has had remarkable activity in relapsed multiple myeloma (MM). Although well-tolerated, reactivation of viral infections may emerge as a problem in this setting (2). We present a case of MM who developed HBV after bortezomib therapy. Case: A 73-year-old Russian female who had history of marginal cell lymphoma was monitored without needing therapy. Three years later, she developed MM requiring vertebral decompression and focal radiation. While on therapy renal failure ensued and she was started on bortezomib and doxorubicin. After five cycles, this was switched to lenalidomide. Prior to therapy, she was seropositive for anti HBs and HBc with negative HBsAg, indicating a prior natural infection. Her aminotransferase level was normal. She was serially monitored for hepatitis serology at dialysis, with seroconversion one month after change in therapy. Tenofovir was started, and patient recovered her immune status within a few months of therapy. Naranjo adverse drug reaction probability score was 5. Discussion: Bortezomib has significant risk of reactivation of infection by the varicella zoster virus, and acyclovir prophylaxis is recommended. A single case report describes reactivation of HBV after 10 cycles of bortezomib. Bortezomib-associated late hepatitis B reactivation appears to be a unique event that requires further confirmation. The contribution of one cycle of lenalidomide to this seroconversion is unknown.

Ventricular Fibrillation after Bortezomib Therapy in a Patient with Systemic Amyloidosis

A 64-year-old female was diagnosed with systemic amyloidosis associated with multiple myeloma. Bortezomib and dexamethasone-therapy was initiated; however, she developed lethal ventricular fibrillation (VF) and cardiac arrest after 84 hours of therapy. Cardiopulmonary resuscitation using direct current shocks with epinephrine and amiodarone was initiated but failed to receive cardiac function. Although her arterial pulsations recovered immediately after the injection of vasopressin, she died of heart failure 8 hours after the onset of VF. Cardiac amyloidosis was verified by autopsy. Although the direct association of bortezomib with lethal VF remained to be clarified in our patient, the current report emphasizes on bortezomib as a substantial risk factor for cardiomyocyte damage. The potential risk of lethal events associated with cardiac amyloidosis should be carefully considered during bortezomib treatment for patients with AL amyloidosis.

Bortezomib-Induced Painful Peripheral Neuropathy: An Electrophysiological, Behavioral, Morphological and Mechanistic Study in the Mouse

Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as other hematological and solid neoplasms. Peripheral neurological complications manifesting with paresthesias, burning sensations, dysesthesias, numbness, sensory loss, reduced proprioception and vibratory sensitivity are among the major limiting side effects associated with bortezomib therapy. Although bortezomib-induced painful peripheral neuropathy is clinically easy to diagnose and reliable models are available, its pathophysiology remains partly unclear.In this study we used well-characterized immune-competent and immune-compromised mouse models of bortezomib-induced painful peripheral neuropathy. To characterize the drug-induced pathological changes in the peripheral nervous system, we examined the involvement of spinal cord neuronal function in the development of neuropathic pain and investigated the relevance of the immune response in painful peripheral neuropathy induced by bortezomib.We found that bortezomib treatment induced morphological changes in the spinal cord, dorsal roots, dorsal root ganglia (DRG) and peripheral nerves. Neurophysiological abnormalities and specific functional alterations in Aδ and C fibers were also observed in peripheral nerve fibers. Mice developed mechanical allodynia and functional abnormalities of wide dynamic range neurons in the dorsal horn of spinal cord. Bortezomib induced increased expression of the neuronal stress marker activating transcription factor-3 in most DRG. Moreover, the immunodeficient animals treated with bortezomib developed a painful peripheral neuropathy with the same features observed in the immunocompetent mice.In conclusion, this study extends the knowledge of the sites of damage induced in the nervous system by bortezomib administration. Moreover, a selective functional vulnerability of peripheral nerve fiber subpopulations was found as well as a change in the electrical activity of wide dynamic range neurons of dorsal horn of spinal cord. Finally, the immune response is not a key factor in the development of morphological and functional damage induced by bortezomib in the peripheral nervous system.

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

BackgroundBruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.MethodsIn this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.ResultsThe median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.ConclusionsIbrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases

Bortezomib therapy is now indispensable for multiple myeloma, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. The development of orally active proteasome inhibitors with distinct mechanisms of action is therefore eagerly awaited. Previously, we identified homopiperazine derivatives as a novel class of proteasome inhibitors with a different mode of proteasome binding from bortezomib. In this study, we show that K-7174, one of proteasome inhibitory homopiperazine derivatives, exhibits a therapeutic effect, which is stronger when administered orally than intravenously, without obvious side effects in a murine myeloma model. Moreover, K-7174 kills bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 induces transcriptional repression of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1, the most potent transactivator of class I HDAC genes. HDAC1 overexpression ameliorates the cytotoxic effect of K-7174 and abrogates histone hyperacetylation without affecting the accumulation of ubiquitinated proteins in K-7174-treated myeloma cells. Conversely, HDAC inhibitors enhance the activity of K-7174 with an increase in histone acetylation. These results suggest that class I HDACs are critical targets of K-7174-induced cytotoxicity. It is highly anticipated that K-7174 increases the tolerability and convenience of patients by oral administration and has the clinical utility in overcoming bortezomib resistance as a single agent or in combination with HDAC inhibitors.

PP272—Migraine and parthenolide inhibition of transient receptor potential ankyrin 1

2013 e103 emerged as a major complication of bortezomib therapy, which usually appears in the first courses of therapy with a number of sensory and painful symptoms, including reduced threshold to mechanical and cold stimuli. No satisfactory explanation or effective treatment exists for bortezomib-evoked CIPN. Patients (or Materials) and Methods: In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Results: Our data demonstrated that CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger α -lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyllysine, a byproduct of oxidative stress. Short-term systemic treatment with either HC-030031 or α -lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Conclusion: Our findings highlight a key role for early activation/ sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists. Disclosure of Interest: None declared.

Failure of bortezomib to cure acute antibody‐mediated rejection in a non‐compliant renal transplant patient

Bortezomib has appeared recently as a potential active treatment for acute AMR for few years. We reported a patient who received two courses of bortezomib for the treatment of an acute AMR associated with de novo HLA DSA that occurred 18months after renal transplantation because of non-compliance. Graft biopsy revealed features of acute humoral rejection with plasmocyte infiltration and C4d staining. Bortezomib was associated with corticosteroid pulses, IVIgs, and PP. Despite this rapid management, the patient lost his graft and carried on dialysis. Bortezomib therapy in addition to current therapy of AMR is not always effective in the treatment for late acute AMR in renal transplantation. We discuss on the place of such a treatment and other therapeutic strategies in this indication.

Bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy for relapsed or refractory multiple myeloma: a multicenter phase 2 study

We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0mg/m(2). We then conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0mg/m(2) was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9mg/m(2) on days 1-4, and dexamethasone 20mg orally on days 1-2, 4-5, 8-9 and 11-12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89% with CR rate of 30%. The median PFS time was 12.1months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22%) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration.

Testicular invading refractory multiple myeloma during bortezomib treatment successfully treated with lenalidomide: a case report

Dear Editor, A 64-year-old man was diagnosed with symptomatic multiple myeloma (MM) in June 2009. No extramedullary region including the testes was detected. Serum protein electrophoresis showed IgA-κmonoclonal protein. Durie-Salmon stagewas IIIA and International Staging System stage was II. Treatment was initiated with pulsed dexamethasone and bortezomib (1.3 mg/m) twice weekly with dexamethasone (20 mg on the day of bortezomib administration and the next day).Without any adverse events, he achieved very good partial response (VGPR) after three cycles of bortezomib therapy [1]. Subsequently, he received high-dose melphalan (200 mg/m) followed by autologous stem cell transplantation (ASCT) in November 2009. After ASCT, he was followed up without any therapeutic agents. However, in September 2010, he complained of hip pain, and serum IgA level was elevated to 2,014 mg/dl. As recurrence of MM was diagnosed, we started weekly bortezomib with dexamethasone. The patient soon experienced improvement of symptoms, and serum IgA decreased to normal levels. In July 2011, during weekly bortezomib and dexamethasone, the patient noticed enlargement of his scrotum. Magnetic resonance image revealed enlarged bilateral testes. Serum IgA levels and all other laboratory data were normal. Bilateral orchidectomy was performed in October 2011. Microscopic examination showed positive results for CD56, CD138, and IgA and κ light chain (Fig. 1a, b). The pathological diagnosis wasmetastasis of plasma cell myeloma to the bilateral testes, and the right spermatic cord had positive margins. In November 2011, serum IgA was elevated to 2,304 mg/dl. At relapse of systemicMM including spermatic margins after orchidectomy, a 28-day cycle of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22) was initiated [2]. Serum IgA levels decreased to 1,026 mg/dl and reached a plateau without stump recurrence of the spermatic cord. After 6 cycles of lenalidomide, the patient was treated with cyclophosphamide, vincristine, adriamycin, and dexamethasone (C-VAD) and achieved VGPR after two cycles of C-VAD therapy. In August 2012, he successfully underwent a second ASCT. Two months after ASCT, he started a 28-day cycle of lenalidomide maintenance therapy (10mg on days 1–21) [3]. As of the time of writing, the patient remains alive without recurrence.

Bortezomib Induced Tumor Lysis Syndrome in Multiple Myeloma

The tumor lysis syndrome (TLS) commonly occurs in the lymphoproliferative disorder, either spontaneously or in response to therapy. TLS is uncommon in multiple myeloma. However, with the use of bortezomib in the treatment of multiple myeloma, cases of TLS have been reported. We report here threepatients who presented with TLS after the administration of bortezomib. Two of them presented mild symptoms and recovered with hydration only. However, death of the other patient was associated with TLS. We should monitor patients who had high tumor burden, especially in early phase of bortezomib therapy and appropriate prophylaxis for high risk patient is also needed.

Effect of a novel agent, SL-401, targeting interleukin-3 (IL-3)-receptor on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and drug resistance.

8582 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and drug resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our recent study utilized in vitro and in vivo MM xenograft models to show that plasmacytoid dendritic cells (pDCs) were significantly increased in MM BM and promote MM growth (Chauhan et al., Cancer Cell 2009, 16:309). Importantly, we found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDCs survival. IL-3R is highly expressed on pDCs. We utilized SL-401, a novel biologic conjugate that targets IL-3R, to examine whether abrogation of IL-3–IL-3R signaling axis affects pDC-MM interaction and its tumor promoting sequelae. Methods: MM cell lines, patient MM cells, and pDCs from healthy donors or MM patients were utilized to study the anti-MM activity of SL-401. MM cells and pDCs were cultured alone or together in the presence or absence of SL-401, followed by analysis of cell growth or viability. Results: SL-401 significantly decreased the viability of pDCs at low concentrations (IC50: 0.83 ng/ml; P &lt; 0.005, n = 3). SL-401 also decreased the viability of MM cells at clinically achievable doses. Co-culture of pDCs with MM cells induced growth of MM cell lines; and importantly, low doses (0.8 ng/ml) of SL-401 blocked MM cell growth-promoting activity of pDCs. MM patient-derived pDCs induced growth of MM cell lines and primary MM cells as well; conversely, SL-401 inhibited pDC-triggered MM cell growth (P &lt; 0.005, n= 5). Tumor cells from 3 of the 5 patients were from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. In agreement with these results, SL-401 blocked pDC-induced growth of dexamethasone-resistant MM cell lines. Conclusions: Our study therefore provides the basis for directly targeting pDCs or blocking the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.

Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).

8531 Background: In PANORAMA 2, PAN + BTZ + DEX recaptured responses in heavily pretreated pts with BTZ-refractory MM; overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) were 34.5%, 52.7%, and 5.4 months, respectively. Here, we evaluate clinical response per baseline characteristics. Methods: Response was based on European Group of Blood and Marrow Transplantation 1998 criteria. High-risk cytogenetics was defined as del(17p), t(4;14), or t(14;16). Quality of life (QoL) was measured with Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) v4.0 scale. Results: Response rate trended higher in pts whose prior BTZ therapy was not their last line of therapy (Table). Although no trend in response rate was noted, PFS appeared longer in pts progressing within 60 days of their last BTZ-containing regimen than in those progressing on their last BTZ-containing regimen. In the 14 pts with high-risk cytogenetics, ORR was 42.9% and CBR was 71.4%. The mean FACT/GOG-Ntx subscale did not exhibit a clinically meaningful change from baseline (mean ± standard deviation [SD], 114.2 ± 21.1; n = 41) to cycle 9 day 1 (day 169; 104.2 ± 15.4; n = 16) as determined by 50% SD threshold for minimally important difference. Other QoL parameters were similarly unchanged. Conclusions: PAN + BTZ + DEX demonstrated activity regardless of baseline demographics in heavily pretreated pts with BTZ-refractory MM. Clinical trial information: NCT01083602. [Table: see text]

Proteasome Inhibitor Therapy for Waldenström's Macroglobulinemia

Proteasome inhibitors effectively kill tumor cells in myeloma and other plasma cell-related diseases. Preclinical data indicated that lymphoplasmatic cells are also vulnerable to proteasome inhibition and proteasome-targeting therapies have proved their clinical activity in Waldenström's macroglobulinemia (WM). Bortezomib is the first in class proteasome inhibitor (PI), and has been used in several clinical trials either alone or in combination with rituximab. Bortezomib treatment alone might induce major responses in 25%-60% of patients with WM but in combination with rituximab major responses might be as high as 50%-83%. Bortezomib might reduce immunoglobulin M levels rapidly and is not myelotoxic. However, peripheral neuropathy remains a major toxicity of bortezomib therapy; alternative schedules and dosing or route of administration (subcutaneous) might reduce neurotoxicity. Second generation PIs, such as carfilzomib, are also promising but further investigation is needed.

The efficacy and safety analysis of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma

To evaluate the efficacy and safety of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma (MM), who previously responded to bortezomib. Retrospective analysis of 76 MM patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to August 2011, received bortezomib retreatment when they relapsed or progressed. The overall response rate (ORR) was 60.5%, among them 6.5% patients achieved CR, 5.8% patients achieved very good partial response (VGPR), 38.2% patients achieved PR. Then we further stratified all patients into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 84.6%, 73.1% and 43.2%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 7(1-39) and 5(1-14) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 16(2-64) and 8(1-28) months, respectively (P<0.05). Adverse events (AE) were identified in 88% patients during bortezomib retreatment, including neutropenia, diarrhea and thrombocytopenia, only 9.2%(7 patients) reached Ⅲ-Ⅳ grade of AE. Severe peripheral neuropathy occurred in only one patient. Bortezomib retreatment regimen is demonstrated a higher response rate in patients who achieved deeper response in initial treatment, with no more adverse events.

Herpes zoster complicating bortezomib therapy of relapsed/refractory indolent B-cell and mantle cell lymphoma: an analysis of two phase II trials

The incidence of herpes zoster (HZ) in patients with non-Hodgkin lymphoma (NHL) receiving bortezomib-based therapy has not been well studied. We reviewed data from two phase II trials in which bortezomib was administered to 236 patients, median age 65 years, with relapsed/refractory mantle cell or indolent NHL. HZ occurred in 24 patients (10.2%) overall, with a comparable incidence in NHL histologic subgroups. Median time to HZ was 39 (range, 11–206) days. In total, 71% of patients who developed HZ were aged ≥ 65 years, compared to 48% without HZ (p = 0.03). Patients with HZ were more likely to have had received ≥ 2 lines of therapy (63% vs. 47%, p = 0.16). Six (25%) of the patients who developed HZ had received purine analogs, compared with 34 (16%) patients without HZ (p = 0.27). As the occurrence of HZ may complicate the course of indolent or mantle cell NHL in patients receiving bortezomib-based therapies, these patients, especially the elderly, should be strongly considered for antiviral prophylaxis.

Acute pancreatitis caused by bortezomib

Drug-induced pancreatitis has been reported rarely. Bortezomib is a selective and reversible proteasome inhibitor used for the treatment of patients with multiple myeloma (MM). Recently, one case report about acute pancreatitis (AP) caused by bortezomib was published in the international literature. Herein we report a case of AP in a 67-year-old male on bortezomib therapy. On the fourth day after the first administration of bortezomib, the patient admitted to the hospital with symptoms of AP. The common etiological factors for AP were all excluded. Than the patient was diagnosed as bortezomib-induced pancreatitis.

Retrospective analysis on therapeutic effect of autologous hematopoietic stem cell transplantation in multiple myeloma patients

To evaluate the efficacy and prognostic factors of autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma (MM) patients. Retrospective analysis was performed in 27 MM patients undergoing ASCT at our hospital from May 2004 to August 2011. After comparing with 28 patients achieving very good partial response (VGPR) or better outcome and not undergoing ASCT, the impact on the extent of response, progression-free survival (PFS) and overall survival (OS) as well as related prognostic factors of MM patients were analyzed. All patients successfully underwent hematopoietic reconstruction without transplantation-related mortality. The complete remission (CR) rate of ASCT group increased from 25.9% (7/27) at pre-ASCT to 70.4% (19/27) at post-ASCT (P < 0.01). The estimated 5-year rate of progression-free survival was 56.2% (median not reached) in the ASCT group and 24.9% (median 29 months) in the non-ASCT group (P < 0.05). The 5-year probability of overall survival was 52.2% (median not reached) in the ASCT group and 33.1% (median 60 months) in the non-ASCT group (P > 0.05). Univariate analysis in ASCT group demonstrated that maintenance/consolidation therapy was associated with PFS (P = 0.010) and OS (P = 0.008).Patients on induction therapy containing bortezomib and early ASCT maintenance therapy all survived without disease progression until final follow-up (P = 0.010). ASCT can further increase the CR rate, prolong PFS and probably OS. The incorporation of novel agents into induction, consolidation and maintenance phases has optimized the anti-myeloma activity of ASCT and may be important for improved long-term outcomes.