Cyclophosphamide and Bortezomib With Prednisone or Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma.

Introduction: Cyclophosphamide, bortezomib, and prednisone (CyBorP) is a highly effective, well-tolerated regimen in relapsed/refractory multiple myeloma. CyBorP, originally developed at our center to include weekly bortezomib (Bor) and alternate-day prednisone (P), was recently modified so that weekly dexamethasone (D) replaced prednisone.

Patients And Methods: To assess the effectiveness and tolerability of CyBorP/D in real-world practice, we identified 96 relapsed/refractory patients who received ≥ 1 28-day cycle of CyBorP/D, consisting of cyclophosphamide 300 mg/m(2) (days 1, 8, 15, and 22), Bor 1.

D(T)PACE as salvage therapy for aggressive or refractory multiple myeloma.

Dexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona.

Rapidity and quality of response to steroid-based induction therapy, without the addition of novel agents, does not affect post transplant outcomes in multiple myeloma.

Background: The goal of induction in younger MM patients is to improve performance status and symptoms, enabling autologous stem cell transplantation (ASCT). It is unclear whether intensification of induction regimens improves post transplant outcomes.

Patients And Methods: We studied 178 MM patients who received conservative steroid-based induction therapy without novel agents before ASCT between 2000 and 2006 and correlated induction parameters (rapidity of response, need for salvage induction therapy, depth of response) with transplant outcomes.

Genomic aberrations and survival of patients with light-chain-only multiple myeloma undergoing autologous stem cell transplantation.

The majority of patients with multiple myeloma (MM) have intact immunoglobulin, but in a subset of patients (∼15%), their tumors produce monoclonal light chains only (LCO). Although specific genomic aberrations have emerged as a major prognostic factor in MM, their incidence and prognostic impact on LCO myeloma patients are not clear. We therefore investigated a cohort of 86 LCO MM cases diagnosed and treated with autologous stem cell transplantation at our institution.

Molecular target characterization and antimyeloma activity of the novel, insulin-like growth factor 1 receptor inhibitor, GTx-134.

Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM.

Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples.

Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone.

Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes.

Impact of cytogenetics in patients with relapsed or refractory multiple myeloma treated with bortezomib: Adverse effect of 1q21 gains.

We investigated the influence of genetic risk factors on the clinical response to bortezomib in 85 relapsed/refractory multiple myeloma (MM) patients. Interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH) detected del(13q), del(17p), del(1p21), t(4;14), and 1q21 gain in 38%, 22%, 26%, 18% and 39% of evaluable cases. Forty-nine patients (49%) responded to bortezomib with median progression free (PFS) and overall survivals (OS) of 5.

Prognostic relevance of 6q deletion in Waldenström's macroglobulinemia: a multicenter study.

The deletion of the long arm of chromosome 6 is the most common cytogenetic abnormality in Waldenstrom's macroglobulinemia (WM), but its prognostic significance is unclear. We investigated 77 patients with WM by interphase cytoplasmic immunoglobulin M fluorescence in situ hybridization (cIgM-FISH) and correlated the 6q status with the patients' clinical features and survival. cIg-FISH detected hemizygous 6q deletions in 32 patients (41.

Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13.

Although the combination of lenalidomide and dexamethasone is effective therapy for patients with relapsed/refractory multiple myeloma, the influence of high-risk cytogenetic abnormalities on outcomes is unknown. This subanalysis of a large, open-label study investigated the effects of the most common unfavorable cytogenetic abnormalities detected by fluorescence in situ hybridization, del(13q), t(4;14), and del(17p13), in 130 evaluable patients treated with this regimen. Whereas patients with either del(13q) or t(4;14) experienced a median time to progression and overall survival comparable with those without these cytogenetic abnormalities, patients with del(17p13) had a significantly worse outcome, with a median time to progression of 2.

The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan.

Purpose: The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma.

Experimental Design: The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated.

Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma.

Myeloma patients with unfavorable molecular cytogenetics have a poor prognosis irrespective of treatment with conventional chemotherapy or autologous stem cell transplant. To investigate whether bortezomib, a new proteasome inhibitor, is active in relapsed/refractory myeloma patients with genetic risk factors, we evaluated the outcome of 65 patients and correlated the clinical response with 13q deletion, translocations t(11;14) and t(4;14) and CKS1B amplification as detected by interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH). Thirty-seven of 61 (61%) evaluable patients had an objective response to bortezomib with median progression free (PFS) and overall survivals (OS) of 9.

Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation.

The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation. CKS1B amplification (3-8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 (P = 0.003) and 13q (P = 0.

Weekly cyclophosphamide and alternate-day prednisone: an effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation.

Objective: To assess the efficacy and tolerability of weekly oral cyclophosphamide in combination with alternate-day prednisone (CP) as salvage therapy for patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (ASCT).

Patients And Methods: We retrospectively reviewed the medical records of all patients identified in our clinical database as having received CP as treatment for relapsed MM after ASCT at Princess Margaret Hospital between July 1998 and May 2004. The CP regimen consisted of oral cyclophosphamide at 500 mg once weekly and oral prednisone at 100 mg on alternate days.

Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance.

Purpose: To determine whether primary drug resistance or rapid relapse explains the poor prognosis seen in t(4;14)-positive multiple myeloma (MM).

Patients And Methods: A total of 131 patients treated with high-dose therapy (HDT) were assessed, of whom 19 were t(4;14) positive. We examined the presentation features, chemotherapy responsiveness at presentation and to salvage therapies at relapse, and overall survival outcomes.

The SH3-SAM adaptor HACS1 is up-regulated in B cell activation signaling cascades.

HACS1 is a Src homology 3 and sterile alpha motif domain-containing adaptor that is preferentially expressed in normal hematopoietic tissues and malignancies including myeloid leukemia, lymphoma, and myeloma. Microarray data showed HACS1 expression is up-regulated in activated human B cells treated with interleukin (IL)-4, CD40L, and anti-immunoglobulin (Ig)M and clustered with genes involved in signaling, including TNF receptor-associated protein 1, signaling lymphocytic activation molecule, IL-6, and DEC205. Immunoblot analysis demonstrated that HACS1 is up-regulated by IL-4, IL-13, anti-IgM, and anti-CD40 in human peripheral blood B cells.

Soluble interleukin-13Ralpha2 decoy receptor inhibits Hodgkin's lymphoma growth in vitro and in vivo.

Recent studies have demonstrated that the malignant Reed-Sternberg cells of Hodgkin's lymphoma (HL) secrete and are responsive to interleukin (IL)-13. We hypothesized that overexpression of a soluble IL-13 decoy receptor (sIL-13Ralpha2) via adenoviral-mediated gene transfer would inhibit IL-13-induced Reed-Sternberg cell proliferation. Western blot and ELISA analysis verified expression of sIL-13Ralpha2 in cell lysates and supernatants of AdsIL-13Ralpha2-transduced COS-7 cells.