Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92443/1/bjh9173.pd

A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

BACKGROUND Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria ofthe European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS Of 193 patients who could be evaluated, 92 percent had been treated with three or more ofthe major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immuno-fixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy

Advances in the Autologous and Allogeneic Transplantation Strategies for Multiple Myeloma

Background: Multiple myeloma is largely an incurable malignant plasma cell neoplasm; however, the landscape of its treatment is rapidly changing. Methods: The recent literature on both autologous and allogeneic transplant approaches for multiple myeloma was reviewed. Results: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) remains an integral component of upfront treatment strategy, and the incorporation of novel immunomodulators and proteasome inhibitor to induction regimens improves response rates and increases overall survivals. Bortezomib-and lenalidomide-based combination chemotherapy regimens have become the standard induction myeloma therapy. When myeloma patients proceed to transplant after novel combination regimens, their response rates are further improved. Despite these recent major improvements, myeloma remains incurable and long-term survival appears elusive. Due in part to a potential graft-vs-myeloma effect, allogeneic HCT is a potentially curative transplant option. However, initial attempts have been hampered by the high transplant-related mortality. With a reduction of toxicity, allogeneic transplant approaches with reduced-intensity conditioning have been utilized, although they are subject to continued disease progression and relapse following transplantation. Recent research efforts have shifted to the use of a tandem autologous-allogeneic HCT approach. The long-term follow-up of this new strategy is awaited. Conclusions: Recent advances in HCT have improved outcomes of patients with multiple myeloma. Ongoing research activity focuses on the strategies to improve outcomes of HCT by incorporation of tandem autologous-allogeneic transplantation schema, novel conditioning regimens, and the use of consolidation and maintenance therapy

Advances in the Autologous and Allogeneic Transplantation Strategies for Multiple Myeloma

Background: Multiple myeloma is largely an incurable malignant plasma cell neoplasm; however, the landscape of its treatment is rapidly changing. Methods: The recent literature on both autologous and allogeneic transplant approaches for multiple myeloma was reviewed. Results: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) remains an integral component of upfront treatment strategy, and the incorporation of novel immunomodulators and proteasome inhibitor to induction regimens improves response rates and increases overall survivals. Bortezomib-and lenalidomide-based combination chemotherapy regimens have become the standard induction myeloma therapy. When myeloma patients proceed to transplant after novel combination regimens, their response rates are further improved. Despite these recent major improvements, myeloma remains incurable and long-term survival appears elusive. Due in part to a potential graft-vs-myeloma effect, allogeneic HCT is a potentially curative transplant option. However, initial attempts have been hampered by the high transplant-related mortality. With a reduction of toxicity, allogeneic transplant approaches with reduced-intensity conditioning have been utilized, although they are subject to continued disease progression and relapse following transplantation. Recent research efforts have shifted to the use of a tandem autologous-allogeneic HCT approach. The long-term follow-up of this new strategy is awaited. Conclusions: Recent advances in HCT have improved outcomes of patients with multiple myeloma. Ongoing research activity focuses on the strategies to improve outcomes of HCT by incorporation of tandem autologous-allogeneic transplantation schema, novel conditioning regimens, and the use of consolidation and maintenance therapy

Involvement of Notch-1 Signaling in Bone Marrow Stroma-mediated De Novo Drug Resistance of Myeloma and Other Malignant Lymphoid Cell Lines

The bone marrow (BM) microenvironment plays a critical role in malignant cell growth, patient survival, and response to chemotherapy in hematologic malignancies. However, mechanisms associated with this environmental influence remain unclear. In this study, we investigated the role of Notch family proteins in myeloma and other malignant lymphoid cell line growth and response to chemotherapeutic drugs. All 8 tested cell lines expressed Notch-3 and Notch-4; 7 cell lines expressed Notch-1; and 6 expressed Notch-2 proteins. Interaction with BM stroma (BMS) activated Notch signaling in tumor cells. However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21WAF/Cip and growth inhibition of cells. Overexpression of Notch-1 in Notch-1- U266 myeloma cells up-regulated p21 and resulted in protection from drug-induced apoptosis. Thus, this is a first report demonstrating that Notch-1 signaling may be a primary mechanism mediating the BMS influence on hematologic malignant cell growth and survival. (Blood. 2004; 103:3503-3510

Primary plasmacytoma involving mediastinal lymph nodes: A diagnostic mimicry of primary mediastinal lymphoma

Plasmacytomas could involve any organ, and at times might pose a diagnostic challenge when the site of involvement is unusual, or if the presentation is similar to other diseases. We describe a 48-year-old man presenting with worsening shortness of breath and chest discomfort with radiologic evidence of mediastinal enlargement, mimicking a lymphoma with mediastinal involvement. An excisional biopsy of a mediastinal lymph node showed a plasma-cell infiltrate strongly positive for CD138, with a flow-cytometry analysis showing a population of lambda-restricted neoplastic plasma cells. He failed to respond to 50 Gy involved-field radiotherapy, but achieved a partial response to combination chemotherapy. He underwent high-dose chemotherapy with melphalan (200 mg/m2) followed by lenalidomide maintenance, and is in complete remission 18 months postautografting. This case illustrates a unique and rare presentation of primary lymph-node plasmacytomas involving the mediastinum potentially mistaken as lymphoid malignancy. Clinicians should be aware of the plasma-cell origin of the mediastinal neoplastic process. Keywords: Mediastinal involvement, Primary plasmacytom