Molecular Mechanisms In Multiple Myeloma

Two new studies may lead to the development of more effective therapies for individuals with multiple myeloma. The research provides new insight into the molecular mechanisms that underlie aberrant NF-ºB activity in MM tumor cells and underscores the relevance of the NF-ºB signaling pathway as a target for MM therapy.

MM is a cancer of the plasma cell, a blood cell that produces antibodies to help the body fight off infections. Previous research implicates abnormal activation of the NF-ºB signaling pathway as a key event in MM pathology. NF-ºB target genes are known to be involved in cell proliferation and cell survival. Although there is significant overlap and interplay between them, there are two separate pathways that lead to activation of NF-ºB, the classical pathway and the alternative pathway.

Constitutive activation of NF-ºB to block apoptosis has been implicated in various types of cancer, but the molecular mechanisms involved are not well understood. Two separate research groups used a variety of sophisticated genomic techniques to examine mutations in hundreds of MM patient samples and cell lines to identify mutations that impact NF-ºB activation.

Dr. Louis M. Staudt from the National Cancer Institute led a research group who revealed the importance of both the classical and alternative NF-ºB pathways in MM pathogenesis. Most MM patient samples examined exhibited NF-ºB pathway activation via diverse genetic abnormalities. Importantly, targeted disruption of the classical NF-ºB signaling blocked myeloma proliferation and induced cell death. "These genetic and functional data provide a molecular framework for the rational development of NF-ºB pathway inhibitors for the therapy of MM," offers Dr. Staudt.

In a separate study, Dr. Rafael Fonseca, from the Mayo Clinic Arizona, and colleagues report mutations in several genes that result in constitutive activation of the alternative NF-ºB pathway. "We propose that the acquisition of the mutations identified in our study results in the accumulation of malignant plasma cells beyond the physiological control of the bone marrow compartment. Our results suggest a mechanism by which MM cells can overcome these limitations through acquisition of mutations that result in constitutive and ligand-independent activation of the alternative NF-ºB pathway," explains Dr. Fonseca.

Taken together, results for these studies define diverse mutations that lead to pathological activation of NF-ºB signaling in MM and describe a shift of plasma cells from dependence on the microenvironment to an environment-independent state during progression of MM. Regardless of the specific method of activation, the NF-ºB pathway plays a central role in MM pathogenesis and is an excellent target for development of new therapeutics.

Source: http://www.cancercell.org/content/article/fulltext?uid=PIIS1535610807002036

Genzyme Announces Second Pivotal Mozobil Trial Meets Primary Endpoint

Genzyme Corp. (Nasdaq: GENZ) today announced that its second phase 3 trial of Mozobil^TM (plerixafor) has successfully met its primary and secondary endpoints, demonstrating positive results in multiple myeloma (MM) similar to those reported two weeks ago in non-Hodgkin’s lymphoma.

The combined strength of these two trials – in which patients with two types of cancer achieved more rapid and effective mobilization of stem cells in preparation for transplant than patients treated with current therapies – will support Mozobil’s regulatory approval, commercialization, and likely adoption as a standard of care in transplantation.

The randomized, double-blind, placebo-controlled trial included 302 patients who were undergoing a hematopoietic stem cell transplant (HSCT) for multiple myeloma at medical centers in the United States, Canada, and Europe. Like the previous trial, it examined the effectiveness of Mozobil in increasing the number of hematopoietic stem cells collected for a transplant, comparing the stem cell yield from patients treated with Mozobil following G-CSF to patients treated with placebo following G-CSF.

Source: http://www.genzyme.com

Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma

Kuruvilla J, Shepherd JD, Sutherland HJ, Nevill TJ, Nitta J, Le A, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Toze CL, Smith CA, Barnett MJ, Song KW.

The Leukemia/Bone Marrow Transplantation Program of British Columbia, Division of Hematology, Vancouver General Hospital, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada.

Allogeneic stem cell transplantation (alloSCT) has been used in the hopes of harnessing the curative potential of the graft-versus-myeloma effect. This study examines the long-term outcomes of a large cohort of patients with myeloma who were treated with myeloablative alloSCT at a single center. Comparisons are made with those who were treated with autologous stem cell transplantation (ASCT). Between January 1989 and February 2002, 158 patients age 10 years post myeloablative alloSCT, similarly there are long-term survivors post-ASCT. Myeloablative alloSCT should not be considered standard treatment, and should only be considered in the context of a clinical trial.

PMID: 17640596 [PubMed - in process]