Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma

de Lavallade H, El-Cheikh J, Faucher C, Fürst S, Stoppa AM, Coso D, Bouabdallah R, Chabannon C, Gastaut JA, Blaise D, Mohty M.

1Unité de Transplantation et de Thérapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille, France.

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P=0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.Bone Marrow Transplantation advance online publication, 25 February 2008; doi:10.1038/bmt.2008.22.

PMID: 18297115 [PubMed - as supplied by publisher]

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma

Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade less than or equal to 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease, demonstrating modest single-agent activity in relapsed/refractory multiple myeloma.

PMID: 18297527 [PubMed - in process]

Mayo Clinic announces genetically engineered model of multiple myeloma progression

The first successful model able to mimic the genetic properties of multiple myeloma (MM) has been presented by Mayo Clinic researchers. The new model, announced in the February 2008 edition of Cancer Cell magazine, is expected to speed development of more effective treatments for myeloma.

"This model helps us understand the genetic properties that lead to multiple myeloma and provides a framework for developing better therapies," said Leif Bergsagel, M.D., a Mayo Clinic physician and lead investigator for the study. "We will now be able to test new treatments on models."

Multiple myeloma is the second most common form of blood cancer after lymphoma, with 15,000 new reported cases per year. It affects the bone marrow cells, called plasma cells, which produce antibodies. MM eventually leads to destruction of bone marrow and painful osteoporosis — an important indicator that malignant cancer is present.

Myeloma is typically preceded by the development of a benign tumor called MGUS (monoclonal gammopathy of undetermined significance). MGUS is the most common lymphoid tumor in humans, and develops in an estimated 3 percent of all individuals over age 50.

In a small percentage of patients, the harmless MGUS progresses to a fully malignant cancer. The agent of change is a cancer-causing gene known as MYC, first identified 25 years ago and suspected of involvement in MM. Dr. Bergsagel and his team proved conclusively that MYC is positively linked to converting MGUS into myeloma.

"We've proven that MYC can cause the conversion," he notes. "Now we can move forward and target new therapies to prevent that from happening."

The genetically engineered mouse model is a critical step in moving researchers past the "one size fits all" approach to treating MM, and into the realm of understanding the specific development of the disease. Until this project, previous efforts to produce models able to simultaneously repeat the precise timing, tissue specificity and nature of oncogenic events had failed.

"Some aspects of the progression of myeloma are due to the acquisition of genetic mutations over time," said Dr. Bergsagel. "With this model we can identify those mutations more quickly, and better understand what's happening with the patient."

The successful development of the mouse model is the end result of six years of research for Dr. Bergsagel, a pioneer of myeloma genetics and an internationally recognized authority on the genetic roots of the disease. Also participating in the project were Marta Chesi, Ph.D., of Mayo Clinic Cancer Center, and 12 others.

Myeloma in patients under age 50 shows better survival

Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J, Fonseca R, Dimopoulos M, Shimizu K, San Miguel J, Westin J, Harousseau JL, Beksac M, Boccadoro M, Palumbo A, Barlogie B, Shustik C, Cavo M, Joshua D, Attal M, Sonneveld P, Crowley J.

Department of Medicine I, Wilhelminenspital, Vienna, Austria.

We analyzed the presenting features and survival in 1,689 patients with multiple myeloma aged <50>/= 50 years of age. 7,765 of the total 10,549 patients received conventional and 2,784 high-dose therapy. Young patients were more frequently male, had more favorable features such as low ISS and D/S stage as well as less frequently adverse prognostic factors including high CRP, low hemoglobin, increased serum creatinine and poor performance status. Survival was significantly longer in young patients (median 5.2 years versus 3.7 years; P<.001) both after conventional (median: 4.5 years versus 3.3 years; P<.001) or high-dose therapy (median: 7.5 years versus 5.7 years; P=.04). Ten-year survival rate was 19% after conventional and 43% after high-dose therapy in young, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. Five of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

PMID: 18268097 [PubMed - as supplied by publisher]

FDA Grants Orphan Drug Designation for Novel Akt Inhibitor Vqd-002 In Multiple Myeloma

VioQuest Pharmaceuticals announced that the U.S. FDA has granted orphan drug designation to the company's product candidate VQD-002 (triciribine phosphate monohydrate or TCN-P) for the treatment of multiple myeloma. VQD-002 is a small molecule anticancer compound that inhibits protein kinase B (PKB or AKT), a key component of a signaling pathway known to promote cancer cell growth and survival as well as resistance to chemotherapy and radiotherapy. VioQuest Pharmaceuticals has reported preliminary Phase I results from ongoing studies in both solid tumors and hematological malignancies and the company plans to advance VQD-002 into Phase II development in 2008.

"Activation of the Akt pathway is increasingly being recognized as a critical factor promoting cancer cell survival and proliferation in multiple myeloma and many other cancers," commented Michael D. Becker, president and chief executive officer of VioQuest Pharmaceuticals. "By de-activating this pathway, VQD-002 has the potential to be an effective treatment for many cancers including multiple myeloma. Orphan drug designation significantly strengthens our opportunity to advance this promising product candidate to late stage clinical development and commercialization."

Orphan drug designation entitles VioQuest Pharmaceuticals to seven years of marketing exclusivity for VQD-002 upon regulatory approval, as well as the opportunity to apply for grant funding from the U.S. government to defray costs of clinical trial expenses, tax credits for clinical research expenses and potential waiver of the FDA's application user fee. Orphan status is granted by the FDA to promote the development of new drug therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

Preclinical studies in myeloma cell lines have demonstrated the synergy of VQD-002 alone and in combination with a range of therapeutic agents. These results support the initiation of clinical stage research. VioQuest Pharmaceuticals is exploring a range of clinical research study opportunities in collaboration with Oncotherapeutics, Inc. in California.

"Activation of the Akt pathway is a critical event in malignant transformation and survival, and its importance in multiple myeloma continues to emerge," commented James Berenson, M.D., president of Oncotherapeutics. "Inhibition of Akt has already been shown to cause cell death, reduce angiogenesis and reverse drug resistance in preclinical studies across various cancers. With its unique mechanism of action, coupled with the benign safety profile evidenced from ongoing Phase I studies, we are hopeful that VQD-002 will find a place in our cancer treatment armamentarium."

About VQD-002

VQD-002 (triciribine phosphate monohydrate, or TCN-P), a tricyclic nucleoside that inhibits the phosphorylation of Akt, has demonstrated anti-tumor activity against a wide spectrum of cancers in preclinical and clinical studies. Amplification, overexpression, or activation of Akt, also named protein kinase B, have been detected in a number of human malignancies, including prostate, breast, ovarian, colorectal, pancreatic, and hematologic cancers. Activation of Akt is associated with cell survival, malignant transformation, tumor invasiveness, and chemo-resistance, while inhibition of Akt activity has been shown to cause cell death. These attributes make Akt an attractive target for cancer therapy.

Targeting akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment

Huston A, Leleu X, Jia X, Moreau AS, Ngo HT, Runnels J, Anderson J, Alsayed Y, Roccaro A, Vallet S, Hatjiharissi E, Tai YT, Sportelli P, Munshi N, Richardson P, Hideshima T, Roodman DG, Anderson KC, Ghobrial IM.

Authors' Affiliations: James P. Wilmot Cancer Center, University of Rochester, Rochester, New York.

PURPOSE: We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells.

EXPERIMENTAL DESIGN: MM cell lines were incubated with perifosine (5 and 10 mumol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination. RESULTS: The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin.

CONCLUSIONS: This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.

Thalidomide for treatment of multiple myeloma: 10 years later

Palumbo A, Facon T, Sonneveld P, Blade J, Offidani M, Gay F, Moreau P, Waage A, Spencer A, Ludwig H, Boccadoro M, Harousseau JL.

Division of Hematology, University of Torino, Azienda Ospedaliera San Giovanni Battista, Torino, Italy.

Thalidomide, bortezomib and lenalidomide have recently changed the treatment paradigm of myeloma. In young newly diagnosed patients, the combination of thalidomide and dexamethasone has been widely used as induction treatment before autologous transplant (ASCT). In two randomised studies, consolidation or maintenance with low-dose thalidomide has extended both progression-free and overall survival in patients who received ASCT at diagnosis. In elderly newly diagnosed patients, two independent randomised studies have reported that the oral combination of melphalan and prednisone plus thalidomide (MPT) is better than the standard melphalan and prednisone (MP). These studies have shown better progression-free survival, and two have shown improved overall survival for patients assigned to MPT. In refractory-relapsed disease, combinations including thalidomide with dexamethasone, melphalan, doxorubicin or cyclophosphamide have been extensively investigated. The risks of side-effects are greater when thalidomide is used in combination with other drugs. Thromboembolism and peripheral neuropathy are the major concern. The introduction of anticoagulant prophylaxis has reduced the rate of thromboembolism to less than 10%. Immediate thalidomide dose-reduction or discontinuation when paresthesia is complicated by pain or motor deficit has decreased the severity of neuropathy. Future studies will define the most effective or the best sequence of combinations which could improve life expectancy.

PMID: 18245666 [PubMed - as supplied by publisher]