Impact of genetic abnormalities on survival after allogeneic stem cell transplantation in multiple myeloma

Schilling G, Hansen T, Shimoni A, Zabelina T, Simon-Perez JA, Gutierrez NC, Bethge W, Liebisch P, Schwerdtfeger R, Bornhäuser M, Otterstetter S, Penas EM, Dierlamm J, Ayuk F, Atanackovic D, Bacher U, Bokemeyer C, Zander A, Miguel JS, Nagler A, Kröger N.

1Department of Oncology and Hematology, Medical Clinic II, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.Leukemia advance online publication, 17 April 2008; doi:10.1038/leu.2008.88.

PMID: 18418408 [PubMed - as supplied by publisher]

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma

Bone Marrow Transplantation advance online publication 10 March 2008; doi: 10.1038/bmt.2008.24

Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT

S K Kumar¹, D Dingli¹, A Dispenzieri¹, M Q Lacy¹, S R Hayman¹, F K Buadi¹, S V Rajkumar¹, M R Litzow¹ and M A Gertz¹

¹Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

Correspondence: Dr SK Kumar, Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: kumar.shaji@mayo.edu

Abstract

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma. Previous studies have suggested a lack of impact of the initial therapy on the outcome after ASCT. It is not clear if incorporation of new agents in the initial treatment regimens will have any impact on the outcome after ASCT. We studied 472 patients undergoing ASCT within 12 months of diagnosis to assess the effect of initial therapy on the outcome after ASCT. Patients received initial therapy with vincristine, adriamycin and dexamethasone (VAD), dexamethasone, thalidomide and dexamethasone or lenalidomide and dexamethasone. While patients treated with dexamethasone alone had higher disease burden at ASCT, no differences were observed in the response rates to ASCT, post transplant complications or treatment-related mortality among the groups. The median time to progression after ASCT was 27.1, 24.7, 21.1 months and did not reach the VAD, Dex, Thal–Dex and Len–Dex group, respectively, P=0.11. The median overall survival from ASCT was 62 months for VAD, 69.6 months for Dex and were not reached for Thal–Dex and Len–Dex groups, P=0.2. For patients undergoing early ASCT for myeloma, the nature of initial treatment utilized has no long-term impact on the outcome of ASCT.

Carfilzomib Receives Orphan Drug Designation for Treatment of Multiple Myeloma

Proteolix, Inc., a clinical-stage company engaged in the development of novel pharmaceutical therapies for the treatment of cancer and immunological conditions, announced today that the U.S. FDA has granted orphan drug designation to carfilzomib, a selective blocker of proteasome activity for the treatment of multiple myeloma.

"I am very pleased by our receipt of this designation for carfilzomib," said Susan Molineaux, Ph.D., the Company's President and CEO. "To date we have been encouraged by carfilzomib's early-stage clinical results in multiple myeloma, and we continue to believe it has the potential to offer cancer patients a new and effective treatment for their disease."

The Orphan Drug Act of 1983 allows the FDA to grant orphan drug status to novel drugs or biologics that treat a rare disease or condition affecting fewer than 200,000 patients in the U.S. According to the SEER Database of the National Cancer Institute (2004), the U.S. prevalence of multiple myeloma was 53,712 patients. The Orphan Drug Act provides the drug developer with several financial benefits and incentives related to the orphan drug, including tax credits for clinical research costs, ability to apply for annual grant funding, clinical research trial design assistance, waiver of Prescription Drug User Fee Act (PDUFA) filing fees, and a seven-year period of U.S. marketing exclusivity if the drug is the first of its type approved for the specified indication.

For more information on multiple myeloma go to http://www.cancer.gov/cancertopics/types/myeloma.

About Proteolix
Proteolix, Inc. is a privately-held biopharmaceutical company, headquartered in South San Francisco, and dedicated to discovering, developing and commercializing pharmaceutical therapies that target certain cancers and immunological conditions by inhibiting the proteasome and thereby disrupting protein turnover in cells. Phase 1 clinical studies with carfilzomib, the Company's lead product, have shown that patients with hematologic malignancies who have relapsed or progressed following multiple therapies can achieve durable anti-tumor responses. Carfilzomib is currently in Phase 2 clinical studies to evaluate its safety and efficacy in multiple myeloma, lymphoma and solid tumor malignancies. Proteolix is also developing a pipeline of next-generation proteasome inhibitors, including an oral proteasome inhibitor and a selective immunoproteasome inhibitor. For more information, visit http://www.proteolix.com/