CITINGS
Published by the International Myeloma Foundation
Volume I : Issue I : Spring 2004
Thalidomide and RevlimidTM Issue
The International Myeloma Foundation (IMF) is pleased to introduce the first
edition of CITINGS, a quarterly publication featuring the most up-to-date information on
research advances and new therapies for the treatment for multiple myeloma. CITINGS will
provide physicians and other health care professionals with references and Internet links to the
most current U.S. and international journal articles, abstracts, and white papers. Each issue
will present articles related to new drugs, either as the focus of the study or as part of the
discussion of myeloma treatment.
CITINGS is an evolving publication. In our next issue, we will focus on data presented at the
American Society of Clinical Oncology (ASCO) and European Hematology Association
(EHA) meetings. In future editions, we will be highlighting articles of special interest and
providing in-depth analysis. We look forward to hearing your comments and suggestions by
calling (800) 452-CURE (2873) or clicking on www.myeloma.org.
--Susie Novis, President, IMF
Clinical pharmacokinetics of thalidomide Teo SK, Colburn WA, Tracewell WG, Kook KA,
Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL.
Clinical Pharmacokinetics [2004;43(5):311-27]
http://www.ingenta.com/isis/searching/ExpandTOC/ingenta;jsessionid=naaox2eae6qm.crescent?issue
=pubinfobike://adis/cpk/2004/00000043/00000005&index=4
This article examines the pharmacokinetics of thalidomide. Thalidomide is minimally metabolised by the
liver, but is spontaneously hydrolysed into numerous renally excreted products. More than 90% of the
absorbed drug is excreted in the urine and feces within 48 hours.
Treatment of multiple myeloma Barlogie B, Shaughnessy J, Tricot G, Jacobson J, Zangari M,
Anaissie E, Walker R, Crowley J.
Blood [Jan 1, 2004;103(1):20-32]
http://www.bloodjournal.org/cgi/content/full/103/1/20
This study found that among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which
are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis
subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year
survival rates of 80% to 90% can be obtained with tandem autotransplantations. The study concluded
that fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms
of treatment failure in the high-risk subgroup.
www.myeloma.org
(800) 452 - CURE (2873)
Funded by an educational grant from Celgene Corporation.
Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes
proliferation and pathological interactions with bone marrow stroma Hurt EM, Wiestner
A, Rosenwald A, Shaffer AL, Campo E, Grogan T, Bergsagel PL, Kuehl WM, Staudt LM.
Cancer Cell [February 23, 2004;Vol. 5, No. 2:191-200]
http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804000194&highlight=c-maf
This study found that overexpression of the c-maf oncogene promotes multiple myeloma proliferation,
whereas c-maf inhibition blocks tumor formation. The authors conclude that one of the four recurrent
translocations in multiple myeloma cells (t(14;16)) deregulates the c-maf gene but the functional
consequences of this translocation remain unclear.
A Phase I study of oral CC-5013 (lenalidomide, Revlimid), a thalidomide derivative,
in patients with refractory metastatic cancer Tohnya TM, Ng SS, Dahut WL, Wright JJ, Arlen
PM, Gulley JL, Parker C, Zeldis J, Figg WD.
Clinical Prostate Cancer [March 2004;2(4):241-3]
http://www.electronicipc.com/journalEZ/detail.cfm?code=39560050020410
The primary study objectives of this current trial are to determine the maximum tolerated dose of
CC-5013 in patients with metastatic cancer that is refractory to therapy of proven efficacy, to
characterize the pharmacokinetic and side effect profiles of CC-5013 in patients, and to define the
dose-limiting toxicity.
The promise of thalidomide: evolving indications Joglekar S, Levin M.
Drugs Today (Barc) [March 2004;40(3):197-204]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&li
st_uids=15148528
This review focuses on thalidomide's mechanisms of action, biochemistry, and pharmacokinetics, and
its use in erythema nodosum leprosum as well as multiple myeloma, graft versus host disease, and
renal cell carcinoma.
Phase I study to determine the safety, tolerability and immunostimulatory activity of
thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and
other advanced cancers Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, Kristeleit H,
Polychronis A, Pandha H, Muller GW, Stirling DI, Zeldis J, Dalgleish AG.
British Journal of Cancer [March 8, 2004;90(5):955-61]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&li
st_uids=14997189
This study demonstrates the safety and tolerability, and suggests the clinical activity of CC-5013 in
the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating
T-cell stimulatory activity of this class of compound in patients with advanced cancer.
Multiple myeloma Sirohi B, Powles R.
Lancet [March 13, 2004;363(9412):875-87]
http://www.sciencedirect.com/science
This article looks at the ways in which myeloma treatment has changed in the past decade. The
authors conclude that biological treatments such as thalidomide, CC-5013, and bortezomib, which
target the myeloma cell and the bone-marrow microenvironment, will hold the key to future success.
www.myeloma.org
(800) 452 - CURE (2873)
Low-dose thalidomide for multiple myeloma: interim analysis of a compassionate use
program Steurer M, Spizzo G, Mitterer M, Gastl G.
Onkologie [April 2004;27(2):150-4]
http://www.ncbi.nlm.nih.gov:80/entrez/utils/lofref.fcgi?PrId=3030&uid=15138347&db=PubMed&
url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=ONK2004027002150
The authors conclude that low-dose thalidomide (50-100 mg/day) alone or in combination is a safe,
well-tolerated and effective form of therapy for patients with myeloma at various stages of disease.
Early response predicts thalidomide efficiency in patients with advanced multiple
myeloma Waage A, Gimsing P, Juliusson G, Turesson I, Gulbrandsen N, Eriksson T, Hjorth M,
Nielsen JL, Lenhof S, Westin J, Wislöff F for the Nordic Myeloma Study Group.
British Journal of Haematology [April 2004;Vol. 125, Issue 2:149]
http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0007-
1048&date=2004&volume=125&issue=2&spage=149
Sixty-five patients who were primary or secondary refractory to melphalan/prednisone or other
chemotherapy, or relapsed within 6 months after high-dose chemotherapy with stem cell support, were
given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median
of 2 years and 22 weeks. The study found no relationship between thalidomide concentration and effect
after 12 weeks.
A low serum level of soluble tumor necrosis factor receptor p55 predicts response to
thalidomide in advanced multiple myeloma Brenne AT, Romstad LH, Gimsing P, Juliusson G,
Turesson I, Romundstad P, Borset M, Sundan A, Waage A.
Haematologica [May 2004; 89(5):552-6]
http://www.haematologica.org/journal/2004/5/552/
The authors conclude that soluble TNFR p55 is an adverse prognostic factor in myeloma patients with
relapsed or refractory disease treated with thalidomide. Patients with a low pre-treatment level of this
receptor have a better response rate and a longer overall survival.
Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration
by thalidomide treatment Du W, Hattori Y, Hashiguchi A, Kondoh K, Hozumi N, Ikeda Y,
Sakamoto M, Hata J, Yamada T.
Pathology International [May 2004;Volume 54 Issue 5:285]
http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1320-
5463&date=2004&volume=54&issue=5&spage=285
This study found that thalidomide seems to be effective in the treatment of multiple myeloma through
the impairment of angiogenesis by decreasing FGF-2 and VEGF production. This is the first report on
pathological evidence in the bone marrow of MM before and after thalidomide treatment, in Japan.
Benefit and timing of second transplantations in multiple myeloma: clinical findings and
methodological limitations in a European Group for Blood and Marrow Transplantation
registry study Morris C, Iacobelli S, Brand R, Bjorkstrand B, Drake M, Niederwieser D, Gahrton G.
Journal of Clinical Oncology [May 1, 2004;Vol 22, No. 9:1674-1681]
http://www.jco.org/cgi/content/abstract/22/9/1674
This study concluded that to improve survival of tandem autologous transplantation in multiple
myeloma, the second transplantation should preferably be performed before relapse and within 6 to 12
months of the first transplantation.
www.myeloma.org
(800) 452 - CURE (2873)
Magnitude of response with myeloma frontline therapy does not predict outcome:
importance of time to progression in Southwest Oncology Group chemotherapy trials
Durie BGM, Jacobson J, Barlogie B, Crowley J.
Journal of Clinical Oncology [May 15, 2004;Vol 22, No. 10:1857-1863]
http://www.jco.org/cgi/content/abstract/22/10/1857
The authors conclude that the magnitude of response, as a single variable, does not predict survival
duration. Patients with response and stable disease have equivalent outcome. Only patients with
progressive disease have a poorer outcome. The best indicator of survival is time to first progression.
Response to thalidomide in multiple myeloma: impact of angiogenic factors Rosinol L,
Cibeira MT, Segarra M, Cid MC, Filella X, Aymerich M, Rozman M, Arenillas L, Esteve J, Blade J,
Montserrat E.
Cytokine [May 21,2004;26(4):145-8]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&li
st_uids=15149630
The authors state that although extramedullary plasmacytomas (EMP) have a high vascularization,
the response of these patients to thalidomide is controversial. Thirty-eight patients with
refractory/relapsed MM were treated with thalidomide. Eleven patients had EMP when therapy was
initiated. The study found that the serum levels of FGF-2 and IL-6 did not correlate with response to
treatment or presence of EMP.
Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the
dose-minimizing peripheral neuropathy
Offidani M, Corvatta L, Marconi M, Malerba L, Mele A, Olivieri A, Brunori M, Catarini M, Candela
M, Capelli D, Montanari M, Rupoli S, Leoni P.
European Journal of Haematology [June 2004;72(6):403-9]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_
uids=15128418
This study investigated the common and rare side effects, especially analyzing peripheral neuropathy, in
order to optimize the thalidomide dose for minimizing this side effect. In patients with advanced multiple
myeloma, the authors found that a thalidomide daily dose of 150 mg minimizes peripheral neuropathy
without jeopardizing response and survival.
www.myeloma.org
(800) 452 - CURE (2873)