CITINGS
Published by the International Myeloma Foundation
Volume II : Issue II : Spring 2005
Thalidomide Issue
The International Myeloma Foundation (IMF) is pleased to present our second issue
of CITINGS for 2005. In this issue we are continuing our series focusing specifically on
publications referring to thalidomide.
CITINGS is a relatively new, quarterly publication of the IMF. The goal of CITINGS is to
provide the latest, most up-to-date list of publications on a key issue related to myeloma, along
with a citation, web address, and brief summary of the study. CITINGS focuses on new
treatments, drug regimens, and procedures that affect myeloma patients. We hope you will find
this
issue
of
CITINGS
focused
on
thalidomide
both
interesting
and
useful.
Please feel free to contact the IMF at (800) 452-CURE or by clicking on www.myeloma.org.
--Susie Novis, President, IMF
Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone
(VAD) as primary therapy in preparation for autologous transplantation for multiple
myeloma.
Cavo M, Zamagni E, Tosi P, et al.
Blood First Edition Paper, prepublished online 2005 March 10 ; DOI 10.1182/blood-2005-02-0522.
http://www.bloodjournal.org/cgi/content/abstract/2005-02-0522v1
This study was a retrospective analysis of 200 patients who intended to undergo an autologous peripheral
blood stem cell (PBSC) transplantation during the period 1996-2004. It compared the relative efficacy of
thalidomide-dexamethasone (Thal-Dex) and vincristine-doxorubicin-dexamethasone (VAD) as a preparatory
regimen for the transplant. In comparison with VAD, Thal-Dex resulted in a significantly higher response rate
(52% versus 76%, respectively; P=0.0004) and effected more profound reduction in myeloma cell mass of
both IgG (P=0.02) and IgA (P=0.03) types.
Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for
previously untreated patients with multiple myeloma.
Schutt P, Ebeling P, Buttkereit U, et al.
Eur J Haematol, 2005 January; 74(1): 40-6.
http://highwire.stanford.edu/cgi/medline/pmid;15613105
The authors evaluated the efficacy and side effects of thalidomide (400 mg/d) in combination with vin-
cristine, epirubicin and oral dexamethasone (VED). Thirty-one patients were enrolled, 12 patients were exclu-
sively treated with thalidomide in combination with VED and 19 patients received high-dose melphalan, for
consolidation. The results showed CR in 19%, PR in 61%, stable disease in 16%, and progressive disease in
one patient (3.2%).
www.myeloma.org
(800) 452 - CURE (2873)
Funded by an educational grant from Celgene Corporation.
Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple
myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and
the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC).
Mohty M, Attal M, Marit G, et al.
Bone Marrow Transplant, 2005 January; 35(2): 165-9.
http://highwire.stanford.edu/cgi/medline/pmid;15531895
This retrospective study shows that thalidomide can be an effective therapy even for patients who have
relapsed after high-dose therapy. The study involved 31 patients receiving thalidomide as salvage therapy after
an allogeneic transplant. Nine patients responded with a partial response (PR) or very good partial response
(VGPR) although three of these did develop graft versus host disease (GVHD).
Results of a "Multicenter Randomized Phase II Trial of Thalidomide and Prednisone
Maintenance Therapy for Multiple Myeloma after Autologous Stem Cell Transplant."
Stewart K, Chen CI, Howson-Jan K, et al.
Clin. Cancer Res., 2004 December; 10: 8170 - 8176.
http://clincancerres.aacrjournals.org/cgi/content/abstract/10/24/8170
All patients received 50 mg of prednisone by mouth on alternate days and thalidomide at a starting dose of
either 200 or 400 mg daily by mouth. The primary end point was the incidence of dropout or dose reduc-
tion due to treatment toxicity within 6 months. Only the 200 mg of thalidomide arm of this trial met the
definition of a tolerable maintenance therapy, defined as no dose reductions or discontinuation due to toxic-
ity in at least 65% of patients for a minimum of 6 months, thus establishing a dosing schedule for phase III
trials.
In vitro dendritic cell generation and lymphocyte subsets in myeloma patients: influence of
thalidomide and high-dose chemotherapy treatment.
Schutt, Buttkereit U, Brandhorst D, Lindemann M, et al.
Cancer Immunol Immunother 2005 May 1; 54(5): 506-12.
http://highwire.stanford.edu/cgi/medline/pmid;15750834
While vaccination with antigen-pulsed dendritic cells (DCs) represents a promising therapeutic strategy in
multiple myeloma, there are still significant hurdles that need to be overcome. To identify potential problems
with this approach, this study analyzed the influence of treatment parameters, in particular high-dose
chemotherapy (HD-CTX) and thalidomide, on in vitro DC generation and peripheral blood lymphocyte
subsets in myeloma patients. The results show that despite the well-known deficiencies in the immune sys-
tem, adequate numbers of DCs can be generated in most myeloma patients. In patients treated with thalido-
mide, however, it remains to be seen whether the reduced expression of co-stimulatory molecules has func-
tional relevance.
The combination of thalidomide and intermediate-dose dexamethasone is an effective but
toxic treatment for patients with primary amyloidosis (AL) .
Palladini G, Perfetti V, Perlini S, Merlini G, et al.
Blood 2005 April 1; 105 ( 7):2949-2951.
http://www.bloodjournal.org/cgi/content/abstract/105/7/2949
The study showed that the combination of thalidomide and dexamethasone is rapidly effective and may rep-
resent a valuable second-line treatment for AL. The study evaluated the combination of thalidomide (100
mg/d, with 100-mg increments every 2 weeks, up to 400 mg) and dexamethasone (20 mg on days 1-4) every
21 days in 31 patients with primary amyloidosis (AL) whose disease was refractory to or had relapsed after
first-line therapy. Overall, 15 (48%) patients achieved hematologic response, with 6 (19%) complete remis-
sions and 8 (26%) organ responses.
www.myeloma.org
(800) 452 - CURE (2873)
Thalidomide in combination with dexamethasone for pretreated patients with multiple
myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate
and for survival.
Schutt P, Ebeling P, Buttkereit U, et al.
Ann Hematol, 2005 March 3; [Epub ahead of print]
http://highwire.stanford.edu/cgi/medline/pmid;15744524
In this study cycles of dexamethasone (20mg/m2/d for 4 consecutive days every 3 weeks) were given until
maximal decline of myeloma protein was achieved, whereas therapy with thalidomide (400 mg/d) was main-
tained until disease progression. In multivariate analysis, pretreatment serum levels of soluble interleukin-2
receptor (sIL-2R) were a significant prognostic factor for event free survival (EFS), and those of ß2
microglobulin (ß2M) and sIL-2R for overall survival (OS). Serum levels of sIL-2R significantly increased after
3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide.
Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple
myeloma.
Tosi P, Zamagni E, Cellini C, et al.
Eur J Haematol, 2005 March 1; 74(3): 212-6.
http://highwire.stanford.edu/cgi/medline/pmid;15693790
The study analyzed long-term toxicity of 40 patients who received salvage therapy with thalidomide and/or
dexamethasone for longer than 12 months. All the patients had achieved at least stable disease on treatment
with thalidomide alone (200-400 mg/d) or thalidomide (200 mg/d) and dexamethasone (40 mg/d for 4 d
every 4 wk). The results suggest that long-term thalidomide therapy in MM may be hampered by the neu-
rotoxicity of the drug at the doses being given, and that a neurological evaluation should be given prior to
thalidomide treatment.
Thalidomide-induced anti-angiogenic action is mediated by ceramide through depletion of
VEGF receptors, and antagonized by sphingosine-1-phosphate.
Yabu T, Tomimoto H, Taguchi Y, et al.
Blood First Edition Paper, prepublished online, 2005 March 1; DOI 10.1182/blood-2004-09-3679.
http://www.bloodjournal.org/cgi/content/abstract/2004-09-3679v1
This study attempts to explain some of the anti-angiogenic effects seen with thalidomide. They suggest that
the effect is regulated by the balance between ceramide (C2-ceramide) and sphingosine-1-phosphate (S1P)
signals causing the depletion of vascular endothelial growth factor (VEGF) receptors such as neuropilin-1 and
Flk-1.
Thalidomide: present and future in multiple myeloma.
Hussein MA
Expert Rev Anticancer Ther, 2005 February 1; 5(1): 25-31.
http://highwire.stanford.edu/cgi/medline/pmid;15757435
Thalidomide, the first of the immunomodulatory family to be used in the management of multiple myelo-
ma, proved not only to be effective in the treatment of multiple myeloma, but also instigated a wide range of
in vitro and in vivo studies to define the pathophysiology of the plasma cell dyscrasia The drug has a side-
effect profile that, if managed appropriately, provides the most unique active molecule in the management of
the disease, where it maintains the same response rate in newly diagnosed patients as in advanced
relapsed/refractory multiple myeloma patients.
www.myeloma.org
(800) 452 - CURE (2873)
Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment.
Ansiaux R, Baudelet C, Jordan BF, et al.
Clin. Cancer Res., 2005 January; 11: 743 ­ 750.
http://clincancerres.aacrjournals.org/cgi/content/abstract/11/2/743
This study focused on the changes in tumor microenvironment with special focus on a possible "normaliza-
tion" of the tumor vasculature that could be exploited to improve radiotherapy. They found that the changes
induced by thalidomide were sufficient to radiosensitize tumors. The fact that thalidomide radiosensitization
was not observed in vitro, and that in vivo radiosensitization occurred in a narrow time window, implies that
initial vascular normalization by thalidomide is responsible.
Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clini-
cal application.
Hayashi T, Hideshima T, Akiyama M, Podar K, et al.
Br J Haematol. 2005 Jan;128(2):192-203.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5638853
It has been reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell
numbers in the peripheral blood of responding myeloma patients. This study investigated the mechanisms
whereby IMiDs augment NK cell cytotoxicity. IMiDs facilitated the nuclear translocation of nuclear factor of
activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with result-
ant IL-2 secretion.
www.myeloma.org
(800) 452 - CURE (2873)