Haematologica 2003 - Supplements

11.Role of novel therapies targeting the
myeloma cells and its marrow
microenvironment
11.1 Thalidomide in refractory MM
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MULTICENTER CLINICAL STUDY OF THALIDOMIDE
EFFICACY IN PATIENTS WITH REFRACTORY AND
RELAPSED
1Dmoszynska A, 1Hus M., 1Soroka-Wojtaszko M., 1Manko
J., 1Jawniak D., 1Legiec W., 1Grzasko N., 2Hellmann A.,
2Ciepluch H., 2Baran W., 3Skotnicki A., 3Wolska-Smolen
T., 4Sulek K., 4Borysewicz-Czajka T., 4Sawicki W., 5Robak
T., 5Szmigielska A., 6Konopka L., 6Pszenna E., 6Szpila T.,
7Kloczko J., 7Piszcz J., 8Zdziarska B.
1Department of Haematooncology and Bone Marrow
Transplantation, Medical University in Lublin, Poland2Department
of Haematology Medical University in Gdansk, Poland3Department
of Haematology Collegium Medicum Jagiellonian University,
Krakow, Poland4Department of Haematology CSK WAM,
Warszawa, Poland5Department of Haematology University
Medical School, Lodz, Poland6Department of Haematology and
Tranfuzjology, Warszawa, Poland7Department of Haematology
University Medical School, Bialystok, Poland8Department of
Haematology University Medical School, Szczecin, Poland
Thalidomide (THAL) shows antitumour efficacy in refractory
and relapsed patients with multiple myeloma (MM) and has
proved to be one of the most potent agent for treatment of MM in
the last 30 years. We present here the results of THAL therapy in
191 refractory and relapsed MM patients (median age 59.7 years;
range, 32 – 79 years) enrolled to the study from March 1999 to
October 2002 in 7 Polish haematological centers. They received a
median of 3 prior regimens (range, 2 – 6 regimens) including
autologous stem cell transplantation in 29 cases. THAL was
administered at a dose of 200 mg increased by 100 mg every
week up to well tolerated dose (maximum 400 mg). 175 patients
received THAL as monotherapy and 16 patients received THAL
with dexamethasone. Major response was defined as ≥75%
monoclonal protein (M-protein) reduction in serum and/or in
urine. Partial and minor responses were defined as ≥50% and
≥25% M-protein reduction respectively. The stable disease was
considered when M-protein reduction was less then 25% without
evidence of disease progression. Clinical response was observed
in 107 patients (56%) including major response in 27 patients
(14.1%). In 18 patients (9.4%) we confirmed nearly a complete
remission with M-protein reduction more than 90%. Then 11
patients from this group (6%) were treated with autologous
peripheral blood stem cell transplantation (autoPBSCT). 84
patients (44%) did not respond to the therapy. Overall survival
(OS) time in the responders was 48.8 months (median 42.4).
Statistical analysis showed that mean survival time from the
beginning of THAL therapy was 14 months (median 10.3) and
the event-free survival (EFS) was on average 10.3 months.
Responses occurred within a median time of 6 weeks. Cumulative
dose of THAL in the whole group of patients was on average
28.7 g after 3 months of treatment. There was no correlation
between the clinical response and the cumulative dose of THAL,
what is suggested by some authors. No treatment-related
mortality was observed. After median follow-up of 8.6 months
(range 0.3 to 39 months) 124/191 patients are alive, whereas
67/191 patients died. Somnolence, constipation and fatigues were
the most common side effects – in over 65% of patients in the
early stage of THAL treatment. These symptomps tend to resolve
after 2-3 weeks of therapy. After 8-10 months of treatment the
most frequent problem was peripheral sensory polyneuropathy
observed in 59% of patients. THAL treatment was stopped at the
first sign of neuropathy. The sensory neuropathy improved in the
majority of pts after cessation of treatment but it persisted several
weeks in 8 pts and in 3 pts it was irreversible.
The results of our study indicate that THAL might be able to
improve the outcome in refractory and relapsed patients with
multiple myeloma and should be the treatment of choice in these
cases even though its unclear ways of action are still not fully
understood.
309
Treatment of advanced multiple myeloma (MM) with
thalidomide (THAL). Long term follow-up in a
prospective study of 121 patients.
B. Grosbois, E. Belissant, P. Moreau, M. Attal, L. Voillat, P.
Muret, B. Pegourie, M. Tiab, C. Berthou, I. Yakoub-Agha,
C. Duguetfor the Intergroupe Francphone du Myelome.
Department of Internal Medecine, Hôpital Sud, 16 Bd de Bulgarie –
35056 Rennes – France. Tél: 33 2 99 26 71 28 – fax: 33 2 99 26
71 98 - mail: bernard.grosbois@chu-rennes.fr
The aim of this prospective study was to describe the efficacy,
tolerance and prognostic factors of therapy with THAL in
patients with advanced MM.
Patients and methods: We studied prospectively 121 patients (62
male, 59 female, median age 65,4 years) who received THAL for
advanced MM (40 refractory, 81 in relapse). The median time
from MM diagnosis to initiation of THAL therapy was 4,5 years.
Thirty nine patients (32 %) had previously been treated with at
least one autologous bone marrow transplantation and 81 patients
(67%) with conventional therapy. After informed consent THAL
was started at a dose of 200 mg/d and increased to 400 mg/d after
2 weeks. Response was evaluated after 2 months of treatment on
the level of the monoclonal component. In 39 patients dosage of
seric THAL by HPLC was performed after 2 months of
treatment. Overall survival and event-free survival were
evaluated in all patients 24 months after inclusion.
Results: After 2 months of treatment, thirty eight patients (31,4
%) had at least a minor response (decrease of monoclonal
component > 25 %), 39 (32,2 %) were non responders and 7 (5
%) non-evaluable. Main toxicities were somnolence (77.1 %) and
constipation (61.2%). Neurologic examination was abnormal in
30.8 % of patients, after 2 months of THAL versus 18.6 % before
treatment. Median seric THAL level was 0.82 ± 0.79 (0.1 – 3.03)
in non responding patients and 0.66 ± 0.49 (2.19) in responding
patients. At 1 year and 2 years overall survival rates were 47.5 ±
8.9 % and 30.0 ± 8.2 % respectively and event-free survival rates
33.3 ± 8.5 % and 15.0 ± 6.4 %. In multivariate Cox regression
analysis the adverse prognostic factors were refractory status at
inclusion,, Beta 2 microglobulin > 3 mg/l and platelets < 100
000/mm3.
Conclusion: In a prospective study of advanced MM treated with
THAL we observed a response rate of 32 %. We did not find any
relationship between response and levels of seric THAL. Finally
the best prognostic factors were status at inclusion (refractory or
relapse), Beta 2 microglobulin level and platelet count.
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