Haematologica 2003 - Supplements

344
COMBINATION OF THALIDOMIDE, DEXAMETHASONE
AND ZOLEDRONATE FOR THE TREATMENT OF
MYELOMA PATIENTS RELAPSED AFTER FRONTLINE
AUTOLOGOUS STEM CELL TRANSPLANTATION
P. Musto, C. Bodenizza, A. Falcone, G. Sanpaolo, N.
Cascavilla, L. Melillo, M. Dell’Olio, S. Mantuano, M. Nobile,
P. Scalzulli, AM. Carella.
Unit of Hematology and Stem Cell Transplantation, IRCCS “Casa
Sollievo della Sofferenza”, 71013, S. Giovanni Rotondo, Italy.
Autologous peripheral blood stem cell transplantation (PBSCT) is
currently considered the first line therapy of choice for a large
number of patients affected by multiple myeloma (MM). However,
PBSCT does not cure MM and relapse is the rule. Thus, strategies
for treating MM patients relapsed after PBSCT are strongly
awaited. Thalidomide induces significant responses in about one
third of patients with pre-treated MM. Even higher rates of
response have been reported with the association of thalidomide
and dexamethasone, another agent with well known efficacy in
MM, due to the possible synergistic activity of these drugs.
Zoledronate is a new generation bisphosphonate, which has been
demonstrated to be active on bone disease in MM, but which also
seems to exert a direct anti-myeloma effect. Based on these data,
we performed a pilot study by administering thalidomide, in
combination with dexamethasone and zoledronate, to 20 patients
with MM (12 males and 8 females, mean age 59 years, range 36-
68), who had relapsed after PBSCT performed as frontline
treatment. Thalidomide was given at the dose of 200 mg/d per os,
at bedtime, after a week in which the patients received only 100
mg/d, to test tolerance. Dexamethasone was given at the dose of 40
mg i.v. or p.o. for 4 days every 4 weeks. Zoledronate was
administered at the dose of 4 mg every 4 weeks, as 15’ i.v.
infusion. The treatment was performed exclusively on an outpatient
basis. Nineteen patients received at least 12 weeks of
therapy. Somnolence, sedation, oedema, constipation and skin rash,
alone or in combination, were the most relevant side effects
observed, occurring in 9 patients. The reduction of thalidomide
dose to 50-100 mg/d resolved adverse events in these cases. Two
additional patients showed hypertension and hyperglicemia, which
disappeared after reduction of the steroid dose to 20 mg.
Asymptomatic hypocalcemia was also observed in 6 patients and
was corrected by substitutive therapy. No patient developed
thrombotic complications, but one patient interrupted early the
trial, due to severe pancytopenia. Among the 19 evaluable patients,
four did not show any modification of hematological parameters
after 12 weeks and stopped the treatment. Four additional patients
showed progressive disease (in two cases after an initial moderate
reduction of M-component) and were also considered
unresponsive. The remaining 11 patients (57.8%) evidenced a
significant response, according to conventional criteria. In
particular, a reduction of M-component > 25%, > 50% and >75%
was observed in 2, 6 and 2 out of patients, respectively, while one
subject achieved complete remission, with complete disappearance
of the paraprotein at immunofixation. Among remitters, two
heavily anemic patients also interrupted their transfusional support.
Accordingly to hematological response, a clear ameloration of bone
pain and decrease of marrow plasma cell infiltration occurred.
Median progression-free and overall survival are still not reached
after 19 months from start of salvage therapy. Interestingly, in 3
patients progression-free survival was longer than that observed
after PBSCT. Our data suggest that this possibly synergistic
association may have significant efficacy and manegeable side
effects as salvage therapy in MM patients relapsed after PBSCT.
345
Cuadruple Maintenance Treatment ( Bisfosfonates +
Interferon + Dexamethasone + Thalidomide) after
Autologous Peripheral Blood Stem Cell Transplant ion
(APBSCT) in Múltiple Myeloma (MM): Preliminary
Experience
A Alegre (1) C.Martínez-Chamorro(2), A. Escudero(2),
B.Aguado (1), S.Osorio(1), S. Nistal(1), R. Córdoba(1), J.J.
Gil-Fernández (2) , JM Fernández-Rañada (1)
Hematology Department. Hospital Universitario de la
Princesa.Clínica Ruber(2). Madrid. Spain.
Introduction: The favourable results of APBSCT in MM, (high
CR rate, low toxicity and longer event free survival and overall
survival), are counteracted by the fact that relapses and
progressions are inevitables even with consolidation regimens.
Due to this circumstance, different strategies must be designed
aiming to extend the anti-myeloma effect achieved with APBSCT
to prevent relapses including different maintenance treatment
(1). We present our preliminary experience with a cuadruple
maintenance therapy scheme including Bisfosfonates + INF2b
+ Dexamethasone + Thalidomide. We decide to include
thalidomide to previous triple maintenance because this drug has
been recently proven to have an impact on myeloma, even at low
dose, through multiple mechanisms. Its role as maintenance
treatment postransplant is still unknown.
Objectives: 1) Evaluate the toxicity and applicability of a
prolonged cuadruple maintenance therapy post-APBSCT in MM
including low dose of oral thalidomide 2) Analize its effects on
the clinical evolution postransplantation (EFS,OS and rate of
relapses.
Patient and Methods: Criteria of inclusion: 1) Diagnosis of
symptomatic MM grade II-III according Durie Salmon criteria.
2) Previous autologous PBSC transplantation with stable
hematopoietic engraftment: >75 x 10e9/L platelets, > 1.5 x
10e9/L neutrophils, 4) ECOG < 2.; 3) Complete remission or
partial response postransplantation or 5) Patients rescued with
standard dose of thalidomide for relapsed with previous triple
maintenance treatment.
Patients included:Six patients with symptomatic MM (1 stage II
and 5 stage III), median of age 58 years ,42-67; 4 M, 2 F, have
been included in the study. 4 patients received intensification
with BUMEL( Busulphan 12 mg/Kg orally and Melphalan 140
mg/m2 i.v.) and two with Melphalan 200 mg/m2 iv). Three
patients following triple maintenance treatment were rescued
with thalidomide for signs of progression before introducing the
cuadruple maintenancetherapy.
Cuadruple Maintenance Tretament: Bisfosfonates: Pamidornate
90 mgs iv or Zolendronate (Zometa®, Novartis) 4 mg iv /month,
minimum x 12 months + INF2b (Intron® Schering-Plough) 3
MU s.c.3 x w until relapse or progression + Dexamethasone 20
mg orally x 4 days every 6 weeks, minimum x 12 months +
Thalidomide (Thalidomide® Grunnenthal-Germany) 50-100
mg/d according tolerance, until relapse or progression.
Results: Maintenance treatment including low dose oral
thalidomide was initiated at a median of 46 days post-transplant
(range 23-138 days) in the three patients without previous
treatment after transplant. The median leukocyte and platelet
counts at the moment of thalidomide initiation were 4800/mL
(range 2800-5900/mL) and 125,000/mL (range 75,000-
240,000/mL), respectively. Thalidomide was started at 50 mg
daily increasing the dose to 100 mg/day according tolerance. No
patient failed to tolerate this dose of thalidomide. The most
common adverse effects were constipation, dry skin and
somnolence No grade 3-4 adverse effects were documented.
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