Haematologica 2003 - Supplements

P10.2.2
SINGLE VERSUS TANDEM HIGH DOSE THERAPY
(HDT) SUPPORTED WITH AUTOLOGOUS BLOOD STEM
CELL (ABSC) TRANSPLANTATION USING
UNSELECTED OR CD34-ENRICHED ABSC: RESULTS
OF A TWO BY TWO DESIGNED RANDOMIZED TRIAL IN
230 YOUNG PATIENTS WITH MULTIPLE MYELOMA
(MM).
Jean-Paul Fermand, Corinne Alberti and Jean-Pierre
Marolleau
For the group "Myélome-Autogreffe", Caen, Créteil, Limoges,
Paris, Strasbourg, France.
In 1996, we initiated a multicenter prospective trial where
patients aged under 56 with newly diagnosed symptomatic MM
were randomly assigned up-front to receive either a single HDT
(HDT1) or two sequential HDT (HDT2). In addition, all patients
were independently randomized to be transplanted with
unselected ABSC (unselected arm) or CD34-enriched ABSC
(CD34 arm).
In all cases, patients first received one or 2 courses of high dose
steroid containing regimens and ABSC were thereafter mobilized
by cytoxan (CTX) (4 g/m2) and lenograstim (10 mg/kg/d). When
appropriate (CD34 arm), part of collected ABSC were selected
using the Isolex®300i system. The selection procedure resulted in
a median purity of 95% (65-100) and in a more than two log
tumor cell depletion. In the HDT1 arm, HDT was preceded by 3
monthly courses of a VAD-like regimen and combined a multidrug
regimen (carmustine, etoposide, melphalan 140 mg/m2
(MLP 140) and CTX 60 mg/kg) with a TBI (12 grays in 6
fractions). Patients treated in the HDT2 arm received MLP 140
alone (always supported by unselected ABSC) followed 2 to 3
months later by a second MLP 140 combined with etoposide (30
mg/kg) and 12-gray TBI. In both arms, TBI including HDT were
supported with unselected or CD34 enriched ABSC.
Two hundred and thirty patients were included in the study. At
the reference date of 01/12/2002, median follow-up was 52
months since randomization. Baseline characteristics of HDT1
(n=94) and HDT2 (n=99) groups were close. Similarly, there was
no significant difference between the unselected (n=94) and
CD34 (n=99) arms.
All analysis were performed in an intent to treat basis. There was
no evidence for benefit of CD34 selection as compared to the use
of unselected ABSC. Post transplant hematological recovery was
similar but immunological recovery was delayed in the CD34
selected group in which the incidence of serious infections was
increased. However, relapse and death rates were not
significantly different between the 2 groups (45 and 51 deaths in
the unselected group and in the CD34 group, respectively. P= 0.3
by the log-rank test.
In HDT groups, treatment completion rates were satisfactory,
with 6/114 transplants not performed in HDT1 group (allogeneic
transplant n=1, refusal n=1, mobilisation failure n=1, early death
due to disease progression n=3) and 9/114 second transplant not
performed in HDT2 group (allogeneic transplant n=3,
mobilisation failure n=2, relapse post first transplant n=1, early
death due to disease progression n=3). Median intervals between
randomization and TBI-including transplant were similar (5
months in the HDT2 arm).
Present analysis did not show any significant difference in terms
of early mortality, disease response and outcome of patients
included in HDT groups. Early death rates (within 9 months post
randomization, including toxic death and fatal progressive
disease) were 12% and 7% in the HDT1 and the HDT2 arms,
respectively. Response (complete response + minimal residual
disease) rates were 39% and 37%, respectively. During followup,
there were 53 deaths in each arm and the 2 OS curves were
not statistically different (p= 0.14 by the log rank test). The EFS
curves were nearly identical (p= 0.55).
In conclusion, present analysis of the study did not show any
significant benefit of single HDT versus tandem HDT and of
CD34+ selection of autografts which appeared to increase the
incidence of serious infections.
P10.2.3
INTENSIVE VERSUS DOUBLE INTENSIVE THERAPY IN
UNTREATED MULTIPLE MYELOMA: UPDATED
ANALYSIS OF THE PROSPECTIVE PHASE III STUDY
HOVON 24 MM*
P Sonneveld, B van der Holt, CM Segeren, E Vellenga, AJ
Croockewit, GEG Verhoef, JJ Cornelissen, MR Schaafsma,
MHJ van Oers, PW Wijermans, WE Fibbe, S Wittebol, HC
Schouten, M van Marwijk Kooy, DH Biesma, JW Baars,
PHM Westveer, MMC Steijaert and HM Lokhorst
For the Dutch-Belgian Haematology-Oncology Cooperative Group
(HOVON), The Netherlands
The benefit of high-dose therapy with hemapoietic stem cell
rescue in the treatment of multiple myeloma has been
demonstrated in phase lI/lII studies. One randomized trial
demonstrated a superior long-term clinical outcome of double as
compared to single high-dose therapy. In 1995 HOVON started a
prospective randomized multicenter trial to compare the efficacy
of intensified treatment followed by myelo-ablative therapy and
peripheral stem cell transplantation with intensified treatment
alone in newly diagnosed patients. We now report the results of a
second analysis in 441 eligible patients with stage II (22%) and
stage III (78%) disease. The median age was 55 years (range 31-
65 years). Remission induction treatment consisted of 3-4 courses
of VAD by rapid infusion. 63 patients up to 55 years who had an
HLA identical sibling were candidates for an allogeneic
transplantation and will be presented separately. After VAD,
patients without a sibling were randomized to receive melphalan
140 mg/m 2 divided in 2 doses of 70 mg/m 2 (IDM) without stem
cell rescue (arm A) or the same regimen followed by myeloablative
treatment with cyclophosphamide (120 mg/kg) and TBI
with peripheral stem cell transplantation (arm B). Peripheral stem
cells were mobilized by cyclophosphamide (4 g/m 2 ) and G-CSF
after VAD. Interferon-α 2-a was given as maintenance therapy in
both arms.
Patient characteristics with regard to sex, age, stage of disease, Ig
isotype, and β2-M were not significantly different between the
two arms. The median follow-up from randomization was 40
months. 81% of patients received both cycles of IDM (79% in
arm A and 83% in arm B) and 82% of patients actually received
autologous peripheral stem cell transplantation in arm B. CR and
PR rate were 14% and 72% in arm A versus 28% and 62% in arm
B (P=0.004). The event-free survival (EFS) at 48 months from
randomization was 15% (arm A) vs 29% (arm B) (logrank
P=0.03). Progression free survival (PFS) at 48 months was not
different between both treatment arms (18% vs 31%, logrank
P=0.08). Overall survival (OS) was equal between both
treatments (55% vs. 50% at 48 months, logrank P=0.31). Time to
Progression (TTP) was significantly worse in arm A (80% vs
61% at 48 months, logrank P=0.003). Multivariate analysis
showed that treatment arm A, hemoglobin ≤ 6.21 mmol/l, serum
β2-M > 3 mg/l and elevated serum LDH were adverse prognostic
factors for EFS. Cytogenetic analysis in 150 registered patients
was abnormal in 37%(45% del 13/13q-, 50% abnormal 1p/q, 32%
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