12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
assays (for lambda or κ chains) and M-Ig analysis using immunofixation
electrophoresis were analysed for three categories (time to reduction of
parameters to 25% (minimal response - MR), 50% (partial response - PR)
and 75% (very good partial response - VGPR) of the pre-treatment values)
to establish their value for the detection of early response. The
cohort of 24 patients from our pilot analysis (2006) was enlarged to a
total of 39 patients who had had at least 5 cycles of therapy. Results. A
total of 21 patients (54%) responded to the therapy (3% complete
response, 15% VGPR, and 36% PR). Further 20% patients achieved minimal
response (MR). Overall treatment responses (i.e. at least PR) were
detected on days 22/33/44/55/66 of the treatment in 41%/49%
/56%/59%/59% of patients using FLC assay versus 13%/18%/41%/
46%/51% of patients using electrophoresis. The differences were statistically
significant for all reported days up to day 55 (p=0.004-0.019).
The results of the two methods became similar on day 66 (59% vs.
51%; p=0.060). Response after day 66 was only seen in one patient,
who achieved PR after 88 days (FLC), or 99 days (M-Ig) of the treatment.
Moreover, the patients who did not respond with at least 25% reduction
of serum single chain as detected by FLC during the first 33 days
never achieved PR. Conclusions. We confirmed our pilot data in that we
did not observe PR in patients who did not have at least 25% reduction
in serum free chain as measured by FLC by day 33. Thus, FLC assay can
be used to detect resistance early during bortezomib treatment. By day
66 (day 1 of cycle 4 in the routine schedule of bortezomib treatment) 20
out of 21 responding patients achieved response (at least PR). With some
limitation, day 66 can be suggested as a cut-off time for the chance of
achieving long-term response to bortezomib-based therapy.
Supported by LC06027 MSMT
0258
EFFICACY AND SAFETY OF MELPHALAN, PREDNISONE, THALIDOMIDE AND DEFIBROTIDE
IN RELAPSED AND REFRACTORY MULTIPLE MYELOMA PATIENTS: RESULTS OF A
MULTICENTER PHASE I/II TRIAL
A. Palumbo, 1 A. Larocca, 1 C. Rus, 1 F. Gay, 1 D. Rossi, 2 P. Pregno, 1
P. Falco, 1 I. Avonto, 1 V. Magarotto, 1 F. D'Agostino, 1 M. Iacobelli, 3
G. Gaidano, 2 C. Mitsiades, 4 P.G. Richardson, 4 K. Anderson, 4
M. Boccadoro1 1 Az. Osp. S. Giovanni Battista, TORINO, Italy; 2 Univ. Studi Piemonte Orientale,
Avogadro, NOVARA, Italy; 3 Gentium S.p.A., COMO, Italy; 4 Dana-Farber
Cancer Institute, BOSTON, USA
Background. Defibrotide (DF) is a novel orally bioavailable oligonucleotide
with protective effects on endothelial cells but without significant
systemic anticoagulant effects and bleeding risk. in vitro, DF showed
minimal inhibitory effect on multiple myeloma (MM) cells growth but
in vivo (human MM xenografts in SCID/NOD mice) markedly increased
the responsiveness of MM cells to cytotoxic agents (melphalan or
cyclophosphamide) and dexamethasone. DF may therefore abrogate
tumor cell interaction with marrow stromal cells and enhance sensitivity
to chemotherapy, thus improving the activity of Melphalan, Prednisone
and Thalidomide, while protecting against thrombosis. Aims. We
designed a study to determine the efficacy and safety of Melphalan,
Prednisone, Thalidomide and Defibrotide (MPTD) as salvage treatment
in patients with relapsed/refractory MM. Safety was assessed by defining
dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of
DF when administered in combination with MPT. DLT was defined by
the occurrence of febrile neutropenia, or Grade 4 neutropenia ≥ a week,
or any other Grade 4 hematologic toxicity, or any ≥ Grade 3 non-hematologic
toxicity, in >30% of patients at first cycle. MTD was the dose
level prior to that resulting in DLT. Methods. Between March and November
2006, 24 patients in first or second relapse (excluding primary refractory
patients and/or patients receiving therapeutic anticoagulation) were
enrolled. MPTD consisted of 6 X 35 days cycles of oral melphalan (0,25
mg/Kg day 1-4), prednisone (1,5 mg/kg day 1-4), thalidomide (50-100
mg/day continuously) and DF at 3 different dose levels (17 mg/Kg i.v. or
2.4 g p.o. D 1-4, 1.6 g p.o. D 5-35; 34 mg/Kg i.v. or 4.8 g p.o. D 1-4, 3.2
g p.o. D 5-35; 51 mg/Kg i.v. or 7.2 g p.o. D 1-4, 4.8 g p.o. D 5-35), without
prophylaxis against deep vein thrombosis (DVT). Results. Nineteen
pts (median age 69 years ;range: 47 - 88) completed at least one cycle and
were evaluable for response. According to EBMT/IBMTR criteria, after
a median of 3 cycles, 42% of patients achieved at least partial response
(including 16% very good partial response). To date no significant difference
in response rate was noted among the 3 DF dose levels, but follow
up remains short. DLT consisted of grade 3 ileus in the 1st dose level,
1 acute myocardial infarction (AMI) in the 2nd (both considered unrelated
to DF) and none in the 3rd. MTD was therefore not reached in any
94 | haematologica/the hematology journal | 2007; 92(s1)
cohort. Greater than or equal to grade 3 hematological toxicities included
neutropenia (47%), thrombocytopenia (10%), and anemia (21%).
Non-hematological toxicities ≥grade 3 were observed in 2 4(14%) 8(22%) n.s.
Hb