Haematologica 2003 - Supplements

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Thalidomide (Thal) an active agent for multiple
myeloma (MM) does not change the prognosis of
plasma cell leukemia (PCL) patients. Experience of a
single center
Maria Teresa Petrucci, Giovanna Palumbo, Vincenza
Martini, Anna Levi, Patrizia Del Bianco, Franco Mandelli.
Ematologia, Dipartimento di Biotecnologie Cellulari ed Ematologia,
Università "La Sapienza", Roma, Italy.
MM is an incurable disease showing a poor prognosis due to the
limited therapeutic options. Among the new therapeutic approach
tested, Thal with its antiangiogenic properties, has re-emerged as
a promising anti-cancer agent in many refractory malignancies.
Between March 2000 and July 2002, 80 refractory or relapsed
MM patients were treated with Thal. Median age was 63.5 (range
33-84) years; 49 were males and 31 females; 1 patient had serum
creatinine > 2 mg/dl and 49 patients were IgG, 21 IgA, and 10
light chains MM; 5 patients had PCL. As for disease status: 36
were refractory (defined as progression while on therapy) to at
least two lines of therapies and 44 were ≥ 2 relapses. Median
follow-up before inclusion in this study was 36 months (range 5-
104). Thal, kindly provided by Grunenthal Stolberg Germany,
was administered as a single agent, through a compassionate-use
protocol, starting at 100 mg daily subsequently increasing by 100
mg every other week, to a maximum of 800 mg/day or according
to the maximum tolerated dose. The median daily dose of Thal
administered to all patients was 500 mg (range 100-600 mg).
None of the five PCL responded, even thought two of them had
reduction in circulating PC. Considering that 4 patients died
during the first 10 days of the treatment and 4 stopped the therapy
during the first month, because of side effects, 72 (treated for at
least one month) were considerate valuable for response defined
as decline in the monoclonal protein level > 25%. Among the
evaluable 72 MM patients 46 (63.5%) were responding to
treatment (14 achieved a decline in the MC > 25%, 17 > 50% and
15 > 75%). The median interval between the start of treatment
and the response was 1 month (range 1-9) and the duration of
response was 13 months. A total of 22 patients relapsed and 17
died for progression disease, 21 patients did not respond to Thal
and 15 of them died. Median survival for the responding patients
was not achieved yet and was 12.5 and 5 months for the overall
population and for no responding patients, respectively. The most
frequently side effects, registered in our patients, during the first
weeks, were lethargy (12.5%), weakness or fatigue (87.5%),
constipation (77.5%), skin rush (7.5%), mood change or
depression (27.5%) These side effects were easily manageable
and reversible by reducing or discontinuing the therapy. More
serious side effects observed in those patients treated for long
time are peripheral neuropathy (13.75%), bradycardia (3.75%)
such us hypothyroidism and deep vein thrombosis (1.25%). The
response obtained in our patients adds further evidence
concerning the efficacy of this drug in resistant and refractory
MM patients but PCL were not affected by Thal. The different
effectiveness of Thal may be can depend of aggressively of
tumor. In conclusion Thal is a true anti-myeloma drug even
thought its toxicity must be taken into account in designing new
clinical trials.
311
RESPONSE TO THALIDOMIDE IN MULTIPLE
MYELOMA: IMPACT OF ANGIOGENIC FACTORS AND
EXTRAMEDULLARY INVOLVEMENT
L. Rosiñol, J. Bladé, M.C.Cid, C. Segarra, M.T. Cibeira, X.
Filella, M. Aymerich, M.Rozman, J. Esteve, E. Montserrat
Hematology Department. Hospital Clínic. IDIBAPS. Barcelona.
Spain.
Background: Thalidomide produces a response rate ranging from
32 to 64% in patients with refractory / relapsed MM. However,
its efficacy in patients with extramedullary plasmacytomas
(EMP) remains controversial. It is postulated that thalidomide has
antiangiogenic and immunomodullatory effects, mediated by
several cytokines such as VEGF, bFGF, HGF, IL-6 and TNFalpha.
Aims: 1) to ascertain whether serum levels of different
angiogenic cytokines can predict response to thalidomide 2) to
assess the response of patients with EMP.
Patients and methods: From November 1999 to December 2002,
38 patients with refractory / relapsed MM were treated with
thalidomide. Eleven patients had EMP when therapy was
initiated. Serum specimens were obtained in all patients before
treatment was started and at the time of maximum response in
responding patients or at thalidomide discontinuation in those
patients showing no response. Serum levels of VEGF, HGF and
bFGF were determined in 18 patients whereas IL-6 and TNFalpha
where measured in 19 patients.
Results: Seventeen of the 38 patients (45%) responded to
thalidomide. Eight (21%) achieved a partial response while 9
(24%) had minimal response. The response rate was significantly
higher in patients without EMP (63% vs 9%, p= 0.0029).Three of
the 11 patients with EMP achieved a minimal response according
to the serum M-protein decrease but had an increase in their softtissue
masses. In addition, two patients without EMP when
therapy was started developed soft-tissue plasmacytomas while
on thalidomide therapy. VEGF serum levels were significantly
higher in patients who achieved a response. In contrast, baseline
serum levels of HGF were significantly lower in responding
patients.Neither, VEGF nor HGF serum levels showed
correlation with the presence or absence of EMP. Baseline TNFalpha
serum levels were significantly lower in responding
patients and in those without EMP. The serum levels of bFGF
and IL-6 did not correlate with response to treatment or presence
of EMP.
Conclusions: Baseline high levels of VEGF and low levels of
HGF and TNF-alpha predict response to thalidomide whereas
only TNF-alpha correlates with the presence of EMP. Patients
with EMP have a poor response to thalidomide. The lack of
efficacy on soft-tissue plasmacytomas supports a bone marrow
microenviromment-mediated mechanism of thalidomide
antimyeloma effect.
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