Haematologica 2003 - Supplements

7. New prognostic criteria for
classification and monitoring MM
7.1 Prognostic markers
163
Prevalence and prognostic significance of sMUC-1
levels in plasma cell dyscrasias
Maria Goldaniga, Stefano Luminari, Fulvia Ceccherelli,
Rossella Calori, Andrea Guffanti, Emilio Bombardieri,
Raffaella Marcheselli, Lilla Cro, Mariangela Colombi,
Massimo Federico, Antonino Neri and Luca Baldini.
1)Unità di Ematologia 1, Dipartimento di Ematologia ed Oncologia,
Ospedale Maggiore IRCCS, Milan, Italy 2)Dipartimento di
Oncologia ed Ematologia, Università di Modena e Rggio Emilia,
Italy 3)Laboratorio di analisi chimico-cliniche e Microbiologia,
Ospedale Maggiore IRCCS, Milan, Italy 4)Divisione di Medicina I,
Ospedale Fatebenefratelli ed Oftalmico, Milan, Italy 5) Unità di
Medicina Nucleare, Istituto Nazionale dei Tumori, Milan, Italy
High serum sMUC-1 levels have been detected in
adenocarcinoma patients and seem to correlate with tumour
burden. It has been shown that patients with multiple myeloma
(MM) have high peripheral blood and bone marrow levels, and
that the latter directly correlate with tumour mass. To define the
prevalence of high sMUC-1 levels in patients with plasma cell
dyscrasias, we tested 89 monoclonal gammopathy of
undetermined significance (MGUS), 76 MM and six plasma cell
leukemia (PCL), admitted consecutively to our Institution during
the last ten years.
Peripheral blood samples were collected at the time of diagnosis
or at any time during follow-up from MGUS patients; for MM
and PCL patients were analized stored serum aliquots, collected
at the time of diagnosis,. Samples obtained from 65, age and sex
matched, healthy subjects, attending our Transfusion Department,
were also evaluated. All of the samples were tested using
Immunolite B27.29 antibody against MUC-1 protein. The sera
from the MM/PCL patients were also tested using Abbot IMX
CA15.3, Boehringer Mannheim Enzymmun CA15-3 and
Centrocor CA15-3 in accordance with the manufacturers’
protocols.
High sMUC-1 levels were found in 11/89 subjects with MGUS
(12.4%), 13/76 with MM (17.1%) and 3/6 with PCL, while in the
healthy control group only one subject had high levels (1.5%)
(p=0.001). The mean sMUC-1 levels were significantly higher in
the Monoclonal Component carrying patients than in the healthy
subjects (43.2 vs 26 U/ml; p=0.001). The median follow-up of the
82 MM/PCL cases was 30 months (range 6 -114), during which
51 patients died: 39/66 (59%) with normal and 12/16 (75%) with
high sMUC-1 levels. The median overall survival (OS) was 44
months. There was a difference in OS between the MM/PCL
patients with normal or increased sMUC-1 levels: median OS 49
vs 25 months, 3-year OS 63% and 25% (p=0.036).
Furthermore, increased sMUC-1 levels in MM patients correlated
with some features associated with high tumour burden, such as
anemia and high serum LDH levels. Finally we tested the
hypothesis that the various antibodies used in sMUC-1 assays
recognise distinct antigen epitopes and their different degrees of
reactivity may depend on the extent of the glycosilation of the
CA15.3 antigen, as reported by many autors. In our MM patients
evaluated using different methods, we found differences in
absolute values but multiple comparisons (Bonferroni’s test)
showed a high degree of correlation.
In conclusion, this study shows that a subset of MM and MGUS
patients, and most PCL cases, had increased sMUC-1 levels. The
frequent presence of high MUC-1 levels in PCL patients suggest
a possible relationship between them and tumor malignancy (cell
proliferation, genetic instability). In patients with MM, high
sMUC-1 levels identify a group with a poor prognosis, showing a
possible role of MUC-1 in tumor progession. Given the short
follow-up of the MGUS patients (median 12 months; range 6 -30)
and the absence of any MM transformation during this time, no
conclusions can be drawn concerning a possible correlation
between high sMUC levels and the relative risk of MM evolution.
164
Serum MUC1 as a Marker of disease status in Multiple
Myeloma (MM) Patients Receiving Thalidomide ±
Interferon-α-2b
Linda R. Mileshkin1,HM Prince1, James J Biagi1, Paul
Mitchell2, David Westerman1, Craig Underhill3, Andrew
Grigg4, Richard Bell5, Joe McKendrick6, Peter Briggs7,
John F. Seymour1
1Peter MacCallum Cancer Institute, Melbourne; 2Austin
Repatriation Medical Centre, Melbourne; 3Border Medical
Oncology, Albury; 4Royal Melbourne Hospital, Melbourne; 5The
Geelong Hospital, Geelong; 6Box Hill Hospital, Box Hill; 7Monash
Medical Centre, Clayton; Victoria, Australia
Objective: MUC-1 is a glycosylated transmembrane protein
normally found on the luminal surface of secretory glands. Serum
MUC-1 (measured by serum CA15-3 assay) has also been
detected on the surface of plasma cells in MM. The aim of this
study was to prospectively assess the role of CA15-3 as a marker
of response.
Methods: We took serial measurements of MUC-1 from pts as
part of a phase-II trial of thalidomide (T) ± interferon-α-2b (INF)
in advanced MM pts. Pts commenced T at 200 mg/d po,
increasing by 200 mg q14d, to 800 mg/d. After 12 weeks pts were
planned to continue T and start concurrent INF (1.5–3.0 MU, SC,
TIW), continuing T ± INF until progressive disease (PD) or
intolerance. CA 15-3 levels were measured at baseline and then
monthly by automated mouse monoclonal B27.29 antibody
immunoassay (ULN of 31U/mL). Bone marrow trephines 36 of
pts were stained for MUC1 by immunohistochemistry (IHC) and
correlated with the serum CA15-3 level.
Results: Analysis of 75 enrolled pts was performed. Overall
response rate (CR+PR) was 28%. 62 of 75 pts had baseline
CA15-3 levels recorded. 22/62 (35%) had CA15-3 levels >ULN.
Median level was 46 U/mL (range 32-158). Of those with
elevated levels, in 19% the level was 32-50U/mL, in 11% >50-
100U/mL and in 5% >100U/mL. There was no correlation
between the baseline CA15-3 and baseline levels of the majority
of other conventional markers (CRP, LDH, Creatinine,
Hemoglobin, Platelet count, %Bone marrow infiltrate, Serum
paraprotein, Bence Jones protein). There was a weak correlation
with baseline levels of Beta-2-microglobulin: correlation
coefficient 0.25 (P =0.0471).
The serum level of CA 15-3 was correlated with the IHC score
(% positive plasma cells x intensity): correlation coefficient 0.43
(P =0.047). Of responding pts, baseline levels were >ULN in
14/18 pts (78%) and ≤ULN in 4/18 (22%). There was no
significant difference in percentage of pts with baseline CA15-3
>ULN who achieved SD or PD. In univariate analysis there was a
trend to CA15-3 ≤ ULN being predictive of response to
S160