ORAL MELPHALAN, PREDNISONE, AND
THALIDOMIDE FOR NEWLY DIAGNOSED
MYELOMA PATIENTS
A. Palumbo*, A. Bertola*, P. Musto°, M. Nunzi°,
V. De Stefano°, L. Catalano°, T. Caravita°,
C. Cangialosi°, S. Bringhen*, M. Boccadoro*.
Divisione Universitaria di Ematologia, Azienda
Ospedaliera S. Giovanni Battista, TorinoItaly*, and the
Italian Multiple Myeloma Study Group°
ABSTRACT
Background: Thalidomide (T) alone or in combination has been tested and proved effective in
multiple myeloma. No data are available on the association of T with oral melphalan and prednisone
(MP) in newly diagnosed patients. Here, we evaluated the potential additive and synergistic effect of
the combination melphalan, prednisone, and thalidomide (MPT). Methods: Between June 2002 and
June 2003, 42 patients (median age 72, range 6180) with newly diagnosed symptomatic multiple
myeloma received 6 courses of MP (melphalan 4 mg/sqm and prednisone 40 mg/sqm for 7 days
every month) plus T 100 mg/day continuously until any sign of disease progression or relapse. The
dose of T was reduced to 50% when grade 2 WHO toxicity occurred and suspended for any grade 3.
All patients have completed the 6 assigned MP courses and were evaluated for both toxicity and
response rate. Results: T increased the hematologic toxicity induced by MP: grade 3-4 WHO
neutropenia was observed in 14% of patients. Constipation occurred in 28% of patients. Neurologic
toxicity was recorded in 38% of patients. The major acute adverse events were infections (26%) and
deep-vein thrombosis (19%). One patient died of septicemia and one of pulmonary
thromboembolism. T discontinuation was required in 36% of patients (thromboembolic event,
infection, constipation, hematologic toxicity). After treatment, partial responses (myeloma protein
reduction >50%) were observed in 93% of patients, no responses (myeloma protein reduction <50%)
in 7%. Complete remissions (disappearance of monoclonal protein and negative immunofixation)
were 26%; near-complete remissions (disappearance of monoclonal protein and positive
immunofixation) were 19%; responses with myeloma protein reduction 90%99% were 12%. Time
required to obtain the maximum response was 4 months in 88% of patients. Conclusions: The
incidence of infections and deep-vein thrombosis was high, suggesting the need for antibiotic and
anticoagulant prophylaxis. MPT induced a response rate significantly higher in comparison with any
other conventional chemotherapy program. The CR rate was similar to those observed after
transplant.
INTRODUCTION
· Thalidomide has activity in the treatment of refractory multiple
myeloma.1,2
o In myeloma patients who received prior treament with
chemotherapy, single-agent thalidomide therapy induced
partial responses of nearly 30%2
o Addition of dexamethasone to thalidomide treatment
increased the overall response rate to 50%3
o Combination of thalidomide, dexamethasone, and a
chemotherapeutic agent further increased overall response
rates to 70%4
· For patients newly diagnosed with multiple myeloma, no data
are available on safety or efficacy of thalidomide in combination
with oral melphalan and prednisone (MP). MP is considered
the standard treatment for myeloma patients >65 years of age,
which represents 73% of the myeloma patients.
AIMS OF THE STUDY
· To evaluate efficacy, in terms of response, of melphalan,
prednisone, and thalidomide (MPT) in patients with newly
diagnosed multiple myeloma
· To evaluate the adverse events profile of MPT in this
population
PATIENTS AND METHODS
· Between June 2002 and June 2003, 42 patients with newly diagnosed
symptomatic multiple myeloma received the MPT regimen after signing an
informed consent approved by the local Ethics Committee
· The treatment regimen included 6 courses of MP (melphalan 4 mg/m2 and
prednisone 40 mg/m2 for 7 days every month) plus thalidomide 100 mg/day
continuously until any sign of disease progression or relapse (Figure 1)
· Response criteria were based on the Blade (ref British Journal of
Hematology102: 115-1123):
o Complete Response (CR) = disappearance of monoclonal protein and
negative immunofixation
o Near Complete Response (nCR)= disappearance of monoclonal protein
and positive immunofixation
o Very Good Partial Response (VGPR) = myeloma protein reduced to 90
to 99%
o Partial Response (PR) = myeloma protein reduction 50% to 89%
· Patient characteristics are shown in Table 1
RESULTS
Clinical Response (Figure 2)
· All 42 patients completed the 6 assigned MP courses and
were evaluated for clinical response
· 45% of the patients developed either a CR and nCR
· CR = 26%
· nCR =19%
· 48% of the patients had a VGPR and PR
· 12% had a VGPR
· 36% had a PR
· No response or progressive disease was 7%
· 88% of patients had achieved maximum response within
4 months of treatment (Figure 3)
Adverse Events
· Hematologic toxicity
· Hematologic toxicity induced by standard MP seems to be
increased with the addition of thalidomide; grade 3-4 WHO
neutropenia was observed in 14% of patients (vs the expected
7%)
· Acute adverse events included infection (26%) and deep-vein
thrombosis (19%) (Figure 4)
· Nonhematologic toxicity
· Constipation (mainly WHO grade I 20.4%) occurred in 28% of
patients
· Neurologic toxicity (mainly WHO grade I and II 30.8%) was
recorded in 38% of patients (Figure 4)
· Thalidomide was discontinued in 36% of patients due to thrombotic
events, infection, constipation or hematologic toxicity (Figure 5)
CONCLUSIONS
· MPT is quite active in previously untreated patients with multiple
myeloma.
- 45% of patients achieved CR and nCR
- 93% of patients achieved a PR
· MPT was generally well-tolerated
· The most serious adverse events with this regimen were infection
and DVT, suggesting the need for prophylaxis with antibiotics and
anticoagulants
· The CR rate was similar to rates observed after high-dose
chemotherapy followed by stem cell transplantation (42%)5
· MPT appears to be a promising regimen. However, a general
recommendation for its adoption cannot be made until the time to
disease progression, overall survival of these patients and the
potential effectiveness of prophylactic antibiotics and anticoagulants
are determined.
Table 1. Patient characteristics
MPT
(n=42)
Median age
72
Range
6180
Gender, n (%)
Male
23 (55)
Female
19 (45)
Stage, n (%)
IIA
18 (43)
IIIA
17 (40)
B
7 (17)
2-microglobulin, n (%)
3 mg/L
14 (33)
>3 mg/L
23 (55)
Data missing
5 (12)
M-protein class, n (%)
IgG
26 (62)
IgA
9 (21)
Bence Jones protein
7 (17)
Figure 1. MPT Treatment Regimen
Continued past the 6
cycles until any sign of
disease progression or
relapse
Thalidomide Daily
MP Daily
x 6 Cycles
Day 1
Day 7
Day 28
Melphalan = 4 mg/m2
Prednisone = 40 mg/m2
Thalidomide = 100 mg/day
Figure 2. RESPONSE AFTER MPT (42 PATIENTS)
50
45%
36%
40
19%
30
Response 20
26%
12%
of 10
7%
%
0
CR+nCR
VGPR
PR
NR
(90%99%)
(50%89%)
Figure 3. TIME TO MAXIMUM RESPONSE
100
ts 80
nie 60
Pat 40
of% 20
0
012
34569
12 15
16
Months
Figure 4. TIME TO ONSET OF ADVERSE EVENTS
40
NEUROLOGIC
30
INFECTION
20
DVT
Patients
of% 10
0
02
4
68
10
12
14
16
Months
Figure 5. TREATMENT DISCONTINUATION
40
30
15 patients
20
Patients
of 10
%
0
02
46
8
10
12
14
16
Months
REFERENCES
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JF. The combination of thalidomide, cyclophosphamide and dexamethasone
(ThaCyDex) is feasible and can be an option for relapsed/refractory multiple
myeloma. Hematol J. 2002;3:43-48.
5. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-
cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502.