Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma
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CLINICAL TRIALS AND OBSERVATIONS
Bortezomib, melphalan, prednisone, and thalidomide for relapsed
multiple myeloma
Antonio Palumbo,1 Maria Teresa Ambrosini,1 Giulia Benevolo,2 Patrizia Pregno,2 Norbert Pescosta,3 Vincenzo Callea,4
Clotilde Cangialosi,5 Tommaso Caravita,6 Fortunato Morabito,7 Pellegrino Musto,8 Sara Bringhen,1 Patrizia Falco,1
Ilaria Avonto,1 Federica Cavallo,1 and Mario Boccadoro,1 for the Italian Multiple Myeloma Network, Gruppo Italiano Malattie
Ematologiche dell’Adulto (GIMEMA)
1Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliera (AO) S. Giovanni Battista, Turin, Italy; 2Ematologia, Azienda Ospedaliera San Giovanni
Battista, Turin, Italy; 3Divisione di Ematologia, Ospedale Centrale, Bolzano, Italy; 4Divisione di Ematologia, Ospedali Riuniti, Reggio Calabria, Italy; 5Divisione di
Ematologia e Trapianto di Midollo Osseo, Azienda Ospedaliera Cervello, Palermo, Italy; 6Cattedra e Divisione di Ematologia, Università Tor Vergata, Ospedale
San Eugenio, Rome, Italy; 7Unità Ospedaliera Complessa (UOC) di Ematologia, Azienda Ospedaliera di Cosenza, Cosenza, Italy; 8UOC di Ematologia e
Trapianto di Cellule Staminali, Centro di Riferimento Oncologico Regionale (CROB), Rionero in Vulture, Italy
In multiple myeloma (MM), the addition of days 1 through 5. Thalidomide was deliv- the 1-year survival from study entry was
thalidomide or bortezomib to the stan- ered at 50 mg on days 1 through 35. Each 84%. Grade 3 nonhematologic adverse
dard oral melphalan/prednisone combina- course was repeated every 35 days. The events included infections (5 patients),
tion significantly increased response rate maximum tolerated dose of bortezomib fatigue (1), vasculitis (1), and peripheral
and event-free survival. In this multi- was 1.3 mg/m2. Thirty patients with re- neuropathy (2); no grade 4 toxicities were
center phase 1/2 trial, dosing, safety, and lapsed or refractory MM were enrolled; 20 recorded. Initial results showed that VMPT
efficacy of the 4-drug combination, bort- patients (67%) achieved a partial re- is an effective salvage therapy with a very
ezomib, melphalan, prednisone, and tha- sponse (PR) including 13 patients (43%) high proportion of responses. The inci-
lidomide (VMPT) was determined. Bort- who achieved at least a very good PR. dence of neurotoxicities was unexpect-
ezomib was administered at 3 dose levels Among 14 patients who received VMPT edly low. (Blood. 2007;109:2767-2772)
(1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on as second-line treatment, the PR rate was
days 1, 4, 15, and 22; melphalan was 79% and the immunofixation-negative
given at a dose of 6 mg/m2 on days 1 complete response rate 36%. The 1-year
through 5 and prednisone at 60 mg/m2 on progression-free survival was 61%, and © 2007 by The American Society of Hematology
Introduction
Multiple myeloma (MM) is a malignant plasma cell proliferative mately 70% in combination with alkylating agents.5,7,8 In 2
disorder that accounts for more than 16 000 deaths each year in independent randomized studies, the combination of MP plus
Europe.1 In the last 50 years, several combination chemotherapy thalidomide (MPT) not only increased the CR rate, but also
regimens have been tested, but no regimen was better than the significantly prolonged event-free and overall survival in compari-
original melphalan and prednisone (MP) regimen.2 During the last son with the original MP.9,10 In the French study, MPT was also
10 years, high-dose melphalan with hematopoietic stem cell superior to a reduced intensity autologous transplantation proce-
support was the only option that significantly increased the rate of dure.9 These findings are now changing the treatment paradigm of
complete response (CR) and extended event-free and overall elderly patients with myeloma.
survival.3,4 Oral low-dose melphalan in elderly patients and Bortezomib is the first proteasome inhibitor to enter into clinical
high-dose melphalan in younger patients, therefore, became the use. Preclinical trials have demonstrated in vitro synergy for
standard of care. However, new drugs, such as thalidomide, bortezomib in combination with several cytotoxic agents, including
lenalidomide, and bortezomib, are changing the therapeutic sce- melphalan.11-14 In newly diagnosed myeloma, the combination of
nario of MM.5 bortezomib with MP was active and well tolerated in elderly
Thalidomide, in combination with dexamethasone or chemo- patients (median age, 75 years), with a response rate of 89%
therapeutic agents, showed in vivo additive or synergistic activity, including a remarkable 32% immunofixation-negative CR rate.15
and often induced high rates of profound tumor regression, similar Similarly, bortezomib plus thalidomide and dexamethasone signifi-
to those achieved after high-dose chemotherapy.6-10 The response cantly increased the response rate induced by thalidomide plus
rate of relapsed myeloma to thalidomide ranges from 25% to dexamethasone.16 Both bortezomib and thalidomide showed in
35%.5,6 When thalidomide is used in combination with corticoste- vivo additive or synergistic activities when combined with melpha-
roids, the response rate increases to about 50% and to approxi- lan, as did the combination of bortezomib with thalidomide.9-16
Submitted August 18, 2006; accepted November 13, 2006. Prepublished The online version of this article contains a data supplement.
online as Blood First Edition Paper, December 5, 2006; DOI 10.1182/blood-
The publication costs of this article were defrayed in part by page charge
2006-08-042275.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
An Inside Blood analysis of this article appears at the front of this issue. © 2007 by The American Society of Hematology
BLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7 27672768 PALUMBO et al BLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7
Figure 1. Treatment schedule. The VMPT schedule is based on
bortezomib at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2)
on days 1, 4, 15, and 22; melphalan at 6 mg/m2 on days 1 through
5, prednisone at 60 mg/m2 on days 1 through 5; and thalidomide
at 50 mg on days 1 through 35. Each course was repeated every
35 days.
These observations provide the rationale for evaluating the tolerabil- the next 10 patients at 1.3 mg/m2, and in the last 10 patients at 1.6 mg/m2.
ity and efficacy of the 4-drug combination bortezomib (Velcade; Melphalan was given orally at the dose of 6 mg/m2/d for 5 days, prednisone
Janssen & Cilag, Milan, Italy), melphalan, prednisone, and thalido- was given orally at the dose of 60 mg/m2/d for 5 days, both followed by a
mide (VMPT). The primary goals of this study were to identify the 30-day rest period (days 6-35). Thalidomide (Pharmion, Windsor, United
Kingdom) was administered orally at 50 mg/d for 35 days. Each cycle was
most appropriate dose of bortezomib in combination with the MPT
repeated every 35 days, for a total of 6 courses (Figure 1).
treatment regimen, which incorporates a reduced dose of thalido- Bortezomib dose was increased whenever at least 3 patients had
mide, and to determine the efficacy. completed 2 courses without a dose-limiting toxicity (DLT). DLT was
defined as the occurrence of grade 4 neutropenia at least once a week,, or
grade 4 hematologic toxicity except neutropenia, or any grade 3 or higher
Patients, materials, and methods nonhematologic toxicity. The maximum tolerated dose (MTD) was defined
as the highest dose level at which 30% or fewer patients experienced a DLT.
Patient selection Bortezomib dose reduction (from 1.6 to 1.3 to 1.0 and then to 0.7 mg/m2)
Between November 2004 and August 2005, a total of 30 patients were and thalidomide dose reduction (from 50 mg/d to 50 mg every other day)
enrolled in 7 Italian centers. All patients had measurable disease, defined as were applied in patients experiencing grade 2 peripheral neuropathy or any
a monoclonal immunoglobulin concentration on serum electrophoresis of at grade 3 or higher nonhematologic or grade 4 hematologic toxicities.
least 10 g/L (1 g/dL) IgG or 5 g/L (0.5 g/dL) IgA, or urinary excretion of at
least 200 mg monoclonal light chain per 24 hours. Patients had a relapse Pretreatment, efficacy, and safety assessments
after a previous chemotherapy or the disease was refractory to salvage
chemotherapy, as defined by progression during treatment or within 60 days Pretreatment evaluations consisted of patient history and physical examina-
after the completion of treatment.17 tion, electrocardiogram, and chest radiographs. Blood samples were
Inclusion criteria were as follows: patients had a relapse or were collected at screening and before each intravenous treatment and again at
refractory after one or 2 lines of treatment; measurable disease; Karnofsky the end of the study. A negative pregnancy test was required for all women
performance status 60% or higher; platelet count 75 ⫻ 109/L or higher; of childbearing potential. A complete neurologic evaluation was done
absolute neutrophil count at least 0.75 ⫻ 109/L; corrected serum calcium during the initial screening, during treatment as needed, and at the end of
3.5 mM (14 mg/dL) or less; serum hepatic aminotransferase levels less than treatment. Assessments of both efficacy and safety were done every 5 weeks
or equal to 2.5 times the upper limit of normal; total bilirubin less than or during chemotherapy regimens and every 2 months thereafter.
equal to 1.5 times the upper limit; and calculated or measured creatinine Treatment response was monitored by measurement of protein in serum
clearance 0.33 mL/s (20 mL/min) or higher. and urine at each participating center every 5 weeks, using the uniformed
Exclusion criteria were: presence of another cancer; psychiatric disease; response criteria of the International Myeloma Working Group to define
grade 2 peripheral neuropathy; or hypersensitivity to bortezomib, boron, responses.18 Briefly, a CR required disappearance of myeloma protein in
mannitol, or thalidomide. Patients agreed to use effective contraception and serum and urine and negative immunofixation. A very good partial response
women of childbearing age had a pregnancy test before enrollment. The (VGPR) required at least 90% reduction of myeloma protein in serum or
study was approved by the institutional review board at each participating urine myeloma protein level less than 100 mg/24 h. A PR required at least
center. All patients gave written informed consent before entering the study, 50% reduction of myeloma protein in serum and a 90% decrease in urine.
which was carried out in accordance with the Declaration of Helsinki. Stable disease (SD) was defined as all responses that did not meet criteria
for CR, VGPR, PR, or progressive disease. Progressive disease was defined
Study design as an increase of 25% or greater in myeloma protein from baseline values.
Responses were confirmed. Bone marrow plasmacytosis, skeletal disease,
This trial was a phase 1/2 multicenter, noncomparative, open-label study on and serum calcium were included in the response evaluation. Progression-
the combination of bortezomib and melphalan/prednisone/thalidomide as free survival was calculated from the time of enrollment until the date of
salvage therapy in patients with advanced MM. The primary objectives progression, relapse, or death or the date the patient was last known to be in
were to determine an acceptable rate of toxicity by showing 30% or fewer remission. Survival was calculated from the time of enrollment until the
patients with grade 4 neutropenia for at least 1 week, or a grade 4 date of death or the date the patient was last known to be alive.
hematologic toxicity except neutropenia, or any grade 3 nonhematologic All adverse events were assessed at each visit and graded according to
toxicity; and the efficacy by showing at least 50% of patients in partial the National Cancer Institute Common Terminology Criteria (version 3).19
remission (PR) or at least 3% of patients in CR following the proposed Causes of death were recorded as attributable to myeloma, study drugs,
regimen. The secondary objectives were to determine the durations of other causes, or a combination of these.
progression-free survival and survival.
Drug administration Statistical analysis
Bortezomib (Janssen & Cilag) was administered by intravenous bolus on Time-to-event analysis was performed with the Kaplan-Meier method.20
days 1, 4, 15, and 22 at 3 dose levels: in the first 10 patients at 1.0 mg/m2, in Further subgroup analyses were done with the Cox model to estimate theBLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7 VMPT IN RELAPSED MYELOMA 2769
Table 1. Patient and disease characteristics received VMPT as second-line therapy, and 16 patients received
Patient or disease characteristics Value VMPT as third-line therapy. Twenty patients received a prior
No. of patients 30 autologous transplant, 10 conventional chemotherapy, and 9 thalido-
Median age, y (range) 66 (38-79) mide-based regimens. Baseline demographics and other character-
Sex, no. (%) istics are listed in Table 1. The median number of cycles
Male 14 (47) administered was 6 (range, 1-6).
Female 16 (53) Six of the 30 VMPT patients did not complete the assigned 6
Stage, no. (%)
cycles because of adverse events (2 patients had grade 3 neuropa-
IIA 7 (23)
thy, 1 had grade 3 vasculitis, 1 had grade 2 confusion, 1 had grade 2
IIIA 22 (73)
IIIB 1 (3)
fatigue, and 1 had grade 3 pneumonia). Bortezomib was reduced
Myeloma protein class, no. (%) from 1.0 to 0.7 mg/m2 for febrile neutropenia (1 patient); from 1.3
IgG 19 (63) to 1.0 mg/m2 for herpes zoster reactivation (2 patients) and grade 4
IgA 6 (20) thrombocytopenia (1 patient); from 1.6 to 1.3 or 1.0 mg/m2 for
Bence Jones protein 5 (17) peripheral neuropathy (1 patient) and grade 4 thrombocytopenia
Karnofsky performance status, no. (%) (1 patient). Thalidomide was reduced from 50 mg/d to 50 mg every
No higher than 70% 4 (13)
other day for grade 2 peripheral neuropathy in one patient and for
80% 11 (37)
At least 90% 15 (50)
grade 2 constipation in 2 patients.
Bone marrow plasmocytosis, median % (range) 45 (5-98) DLTs during the dose escalation of bortezomib were as follows.
Median 2-microglobulin level, mg/L (range)* 3.4 (0.4-1.8) In the first 10 patients who received bortezomib at 1.0 mg/m2, one
No higher than 3.5 mg/L, no. (%) 14 (47) patient experienced grade 3 pneumonia, one patient grade 3 febrile
More than 3.5 mg/L, no. (%) 13 (43) neutropenia, and one grade 3 vasculitis. In the next 10 patients who
Data missing, no. (%) 3 (10) received bortezomib at 1.3 mg/m2, 3 patients experienced DLTs (2
Median albumin level, g/L (range) 25 (25-46)
grade 4 thrombocytopenia, 1 grade 4 anemia, and 2 grade 3 herpes
Median C-reactive protein level, mg/L (range) 2 (0.13-195)
zoster reactivation). In the last 10 patients who received bort-
Median hemoglobin level, g/L (range) 108 (80-151)
Median platelet count, ⫻ 109/L (range) 182 (87-386)
ezomib at 1.6 mg/m2, 4 patients experienced DLTs (2 grade 4
Median creatinine level, M (range) 79.6 (44.2-185.6) thrombocytopenia, 2 grade 3 peripheral neuropathy, 1 grade 3
Median calcium level, mM (range) 2.35 (1.5-2.8) esophagitis, and 1 grade 3 fatigue). Bortezomib at 1.3 mg/m2 was
Abnormal cytogenetics, no. (%) therefore considered the MTD.
Del 13 7 (23)
Data missing 4 (13) Efficacy
Prior lines of treatment, no. (%)
1 14 (47)
A high proportion of patients had CRs or VGPRs (Table 2). A CR or
2 16 (53) VGPR was achieved in 13 of 30 patients (43%) and at least a PR in
Prior treatments, no. (%) 20 of 30 patients (67%). In the subgroup of patients who received
Stem cell transplantation 20 (67) second-line VMPT, immunofixation-negative CRs were observed
Conventional chemotherapy 10 (33) in 5 of 14 subjects (36%) and CR or VGPR in 8 of 14 subjects
Thalidomide-based regimen 9 (30) (57%). The median time to the best response was 15 weeks (range,
*To covert 2-microglobulin values to SI units (nM), multiply by 85. 35-210 days). The best response occurred within the first 3 cycles
in 68% of patients (Figure 2). The response rate was not signifi-
hazard ratios (HRs) and the 95% confidence intervals (95% CIs) and to detect cantly different in the subgroups of patients treated with bort-
clinically relevant interactions between treatment and clinical factors. ezomib at 1.0, 1.3, or 1.6 mg/m2.
The incidence of any adverse event was compared by the 2 test or The median duration of follow-up from study entry was 11
Fisher exact test when cell counts were lower than 5. The analyses were months (range, 8-17 ⫾ 3.2 [SD]) for survivors. Progression, re-
performed with SAS (version 8.2; SAS Institute, Cary, NC). lapse, or death occurred in 15 of 30 patients (50%). The 1-year
progression-free survival was 61% in all patients (Figure 3A). The
1-year progression-free survival among patients who received
Results second-line VMPT was 100% as compared with 27% in patients
Patients and dose escalation
receiving third-line VMPT (HR for second-line VMPT 0.17; 95%
CI, 0.05-0.64; P ⫽ .009; Figure 3B). In patients who never
At the time of the analysis, all 30 patients enrolled in the study had received thalidomide before study entry, the HR of the progression-
completed the assigned treatment schedule. Fourteen patients free survival was 0.29 (95% CI, 0.09-0.9; P ⫽ .03) in comparison
Table 2. Clinical response of patients with relapsed/refractory MM receiving VMPT
All patients, VMPT as second-line VMPT as third-line
no. (%) therapy, no. (%) therapy, no. (%)
No. of patients 30 14 16
CR or VGPR: greater than 90% myeloma protein reduction 13 (43) 8 (57) 5 (31)
CR: immunofixation-negative 5 (17) 5 (36) 0 (0)
VGPR: 90%-99% myeloma protein reduction 8 (27) 3 (21) 5 (31)
PR: 50%-89% myeloma protein reduction 7 (23) 3 (21) 4 (25)
SD 8 (27) 3 (21) 5 (31)
Progressive disease 2 (7) 0 (0) 2 (13)2770 PALUMBO et al BLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7
grade 1-2 neuropathy developed in 8 patients and grade 3
neuropathy developed in one patient. Among 7 patients with
pre-existing grade 1 neuropathy, neuropathy worsened to grade 2 in
2 patients, to grade 3 in one patient, and resolved in one patient. All
grade 3 neuropathies were observed in the subgroup of patients
who received bortezomib at 1.6 mg/m2. After the introduction of
acyclovir prophylaxis, no herpes zoster reactivation was recorded.
The majority of grade 3-4 adverse events occurred during the first 2
cycles of therapy (36 events during cycles 1-2 versus 11 events
during cycles 3-6, P ⫽ .04) and in patients who received third-line
VMPT of therapy (27 events) compared with second-line VMPT
therapy (10 events; P ⫽ .06).
Figure 2. Time to best response. The proportion of patients achieving their best
response to VMPT during every cycle of therapy is shown.
Discussion
with those who received prior thalidomide. The 1-year progression- In this phase 1/2 trial, we evaluated the efficacy and safety profile
free survival was 67.3% in patients who achieved at least a PR. The of the 4-drug combination, VMPT, in patients with relapsed,
1-year survival from the start of therapy among all patients was refractory MM. The CR or VGPR rate was 43%. In the subgroup of
84% (Figure 3C); 5 deaths were observed, all caused by disease patients who received VMPT as second-line therapy, the immuno-
progression. The 1-year survival from start of therapy was 100% in fixation-negative CR rate was 36%. The median progression-free
patients who achieved at least a PR. survival was 12 months.
Other secondary end points included additional measures of Because CR or VGPR are considered important surrogates for
clinical benefit. None of the patients with at least a PR required remission duration and survival,3,4,21,22 the high proportion of such
transfusion after the first treatment cycle. Responses were also responses observed after VMPT were encouraging. The combina-
associated with increases in the platelet count, levels of normal tion of bortezomib plus melphalan in advanced myeloma induced a
immunoglobulins, and Karnofsky performance status scores. CR or VGPR rate of 12%,23,24 whereas the combination of
Subgroup analyses did not show any statistical or clinical bortezomib with thalidomide and dexamethasone induced a near-CR
difference between responses and either age, 2-microglobulin, rate of 16%.25 The VMPT regimen almost doubled these numbers.
C-reactive protein, line of treatment, or dosage of bortezomib. Interestingly, the response rate induced by VMPT in advanced
Responses occurred in patients with or without abnormalities in myeloma was quite similar to the response rate achieved by MPT in
chromosome 13 (71% versus 68%, P ⫽ .4). Serum albumin level patients with newly diagnosed myeloma. Following MPT, the PR
less than 35 g/L (3.5 g/dL) was loosely associated with a lower rate was 76% and the VGPR rate was 36%.10
response rate (25% versus 77%, P ⫽ .09). There was a peculiar pattern of response to VMPT. Responses
Safety occurred rapidly, with an improvement in the quality of responses
(VGPR or CR) observed with subsequent treatment cycles. A
The most common grade 1-2 adverse events were gastrointestinal maximum response was achieved in 32% of patients after the third
symptoms, dermatologic rash, fatigue, sensory neuropathy, and cycle. In the international phase 3 study of bortezomib (assessment
pneumonia (Table 3). Gastrointestinal and dermatologic events of proteasome inhibition for extending remissions [APEX]) or in
were typically mild to moderate and were manageable with routine the phase 1/2 study of bortezomib, melphalan, and prednisone
support. The most common grade 3 adverse events were neutrope- (VMP), best responses continued to improve over the treatment
nia (23%), anemia (13%), thrombocytopenia (20%), herpes zoster course, with approximately 30% of patients achieving maximum
reactivation (7%), pneumonia (3%), and neuropathy (7%). Grade 4 M-protein reduction beyond the first 18 weeks of therapy.15,26
events included only hematologic toxicities, which were thrombo- These data suggest that a prolongation of VMPT from 6 to 9
cytopenia (13%) and neutropenia (20%). No patient had grade 4 treatment cycles might further improve results.
neuropathy or nonhematologic toxicities. No death was reported as Responsiveness to bortezomib did not correlate with most of the
a consequence of adverse events. Eleven (37%) patients received standard prognostic factors, including chromosome 13 deletion,
granulocyte colony-stimulating factor (G-CSF) support. Among which predicts a poor outcome with conventional therapy.27,28 It is
the 23 patients who did not have neuropathy before study entry, possible that the unique mechanism of action of bortezomib
Figure 3. Progression-free survival and overall survival. (A) Progression-free survival in the patients treated with VMPT. (B) Progression-free survival in the subgroup of
patients who received VMPT as second- or third-line therapy. (C) Survival from study entry among all 30 patients.BLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7 VMPT IN RELAPSED MYELOMA 2771
Table 3. All adverse events occurring in the 30 patients delivered at days 1, 4, 15, and 22, every 35 days, and thrombocyto-
receiving VMPT penia was less evident.
Grade, no. of patients (%) No cases of grade 4 peripheral neuropathy occurred. Severe
Adverse event Grades 1-2 Grade 3 Grade 4 grade 3 peripheral sensory neuropathy was observed in 2 patients
Hematologic only, with both patients found to be in the subgroup of patients who
Neutropenia ND 7 (23) 6 (20) received bortezomib at 1.6 mg/m2. In the APEX and VMP trials, the
Thrombocytopenia ND 6 (20) 4 (13) incidence of grade 3 neuropathy was 12% and 17%, respec-
Anemia ND 4 (13) 1 (3) tively.15,31 In the VMPT trial, the incidence was 6% despite the
Infective concomitant administration of thalidomide. In a previous phase 1/2
Herpes zoster 1 (3) 2 (7) 0 (0) dose-escalation study of bortezomib, thalidomide, and dexametha-
Pneumonia 4 (13) 1 (3) 0 (0)
sone (VTD) in patients with advanced myeloma, no MTD of
Febrile neutropenia 0 (0) 1 (3) 0 (0)
thalidomide was reached in combination with bortezomib at
Candida esophagitis 0 (0) 1 (3) 0 (0)
Upper respiratory 3 (10) 0 (0) 0 (0)
1.0 mg/m2, whereas the MTD of thalidomide was 150 mg/d in
Constitutional combination with bortezomib at 1.3 mg/m2.25 In the VMPT
Fatigue 8 (27) 1 (3) 0 (0) study, a reduced dose intensity of both bortezomib (1.3 mg/m2 at
Fever 4 (13) 0 (0) 0 (0) days 1, 4, 15, 22) and thalidomide (50 mg/d) seems safe and
Dermatology very well tolerated.
Rash 4 (13) 0 (0) 0 (0) Despite the absence of any anticoagulant prophylaxis, no deep
Vasculitis 0 (0) 1 (3) 0 (0) vein thrombosis was reported. These data are consistent with
Gastrointestinal previous studies, which showed that relapsed and refractory
Constipation 8 (27) 0 (0) 0 (0)
patients appear to have a lower risk of deep vein thrombosis in
Diarrhea 1 (3) 0 (0) 0 (0)
comparison with patients with newly diagnosed disease.32
Nausea 1 (3) 0 (0) 0 (0)
Vascular
In conclusion, the novel proteasome inhibitor bortezomib in
Phlebitis 3 (10) 0 (0) 0 (0) combination with melphalan, prednisone, and thalidomide induced
Cardiac arrhythmia clinically significant responses, with manageable toxic effects, in
Sinus bradycardia 1 (3) 0 (0) 0 (0) patients with relapsed or relapsed and refractory myeloma. A
SV extrasystoles 1 (3) 0 (0) 0 (0) national, randomized, multicenter phase 3 trial is currently evaluat-
Peripheral neuropathy ing this combination in patients with disease at an earlier stage.
Baseline 7 (23) 0 (0) 0 (0)
De novo 8 (27) 1 (3) 0 (0)
Worsened 2 (7) 1 (3) 0 (0)
Tremors 3 (10) 0 (0) 0 (0) Acknowledgments
Confusion 2 (7) 0 (0) 0 (0)
This study was sponsored by the Università degli Studi di Torino,
SV indicates supraventricular; ND, not determined. Turin, Italy, and supported in part by research funding from
Janssen-Cilag (M.B.) and by Fondazione Neoplasie Sangue Onlus,
overcomes the influence of these adverse prognostic factors. This is Associazione Italiana Leucemie, Compagnia di S Paolo, Fondazi-
consistent with the results of both the APEX and the VMP trials, in one Cassa di Risparmio di Torino, Ministero dell’Università e della
which bortezomib appeared to overcome the adverse impact of Ricerca (MIUR), and Consiglio Nazionale delle Ricerche (CNR).
cytogenetic abnormalities on response rate.15,29 We thank the patients, nurses, physicians, the Clinical Trial
Whether a sequential single-agent treatment would yield similar Office staff (Tiziana Marangon, Federica Leotta, Antonella Bono,
survival benefit with less toxicity in comparison with a more Maria Josè Fornaro), and Rosalba Rosato from CPO Piemonte.
complex combinational regimen administered at diagnosis, re-
mains an important unanswered question. Fermand et al recently
analyzed the activity of high-dose chemotherapy in comparison Authorship
with conventional treatment. No survival influence of treatment
choice was reported, but the period of time without symptoms, Contribution: A.P. and M.B. designed the study, supervised its
treatment, and treatment toxicity was significantly longer in conduct and data analysis, and wrote the report; P.M. reviewed and
patients who received the more complex high-dose regimen.30 commented on the draft of the report; M.T.A., S.B., P.F., I.A., and
Accordingly, if a combinational approach is superior to single- F.C. recruited patients, analyzed data, and assisted in writing the
agent therapy, it might be considered at diagnosis, when there is manuscript; and G.B., P.P., N.P., V.C., C.C., T.C., and F.M.
the best chance to induce a prolonged remission duration. A recruited patients.
sequential approach might then be considered at first and Conflict-of-interest disclosure: A.P. and M.B. have received
subsequent relapses, when less intense and more palliative scientific adviser board and lecture fees from Pharmion and
approaches might be suggested. Janssen-Cilag. The other authors declare that they have no conflict
Most adverse events could be managed with the use of standard of interest.
approaches. No nonhematologic grade 4 adverse event was shown. A list of the participating members of GIMEMA appears as a
Severe myelosuppression was observed in 50% of patients, with data supplement to the online version of this article (Document S1,
febrile neutropenia occurring in less than 5%. Neutropenia was the available on the Blood website; see the Supplemental Materials
most common adverse event; thrombocytopenia was less common. link at the top of the online article).
In the APEX and VMP trials, bortezomib was administered at days Correspondence: Antonio Palumbo, Divisione di Ematologia
1, 4, 8, and 11, every 21 days, and thrombocytopenia was the most dell’Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Via
common adverse event.15,31 In the VMPT trial, bortezomib was Genova 3, 10126 Torino, Italy; e-mail: appalumbo@yahoo.com.2772 PALUMBO et al BLOOD, 1 APRIL 2007 䡠 VOLUME 109, NUMBER 7
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