Einsele_EU Haematology 03/03/2010 13:50 Page 72
Haematological Malignancies Lymphoproliferative Disorders
Table 1: Novel Agents in First-line Treatment of Elderly Myeloma Patients
Study Regimen ORR (≥PR) (%) VGPR (%) CR (%) Median PFS Median EFS Median OS
(Months) (Months) (Months)
Waage et al.
28
MPT 42 NA 6 20 NA 29
MP 28 NA 3 18 NA 33
Wijermans et al.
27
MPT 36 28 2 14 13 37
MP 37 8 2 10 9 30
Straka et al.
22
Induction →
Mel 140 64 NA 16 NA 22 63
Mel 140 69 NA 18 NA 20 65
Ludwig et al.
29
Thal/dex 68 24 2 16.7 NA 41.5
MP 50 11 2 20.7 NA 49.4
Hulin et al.
26
MPT 62 21 7 24.1 NA 44
MP 31 7 1 18.5 NA 29.1
Palumbo et al.
25
MPT 68.9 29.3 15.6 21.8 NA 45
MP 47.6 11 3.7 14.5 NA 47.6
Facon et al.
18
MPT 76 47 13 27.5 NA 51.6
MP 35 7 2 17.8 NA 33.2
Mel 100 65 43 18 19.4 NA 38.3
San Miguel et al.
30
VMP 74 8 33 24 NA NR
MP 39 4 4 16.6 NA NR
2
CR = complete remission; EFS = event-free survival; Mel 140 = high-dose melphalan chemotherapy at a cumulative dose of 140mg/m ;MPT = melphalan, prednisone, thalidomide;
NA = not available; NR = not reached; OS = overall survival; ORR = overall response rate; PFS = progression-free survival; PR = partial response; Thal/dex = thalidomide and dexamethasone;
VGPR = very good partial remission; VMP = bortezomib, melphalan and prednisone.
with MP (VMP) versus MP alone was subsequently tested in a or better, with a trend for better OS compared with pair mates treated
randomised phase III study: patients allocated to VMP had better without thalidomide.
36
The Italian group reported PFS at four years of
outcomes for response rate and all survival parameters and also 51% with versus only 31% without TD. Post-relapse survival was
achieved responses more rapidly.
30
comparable (24 months with versus 25 months without previous
thalidomide). The Arkansas group incorporated thalidomide in a
A subgroup analysis suggested that VMP is also active in unfavourable randomised fashion throughout all treatment phases into their
cytogenetic subgroups. Median time to progression was prolonged by ‘TotalTherapy2’ protocol.
37
Considering the primary end-point (five-
approximately seven months following VMP, with patients achieving year EFS), the subjects allocated to thalidomide fared significantly
CR having duration of that remission of two years. Recently, an Italian better: 56 versus 43% EFS without thalidomide. Of note, post-relapse
group reported on their experience with the MPR regimen
31
survival was significantly shorter for patients having received
(melphalan, prednisone and lenalidomide). Subjects having received thalidomide in their first-line therapy: 1.1 with versus 2.7 years
the maximum tolerated dose of MPR achieved a median PFS of 28.5 without prior thalidomide exposure. This contributed to an identical
months and a two-year OS of 91%
32
(see Table 1). OS, leading to speculation that thalidomide may induce myeloma drug
resistance if (in comparison with the Italian schedule) it is
Novel Compounds in Patients administered for a long time.
Eligible for Transplantation
TD given to patients with newly diagnosed MM resulted in significantly Bortezomib/dexamethasone (VelDex) given to patients <65 years of
more severe (grade >3) toxicity compared with high-dose age with untreated myeloma resulted in significantly higher overall
dexamethasone alone: 45% for TD versus 21% for dexamethasone. response rate (ORR) and higher VGPR when randomly compared
However, the response rate was significantly higher in the with standard VAD in a French trial.
37
Those results were valid for
combination arm (63 versus 41%).
33
The difference in response assessment before and after high-dose chemotherapy. At a
favouring TD over dexamethasone was retained in a larger phase III relatively short follow-up, two-year PFS was significantly extended
trial, while the difference in grade 4 toxicity was less pronounced following VelDex, but did not translate into superior OS at two years
(30% TD versus 23% dexamethasone).
34
Since it is currently not known from randomisation. Recently, the German DSMM group reported
whether a favourable response to novel drug combinations can an interim analysis on an ongoing up-front trial. Bortezomib,
abrogate high-dose chemotherapy and PBPC transplantation, cyclophosphamide and dexamethasone (VelCD) was administered to
numerous clinical protocols use such combinations to improve patients with newly diagnosed disease before stem cell transplant.
38
disease control in the early stages while continuing to use the The maximum tolerated dose of cyclophosphamide had previously
consolidatory high-dose effect. Comparing standard vincristine/ been determined to be 900mg/m
2
on cycle day one.
39
The ORR to
doxorubicin/dexamethasone (VAD) induction with thalidomide/ VelCD was 84%, and in the interim analysis no statistically significant
doxorubicin/dexamethasone (TAD) followed by stem cell mobilisation differences of response in relation to presence of adverse cytogenetic
and single or tandem transplant, a Dutch–German co-operative group factors including del(17p) were detected. The thalidomide analogue
found a higher VGPR rate both before and after transplant, while CRs lenalidomide (Revlimid
®
) is known to be effective in relapsed MM. A
were not significantly different.
35
Data for PFS/EFS and OS are still study investigated this immunomodulatory drug with dexamethasone
awaited. The addition of thalidomide to standard therapy in a tandem- in treatment-naïve patients randomly comparing conventional-dose
transplant setting yielded a higher rate and a longer duration of VGPR (RD) with dose-reduced dex (Rd).
40
Not only was toxicity significantly
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