From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on October 23, 2008. For personal
use only.
2008 112: 2998-2999
doi:10.1182/blood-2008-06-163022
Crossover confusion: MPT still best
Brian G. M. Durie
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From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on October 23, 2008. For personal
use only.
in the protein's DNA contact regions that
a transcriptional "signature of genes" of that
and overall survival. The Facon et al trial2 en-
weaken the binding of the protein to its tar-
mutant p53 protein, disrupting the function of
rolled patients aged 65 to 75 years; the Hulin et al
geted DNA but retain a similar protein struc-
other transcription factors. The concept that
trial,3 patients age 75 or more years, as summa-
ture. It is this second class that both gives rise
tumor suppressor genes contribute to the ori-
rized and compared in the table. Collectively,
to the adverse prognosis of DLBCL and often
gins and development of cancers by their loss
these data led to the approval of MPT in the
demonstrates allele-specific "gain-of-function
of a function will now have to be modified to
frontline nontransplant setting in Europe. The
mutations"5,6 that confers new properties on a
include the oncogene-like activity of a mutant
MPT PFS data at 24.1 to 27.5 months are very
mutant p53 protein. These mutant proteins
p53 protein that has a "gain-of-function."
consistent: the major difference between the
apparently bind to other transcription factors
Conflict-of-interest disclosure: The authors
trials is the remarkably good overall survival in
(like p73) and alter their functions, making the
declare no competing financial interests.
the MP arm of the Palumbo study, which results
cell more resistant to apoptosis and chemo-
in no comparative survival benefit for the MPT
therapy. These "gain-of-function" pheno-
arm. This is most likely because of the short MP
types have been demonstrated in cell cultures
REFERENCES
induction of 6 months followed by rapid cross-
and in transgenic mice.7 The observations
1. Levine AJ, Hu W, Feng Z. The p53 pathway: what
over, with relapse treatment incorporating novel
made in these papers suggest the possibility
questions remain to be explored? Cell Death Differ. 2006;
13:1027-1036.
agents including thalidomide. There is, in addi-
that allele-specific "gain-of-function" muta-
2. Hollstein M, Sidransky D, Vogelstein B, et al. p53 mu-
tions can act in humans to contribute to poor
tion, the sense that the now-recommended
tations in human cancers. Science. 1991;253:49-53.
overall survival. Unlike many tumor suppres-
longer frontline 12-cycle (18 months') MPT
3. Borresen AL, Andersen TI, Eyfjord JE, et al. TP53 mu-
sor gene mutations, most of the p53 mutations
tations and breast cancer prognosis: particularly
induction regimen in the Intergroupe Franco-
found in tumors are missense mutations (92 in
poor survival rates for cases with mutations in the zinc-
phone du MyeŽlome (IFM) trials is more effective
binding domains. Genes Chromosomes Cancer. 1995;
the DLBCL study), rather than deletions or
as a synergistic combination versus the 6-cycle
14:71-75.
insertions (10 in that study) that destroy the
4. Olivier M, Langerod A, Carrieri P, et al. The clinical
MPT regimen followed by thalidomide mainte-
structure of the protein. That observation sug-
value of somatic TP53 gene mutations in 1,794 patients with
nance. However, it is known that thalidomide
breast cancer. Clin Cancer Res. 2006;12:1157-1167.
gests that tumors may select for a p53 missense
maintenance does improve survival for patients
5. Blandino G, Levine AJ, Oren M. Mutant p53 gain of
mutation that provides a helpful "gain-of-
with at least 10% residual disease (ie,
function: differential effects of different p53 mutants on
function" for tumor growth and survival be-
resistance of cultured cells to chemotherapy. Oncogene.
VGPR),4 which is a confounding factor in the
fore and during treatments. This idea will
1999;18:477-485.
Palumbo et al trial. Further clarification is also
clearly need additional studies examining the
6. Song H, Hollstein M, Xu Y. p53 gain-of-function can-
awaited with regard to 2 MPT versus MP stud-
cer mutants induce genetic instability by inactivating ATM.
possible altered transcriptional patterns
Nat Cell Biol. 2007;9:573-580.
ies that show prolongation of PFS but no overall
brought about in a p53 mutant allele-specific
7. Lozano G, Zambetti GP. What have animal models taught
survival benefit.5,6
fashion in DLBCL and FL. There ought to be
us about the p53 pathway? J Pathol. 2005;205:206-220.
Right now, the final analysis is that MPT is a
very effective new standard of care for patients in
CLINICAL OBSERVATIONS
the nontransplant setting. Increasingly, cross-
over therapy can be expected to confuse the in-
Comment on Palumbo et al, page 3107
terpretation of frontline trials. Recently, Morgan
Crossover confusion: MPT still best
et al have used a new statistical approach assess-
ing "life-years" in an effort to compensate for the
----------------------------------------------------------------------------------------------------------------
impact of crossover.7 The duration of induction
Brian G. M. Durie
therapy is also a crucial variable deserving more
CEDARS-SINAI COMPREHENSIVE CANCER INSTITUTE
attention, particularly since magnetic resonance
In this issue of Blood, Palumbo and colleagues describe the long-term results of adding tha-
imaging data indicate slow evolution of remis-
lidomide to MP as treatment for myeloma in elderly patients. Primary induction with MPT
sions over 12 to 18 months.8
versus MP improves response and PFS, but not overall survival, in this study.
As far as comparative efficacy is concerned,
Howbesttousethalidomideandother
4-week cycles followed by ongoing thalido-
it is important to note a recent randomized
novel agents like lenalidomide and bor-
mide (100 mg) as maintenance versus MP
trial indicating equivalent, but not better, PFS
tezomib is the key question in myeloma clini-
alone in 164 patients for 6 cycles. Both re-
with thalidomide and dexamethasone versus
cal research today. Introduction of these
sponse (partial response [PR], 68.9% vs
MP.9 Conversely, a large randomized trial4
agents has improved overall survival for my-
47.6%;
very good partial response [VGPR]
comparing 12.5 months of bortezomib plus
eloma patients, as illustrated by a recent Mayo
44.9% vs 14.7%) and progression-free sur-
MP (VMP) versus MP showed striking re-
Clinic analysis.1 However, which is the best
vival (PFS) are substantially better
sponse and PFS superiority of VMP versus
combination and/or sequencing of agents?
(21.8 months vs 14.5 months) with MPT ver-
MP. However, the PFS of 21.7 months is
The trial by Palumbo and colleagues that led
sus MP. However, overall survival is roughly
similar to MPT, and greater neurotoxicity
the way in evaluating modifications to the mel-
equivalent at 45 months versus 47.6 months.
with bortezomib is a concern. There is excite-
phalan and prednisone (MP) regimen involved
So how do we explain this and what can be
ment about what can become the next new
331 patients: 167 patients received melphalan,
recommended to patients? In the 2 French trials,
standard in the nontransplant setting. Strong
prednisone, and thalidomide (MPT) for six
MPT produced an improved response, PFS,
candidates are MP plus lenalidomide (MPR)
2998
15 OCTOBER 2008 I VOLUME 112, NUMBER 8 blood
From www.bloodjournal.org at Cedars-Sinai Medical Center Medical Library on October 23, 2008. For personal
use only.
MPT comparisons: treatment durations and crossover therapy
Response at 6
PFS
to 18 mo, %
median, mo
Duration of induction
Thalidomide
Thalidomide at
Median overall
Trial
> PR
> VGPR
MPT
MP
MP and MPT, mo
maintenance
relapse for MP
survival for MPT, mo
Italian (ages
65 and
75)
Palumbo et al
68.9
44.9
24.7
15
6 (6
4-wk cycles)
Yes, ongoing for MPT arm
Yes (41.5%)*
45.0 (vs 47.6)
French (IFM)
Facon et al2 (age 65
75)
76
47
27.5
17.8
18 (12
6-wk cycles)
No
Yes (44%)
51.6 (vs 33.2)
Hulin et al3 (age
75)
62
22
24.1
19
18 (12
6-wk cycles)
No
Yes (77%)
45.3 (vs 27.7)
*Thalidomide and bortezomib combinations used.
and lenalidomide plus low-dose dexametha-
alone or reduced-intensity autologous stem cell transplanta-
Totaltherapy2(TT2)wasarandomized
sone.4 Early data indicate excellent PFS and
tion in elderly patients with multiple myeloma (IFM 99-
prospective treatment trial composed of
06): a randomized trial. Lancet. 2007;370:1209-1218.
overall survival results with both. The 82%
a complex regimen (induction, 2 autologous
3. Hulin C, Facon T, Rodon P, et al. Melphalan-pred-
2-year survival seen with ongoing lenalido-
nisone-thalidomide (MP-T) demonstrates a significant
peripheral blood stem cell transplantations
mide/low-dose dexamethasone therapy (for
survival advantage in elderly patients
75 years with
[ASCTs], consolidative chemotherapy, and
multiple myeloma compared with melphalan-prednisone
patients
65 years) is particularly promis-
maintenance) given with or without thalido-
(MP) in a randomized, double-blind, placebo-controlled
ing.10 This ECOG trial also brings into focus
trial, IFM 01/01 [abstract 75]. ASH Meeting Abstracts.
mide during all phases of treatment.1 In
the need to assess best response and survival
2007;110:31a.
their original report with 42 months' follow-
over time. The results of direct comparative
4. Rajkumar V, Hayman SR. Controversies surrounding
up, the higher complete response and event-
the initial treatment of multiple myeloma. ASCO Educa-
trials are awaited with great anticipation.
tional Book. 2008:369-374.
free survival rates enjoyed by patients on the
For now, the current standard is MPT,
5. Gulbrandsen N, Waage A, Gimsing I, et al. A random-
thalidomide arm had not translated into su-
which is a well-tolerated oral regimen with a
ized placebo controlled study with melphalan/prednisone
perior OS. However, in the current paper at
manageable side effect/toxicity profile. A per-
versus melphalan/prednisone/thalidomide: quality of life
72 months' follow-up, a distinct survival
and toxicity. Haematologica Abstract Book. 2008; abstract
sonalized approach to treatment selection is
no. 0209.
advantage was seen for the 30% of patients
recommended, and can allow use of MP alone
6. Wijermans P, Schaafsma M, Van Norden Y, et al. Mel-
with abnormal cytogenetics.
for very elderly or frail patients and stronger
phalan
prednisone versus melphalan
prednisone
This paper carries 3 important messages.
consideration of VMP in the setting of high-
thalidomide induction therapy for multiple myeloma in
The first but simplest is a reminder that early
elderly patients: first interim results of the Dutch coopera-
risk cytogenic features8 and/or renal impair-
tive group HOVON. Haematologica Abstract Book. 2008;
reports of OS may be misleading. The second
ment and/or if deep vein thrombosis risk is a
abstract no. 0440.
is that with novel agents and transplantation,
particular concern. Neurotoxicity can be pro-
7. Morgan G, Ishak B, Deniz M, et al. Overall survival
in selected patient populations, unprec-
with dexamethasone in phase III multiple myeloma trials
actively managed for both MPT and VMP
after adjustment for cross-over to lenalidomide [abstract
edented OS rates can be achieved; for TT2,
with appropriate dose modifications as neces-
0441]. EHA 13th Congress Abstract. 2008.
the median OS was 8 years!
sary. It is wonderful to finally have effective
8. Walker R, Barlogie B, Haessler J, et al. Magnetic reso-
The third concept is that thalidomide
new options available for tailored use.
nance imaging in multiple myeloma: diagnostic and clinical
administration as part of the initial treat-
implications. J Clin Oncol. 2007;25:1121-1128.
Conflict-of-interest disclosure: The author is
9. Ludwig H, Tothova E, Hajek R, et al. Thalidomide-
ment strategy for patients with myeloma has
on the advisory boards of both Celgene and Mil-
dexamethasone versus melphalan-prednisone as first line
an important impact on long-term OS for
lennium Pharmaceuticals.
treatment in elderly patients with multiple myeloma: sec-
the subgroup of patients with abnormal cy-
ond interim analysis [abstract 0446]. Haematologica.
2007;92:166s.
togenetics. Given the potential for toxicity
REFERENCES
10. Rajkumar SV, Jacobus N, Callander R, et al. Random-
using this drug (grade 3-4 peripheral neu-
1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Im-
ized trial of lenalidomide plus high-dose dexamethasone in
ropathy in 27% for TT2 with thalidomide
proved survival in multiple myeloma and the impact of
newly diagnosed myeloma (E4A03), a trial coordinated by
novel therapies. Blood. 2008;11:2516-2520.
the Eastern Cooperative Oncology Group: analysis of re-
vs 17% without)1 and 80% 5 year OS in
2. Facon T, Mary JY, Hulin C, et al. Melphalan and pred-
sponse, survival, and outcome [abstract 8504]. J Clin Oncol.
other less complex tandem transplant strate-
nisone plus thalidomide versus melphalan and prednisone
2008;26:455.
gies for low-risk patients (low -2 micro-
globulin and no deletion 17, deletion 13, or
CLINICAL OBSERVATIONS
t[4;14]) by fluorescence in situ hybridization
[FISH]),9 it is a critical observation that the
Comment on Barlogie et al, page 3115
70% of patients with normal cytogenetics do
not benefit from thalidomide incorporated
Biology, treatment, and time
into TT2.
----------------------------------------------------------------------------------------------------------------
There are 7 other randomized trials that
address the role of thalidomide in association
Angela Dispenzieri MAYO CLINIC
with alkylator-based therapy; however, none
Barlogie and colleagues report that patients with abnormal baseline metaphase cy-
focuses on the heterogeneity of myeloma biol-
togenetics and enrolled on TT2 had better overall survival (OS) rates when ran-
ogy and its interaction with thalidomide. The
domized to thalidomide.
Intergroupe Francophone du Myelome (IFM)
blood 15 OCTOBER 2008 I VOLUME 112, NUMBER 8
2999