The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.

Abstract

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

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doi:10.1182/blood-2011-06-357038
Prepublished online October 20, 2011;




Owen, Fiona M. Ross, Graham H. Jackson and J. Anthony Child
Nuria N. Coy, Gordon Cook, Nigel H. Russell, Claudius Rudin, Huw Roddie, Mark T. Drayson, Roger G.
Gareth J. Morgan, Walter M. Gregory, Faith E. Davies, Sue E. Bell, Alexander J. Szubert, Julia M. Brown,
Myeloma IX results and meta-analysis
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The role of maintenance thalidomide therapy in multiple myeloma:
MRC Myeloma IX results and meta-analysis

*Gareth J. Morgan,1 *Walter M. Gregory,2 Faith E. Davies,1 Sue E. Bell,2 Alexander J. Szubert,2
Julia M. Brown,2 Nuria N.Coy,2 Gordon Cook,3 Nigel H. Russell,4 Claudius Rudin,5 Huw Roddie,6
Mark T. Drayson,7 Roger G. Owen,3 Fiona M. Ross,8 Graham H. Jackson,9 and J. Anthony
Child;2 on behalf of the NCRI Haematological Oncology Clinical Studies Group

1Institute of Cancer Research, Royal Marsden Hospital, London, UK; 2Clinical Trials Research
Unit, University of Leeds, Leeds, UK; 3St James’s University Hospital, Leeds, UK; 4Nottingham
University Hospital, Nottingham, UK; 5Royal Devon and Exeter Hospital, Exeter, UK; 6Western
General Hospital, Edinburgh, UK; 7University of Birmingham, Birmingham, UK; 8Wessex
Regional Genetics Laboratory, University of Southampton, Salisbury, UK; and 9University of
Newcastle, Newcastle-upon-Tyne, UK

*G.J.M. and W.M.G. contributed equally to this work and should both be considered first authors

Correspondence: Gareth J. Morgan, Section of Haemato-Oncology, Institute of Cancer
Research, Brookes Lawley Building, 15 Cotswold Rd, Belmont, Sutton, Surrey SM2 5NG, UK;
e-mail: gareth.morgan@icr.ac.uk
Tel.: +44 20 8722 4265; fax: +44 20 8722 4432.

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Abstract
Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after
an initial response. This trial compared the effect of thalidomide maintenance and no
maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients.
Following intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were
randomized to open-label thalidomide maintenance until progression, or no maintenance.
Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly
longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between
regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and
a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed
no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced
survival after progression, translating into a significant OS benefit. Meta-analysis of this and
other studies show a significant late OS benefit (P < .001, 7-year difference HR = 12.3, 95% CI
5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with
improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy.
Overview analysis demonstrated that thalidomide maintenance was associated with a significant
late OS benefit. (ISRCTN:68454111)
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Introduction
Multiple myeloma (MM) is incurable and relapse is inevitable because of residual disease.1,2
Thalidomide is active in both newly diagnosed3-7 and relapsed or refractory MM.8,9 Its mode of
action includes direct apoptotic, antiangiogenic effects, and modulation of the bone marrow
microenvironment.10,11 These activities against the myeloma clone suggest that following
induction therapy either a consolidation block or maintenance therapy with thalidomide may
reduce or suppress residual disease, prolonging the disease-free interval and potentially
improving survival.
Results of thalidomide maintenance trials are conflicting. Following autologous stem cell
transplantation (ASCT), thalidomide maintenance therapy has been associated with improved
progression-free survival (PFS) in some studies,12-15 but not others.16 Similarly, an overall
survival (OS) benefit has not been demonstrated consistently, although a recent meta-analysis
did show a trend toward improved OS.17 The outcomes of thalidomide maintenance in specific
subgroups of patients, including those defined by cytogenetic characteristics, are also
variable.15,16,18 Furthermore, the use and type of relapse therapies also affects the interpretation
of maintenance studies. The Medical Research Council (MRC) IX study is a large, randomized
study that compared PFS and OS outcomes with thalidomide maintenance versus no
maintenance. It included a full interphase fluorescence in situ hybridization (iFISH) cytogenetic
assessment and collation of treatment data at progression.

Methods
Patients
Patients aged 18 years or older with newly diagnosed MM (NDMM) were eligible for inclusion.
Exclusion criteria included pregnancy, acute renal failure, asymptomatic myeloma, solitary bone
plasmacytoma, extramedullary plasmacytoma, and previous or concurrent active malignancies.
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A multicenter research ethics committee and local ethics committees of all participating
institutions approved the protocol; all patients gave written informed consent in accordance with
the Declaration of Helsinki.

Study design
The MRC Myeloma IX study was a multicenter, phase 3, factorial design trial. Patients were
assigned to induction treatment via either an intensive or a nonintensive treatment pathway, as
determined by performance status, informed discussion, and patient preference (Figure 1).
There was no rigid age cutoff.
In the intensive pathway, patients were randomized to 21-day cycles of CVAD
(cyclophosphamide 500 mg/day on days 1, 8, and 15; vincristine 0.4 mg/day on days 1-4;
adriamycin 9 mg/m2/day on days 1-4; and dexamethasone 40 mg/day on days 1-4 and 12-15) or
21-day cycles of CTD (cyclophosphamide 500 mg/day on days 1, 8, and 15; thalidomide 100
mg/day increasing to 200 mg/day if tolerated; and dexamethasone 40 mg/day on days 1-4 and
12-15) both given to maximum response. After 4 to 6 cycles, patients received high-dose
melphalan (200 mg/m2) with supporting ASCT.
Nonintensive pathway patients were randomized to 28-day cycles of MP (melphalan
7 mg/m2/day and prednisolone 40 mg/day on days 1-4 for 6-9 cycles) or 28-day cycles of an
attenuated CTD (CTDa) regimen (cyclophosphamide 500 mg/day on days 1, 8, and 15;
thalidomide 50 mg/day increasing to a maximum of 200 mg/day if tolerated; and
dexamethasone 20 mg/day on days 1-4 and 15-18). Patients in both pathways were
randomized at study entry to either sodium clodronate (C; given continuously at a dose of 1600
mg/day orally) or zoledronic acid (Z; 4 mg as an infusion every 3 or 4 weeks during induction
depending on the chemotherapy cycle, and every 4 weeks thereafter). Bisphosphonates were
continued at least until progression.

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