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Chapter 86 Plasma Cell Neoplasms 1405

in the United Kingdom (MRC Myeloma IX Trial). The CTD regimen of improving the outcome of patients with unfavorable genetic
consisted of cyclophosphamide 500 mg weekly, thalidomide 100 mg markers.
daily, and dexamethasone 40 mg for 4 days every other week. The
induction chemotherapy was given for a minimum of six cycles and
up to nine cycles or until maximum response. The postinduction Lenalidomide
ORR was significantly higher with CTD versus CVAD (82.5% vs.
71.2%; p < .0001); likewise, CR rates were also higher with CTD Lenalidomide and dexamethasone are an effective combination
(13% vs. 8.1%; p = .0083). This differential response was maintained therapy for the treatment of previously untreated symptomatic
following autologous stem cell transplant with regard to posttrans- myeloma patients. A large, open-label, phase III randomized trial
plant CR (50% vs. 37.2%; p = .00052). With a median follow-up comparing lenalidomide plus high-dose dexamethasone or lenalido-
of 47 months, there was no difference in PFS or OS between the two mide plus weekly dexamethasone conducted by the Eastern Coopera-
groups. This establishes CTD as an acceptable induction therapy tive Oncology Group established lenalidomide and dexamethasone
before transplant. as a simple oral regimen that could be used as an induction therapy
For elderly patients and patients otherwise ineligible for HDT, before transplant or as a first-line therapy without a stem cell trans-
CTD was compared with MP. The dose of cyclophosphamide was plant. Administration of lenalidomide 25 mg daily for 3 weeks on
500 mg weekly, thalidomide 50 mg daily, and dexamethasone 20 mg and 1 week off, along with dexamethasone 40 mg in a pulsed fashion
for 4 days every other week. Both arms were oral regimens. CTD (days 1–4, 9–12, and 17–20) for the first four cycles only (high-dose
therapy was associated with a superior ORR (63.8% vs. 32.6%; dexamethasone arm), gave a higher response rate of 79% compared
p < .0001) and CR rate (13.1% vs. 2.4%) and VGPR (16.9% with weekly dexamethasone 40 mg (low-dose dexamethasone arm;
vs. 1.7%). After a median follow-up of 44 months, PFS and OS 60%); however, the high-dose dexamethasone arm was associated
were similar between the groups. CTD was associated with higher with a higher incidence of infections and venous thromboembolism
rates of thromboembolic events, constipation, infection, and neu- and an inferior 1-year survival rate (87%) compared with the low-
ropathy. This study also illustrated that thalidomide was incapable dose dexamethasone arm (1-year survival rate of 96%). However,
with longer follow-up, there was no survival difference between the
two arms.
In a large, open-label, international randomized clinical trial,
1623 patients who were transplant ineligible were randomly assigned
TABLE MPT Versus MP: Efficacy in Newly Diagnosed Elderly to lenalidomide and dexamethasone (RD) administered as 28-day
86.15 Patients With Myeloma cycles until disease progression occurred (535 patients), to the same
b
c
a
• Three trials (IFM99 , IFM01 , HOVON ) >RR, PFS, and OS combination of RD for 72 weeks (18 cycles; 541 patients), or to MPT
• Two trials (GIMEMA , Turkish ) >RR, PFS for 72 weeks (547 patients). The median PFS rates were 25.5 months
d
e
• One trial (Nordic ) >RR with continuous RD, 20.7 months with 18 cycles of RD, and 21.2
f
RR 64% vs. 37% (>27%) months with MPT (hazard ratios for the risk of progression or death
0.724 for continuous RD vs. MPT and 0.704 for continuous RD vs.
CR 10% vs. 2.5% (>8 %) 18 cycles of RD; p < .001 for both comparisons). OS rates at 4 years
PFS 20.3 vs. 14.9 mo (6 mo) HR, 0.67 were 59% with continuous RD, 56% with 18 cycles of RD, and 51%
OS 39.3 vs. 32.7 mo (>6 mo) HR, 0.82 with MPT.
A retrospective case-control study done at a single institution by re-
• Thal maintenance in Italian, Nordic , HOVON c searchers who compared lenalidomide-dexamethasone with thalidomide-
f
a Facon T, Mary JY, Hulin C, et al: Lancet 370:1209, 2007. dexamethasone revealed that lenalidomide-dexamethasone was better
b Hulin C, Facon T, Rodon P, et al: J Clin Oncol 27:3664, 2009. tolerated, with a higher ORR (80% vs. 61%), higher VGPR (34% vs.
c Wijermans P, Schaafsma M, Termorshuizen F, et al: J Clin Oncol 28:3160,
2010. 12%), improved PFS (27 months vs. 17 months), and improved OS.
d Palumbo A, Bringhen S, Liberati AM, et al: Blood 112:3107, 2008. Addition of clarithromycin to lenalidomide and low-dose dexametha-
e Beksac M, Haznedar R, Firatli-Tuglular T, et al: Eur J Haematol 86:16, 2011. sone resulted in an ORR of 90%, a VGPR rate of 74%, and a CR for
f Waage A, Gimsing P, Fayers P, et al: Blood 116:1405, 2010; Waage A, 39% of patients.
Palumbo AP, Fayers P, et al: J Clin Oncol 28:15S [abstract 8130], 2010;
Kapoor P, Kumar S, Mandrekar SJ, et al: Leukemia 25:1195, 2011. Thus the combination of lenalidomide and dexamethasone is an
CR, Complete response; HR, hazard ratio; IFM, Intergroupe Francophone du excellent induction regimen as first-line therapy for newly diagnosed
Myélome; MP, melphalan-prednisone; MPT, melphalan-prednisolone- patients with MM. Results with lenalidomide combinations in
thalidomide; OS, overall survival; PFS, progression-free survival; RR, relapsed/ relapsed and newly diagnosed patients are summarized in Tables
refractory.
86.16 and 86.17. Lenalidomide has also been combined with MP
TABLE Lenalidomide Regimens in Relapsed/Refractory Multiple Myeloma
86.16
Trial Regimen/Dose Number of Patients ORR (%) Median TTP (Mo) Median OS
Weber Len + Dex 177 61 11.1 30 mo
Dex 176 20 4.7 20 mo
Dimpopoulos Len + Dex 176 60 11.3 NR
Dex 175 24 4.7 21 mo
Richardson Len 30 mg once daily 67 18 7.7 28 mo
Len 15 mg twice daily 35 14 3.9 27 mo
Richardson VRD 36 61 7.7 37 mo
Knop RAD 69 73 6.2 88% at 1 yr
Morgan CRD 21 65 5.6 Approximately 80% at 1 yr
CRD, Lenalidomide-cyclophosphamide-dexamethasone; Dex, dexamethasone; Len, lenalidomide; NR, no response; ORR, Overall response rate; OS, overall survival;
RAD, lenalidomide-adriamycin-dexamethasone; TTP, time to progression; VRD, bortezomib-lenalidomide-dexamethasone.