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Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

Peter M. Fayers, Antonio Palumbo, Cyrille Hulin, Anders Waage, Pierre Wijermans, Meral Beksaç, Sara Bringhen, Jean-Yves Mary, Peter Gimsing, Fabian Termorshuizen, Rauf Haznedar, Tommaso Caravita, Philippe Moreau, Ingemar Turesson, Pellegrino Musto, Lotfi Benboubker, Martijn Schaafsma, Pieter Sonneveld and Thierry Facon on behalf of the Nordic Myeloma Study Group, Italian Multiple Myeloma Network, Turkish Myeloma Study Group, Hemato-Oncologie voor Volwassenen Nederland, Intergroupe Francophone du Myélome, and European Myeloma Network

Article Figures & Data

Figures

  • Figure 1

    OS: all patients, by treatment. Cox model for treatment, with analysis stratified by study using a random effects (frailty) model: HR = 0.83 (95% CI, 0.73-0.94) in favor of MPT; P = .004. Median survival: MP 32.7 months (95% CI, 30.5-36.6 months); MPT 39.3 months (95% CI, 35.6-44.6 months).

  • Figure 2

    Forest plot: OS HR of MPT versus MP, by study. The HR and 95% CI are shown for each study, and the overall HR (where the dotted line bisects the diamond) and 95% CI (indicated by left and right corners of the diamond), assuming a random effects model. For each treatment arm of each study, the number of events (deaths) and number of patients (E/N) is given. There is evidence of heterogeneity (I2 = 61%) that may jeopardize the P value and CI of the estimated overall effect (0.82).

  • Figure 3

    Forest plot: OS HR of MPT versus MP, for each ISS stage subdivided by study. The 95% CIs are shown. Diamonds represent the HR and 95% CI for each stage and finally for the overall estimate, assuming a fixed effects model. For each treatment arm of each study, the number of events (deaths) and number of patients (E/N) is given.

  • Figure 4

    Forest plot. OS HR of MPT versus MP for ISS (A), DS stage (B), WHO-PS (C), and age (D), creatinine (E), β2-microglobulin (Beta2; F), albumin (G), LDH (H), and hemoglobin (Hb; I). E/N is the ratio of events (deaths) to the number of patients.

  • Figure 5

    PFS: all patients, by treatment. Cox model for treatment, stratified random effects (frailty) model for study: HR = 0.68 (95% CI, 0.61-0.76); P < .0001. Median survival: MP 14.9 months (95% CI, 14.0-16.6 months); MPT 20.3 months (95% CI, 18.8-21.5 months).

  • Figure 6

    Forest plot: PFS HR of MPT versus MP, by study. The HR and 95% CI are shown for each study, and the overall HR (where the dotted line bisects the diamond) and 95% CI (indicated by left and right corners of the diamond), assuming a random effects model. For each treatment arm of each study, the number of events (deaths) and number of patients (E/N) is given. Overall test of HR = 1: P < .0001.

Tables

  • Table 1

    Characteristics of the trials

    CharacteristicGIMEMAHOVONIFM-IIFM-IINMSGTMSG
    Trial labelGIMEMAHOVON49IFM99–06IFM01/01NMSG12TMSG
    CountryItalyThe Netherlands/BelgiumFranceFranceNordicTurkey
    No. of patients331333321229357114
    Inclusion year2002-052002-072000-052002-062002-072006-09
    Age, y> 65> 6565-75> 75> 65> 55
    SD stageII, IIIIb, II, IIIII, III, and I high-riskII, III, and I high-riskI-III symptomaticI-III symptomatic
    WHO status0-40-30-40-40-40-2
    PlaceboNoNoNoYesYesNo
    Melphalan4 mg/m20.25 mg/kg0.25 mg/kg0.20 mg/kg0.25 mg/kg9‖mg/m2
    Prednisonedays 1-4days 1-5days 1-4days 1-4days 1-4days 1-4
    40 mg/m21 mg/kg2 mg/kg2 mg/kg100 mg60 mg/m2
    days 1-7days 1-5days 1-4days 1-4days 1-4days 1-4
    No. of cycles/interval (weeks)6/48/412/612/6Until plateau/68/6
    Thalidomide, mg/day100200100-400*100200-400100
    DurationUntil relapse8 cycles12 cycles12 cyclesUntil relapse8 cycles
    Crossover to MPT from MPNoNoNoNoNo18%
    Second-line thalidomide after relapse, % of MP patients34573845457
    • HOVON indicates Hemato-Oncologie voor Volwassenen Nederland.

    • * Recommended dose was 200 mg/day with rapid increase if well tolerated, up to maximum 400 mg/day.

    • A total of 200 mg/day from plateau until relapse.

    • Second-line thalidomide or bortezomib.

  • Table 2

    Patient characteristics

    CharacteristicGIMEMA (n = 331)HOVON (n = 333)IFM-I (n = 321)IFM-II (n = 229)NMSG (n = 357)TMSG (n = 114)
    Median age, y72.572.669.478.574.470.6
    Sex, %
        Male545654455554
        Female464446554546
    DS stage, %
        DS I00109155
        DS II382626233653
        DS III627464684540
        Not known000042
    ISS, %
        ISS 1192531221618
        ISS 2382434384035
        ISS 3231827283338
        Not known20328121110
    WHO-PS, %
        052362419157
        1244650452343
        2191419282846
        35467234
        4102070
        Not known000041
    Ig heavy chains, %
        IgG646067586268
        IgA253021282115
        IgD000013
        Light only1110101282
        Other002001
        Not known0002811
    Ig light chains, %
        K06265655052
        L03832343141
        Not known100022197
    Median β2-microglobulin, mg/L3.74.03.94.34.25.0
    Median hemoglobin, g/dL10.610.510.510.610.69.8
    Median albumin, g/L36.034.038.038.033.036.0
    Median creatinine, μM70.796.092.590.094.597.3
    Median LDH, U/LNR293.0337.0331.5223.5238.5
    • HOVON indicates Hemato-Oncologie voor Volwassenen Nederland; and NR, not recorded.

  • Table 3

    Best response recorded in first year, by treatment (percentage of patients)

    StudyMPTMPTotal
    No. of patients8158701685
    Best response, %
        VGPR or better25917
        PR342831
        No response234434
        Death 1 year171918
    • Response was unknown for 46 (3%) of patients living at 1 year (27 MPT, 19 MP), and these were assumed to be “no response.” Overall χ2 (3 degrees of freedom): P < .0001.