TY - CHAP
T1 - Feasibility and efficacy of dose adjusted melphalan-prednisone-bortezomib (MPV) in elderly patients > 75 years of age with newly diagnosed multiple myeloma; The non-randomised phase II HOVON 123 study
AU - S., Zweegman
AU - M.-D., Levin
AU - S.K., Klein
AU - E.G.M., De Waal
AU - C.M., Eeltink
AU - P.F., Ypma
AU - A.C., Dijk
AU - M., Westerman
AU - W., Deenik
AU - B., Tanis
AU - M.S., Slee-Valentijn
AU - M., Minnema
AU - H., Visser-Wisselaar
AU - C., Stege
AU - N.W.C.J., Van De Donk
AU - K., Nasserinejad
PY - 2016
Y1 - 2016
N2 - BACKGROUND There is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients >75 years. Therefore, we investigated the feasibility of a dose-adapted MPV scheme in patients >75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment. METHODS Patients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1, 8, 15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles. RESULTS Of the 96/100 evaluable patients, none were fit (because of age >75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age >80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome. The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients >80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients. Response on protocol was >PR 69%, >VGPR 29% and >CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients. Conclusions Treatment of elderly NDMM patients >75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients. Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.037 4 p=0.014 Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients. FISH analysis of isolated plasma cells will be available in the majority of patients. This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411) and by an unrestricted grant from Janssen-Cilag.
AB - BACKGROUND There is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients >75 years. Therefore, we investigated the feasibility of a dose-adapted MPV scheme in patients >75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment. METHODS Patients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1, 8, 15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles. RESULTS Of the 96/100 evaluable patients, none were fit (because of age >75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age >80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome. The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients >80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients. Response on protocol was >PR 69%, >VGPR 29% and >CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients. Conclusions Treatment of elderly NDMM patients >75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients. Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.037 4 p=0.014 Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients. FISH analysis of isolated plasma cells will be available in the majority of patients. This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411) and by an unrestricted grant from Janssen-Cilag.
KW - feasibility study
KW - multiple myeloma
KW - aged
KW - bortezomib
KW - clinical trial
KW - controlled clinical trial
KW - controlled study
KW - death
KW - diagnosis
KW - drug therapy
KW - drug withdrawal
KW - female
KW - follow up
KW - frailty
KW - functional assessment
KW - genetic marker
KW - geriatric assessment
KW - grip strength
KW - human
KW - major clinical study
KW - male
KW - model
KW - overall survival
KW - prediction
KW - progression free survival
KW - randomized controlled trial
KW - sarcopenia
KW - senescence
KW - toxicity
KW - walking speed
M3 - Chapter
SN - 1528-0020
T3 - Blood
SP - no pagination
BT - Blood
PB - American Society of Hematology
CY - S. Zweegman
ER -