INTRODUCTION: Significantly improved response, time to progression and overall survival with lenalidomide plus high dose dexamethasone (Len+Dex) vs Dex alone was demonstrated in two pivotal trials (MM-009/010) (

Weber et. al., NEJM 2007, 357:21
and
Dimopoulos et. al., NEJM 2007, 357:21
). Grade 3 or 4 adverse events (AEs) were reported in 83% of patients receiving Len+Dex and 70% with Dex alone. The risk of AEs was not constant over the course of treatment, however. AE rates in the two groups over time are reported here, along with the percentage of dose modifications (interruptions or reductions) of lenalidomide in response to AEs.

METHODS: Data on patients from the MM-009/010 trials were pooled for these analyses. Monthly hazard rates of grade 3 or 4 neutropenia, thrombocytopenia (TCP) and deep-vein thrombosis (DVT) were calculated as the ratio of events observed to person-time accrued each month. Patients alive at the start of a month were included in that month’s calculation. Patients alive and followed through the month contributed a full month to the denominator; patients whose follow-up ends during the month only contributed the fraction of time followed. Rates were calculated at three-month intervals. Similarly, treatment interruptions and dose modifications were quantified in each cycle (28 days) by counting person-days without medication (i.e., interrupted) on each dose of Len.

RESULTS: Of the 353 patients randomized to Len+Dex, 35% experienced neutropenia, 13% TCP and 8% DVT. With Dex alone (N=351), the corresponding percentages were 5%, 7%, and 4%. The hazard rates were highest during the first three months of treatment, and declined thereafter. For example, with Len+Dex, the rate of grade 3 neutropenia was 38 per 1000 person-months, but dropped to 21 per 1000 person-months during months 10–12. The corresponding rates with Dex alone were 4 and 0 per 1000 person-months. The reduction in rates was more pronounced for grade 3 TCP and DVT: from 25 per person-months during months 1–3 to 3 per 1000 person-months during months 10–12 for TCP with Len+Dex, and from 15 to 0 per 1000 person-months for Dex alone. Grade 4 AEs occurred much less frequently but followed a similar pattern. Treatment interruptions were highest during the in first 4 cycles, with patients off treatment between 5 and 8% of follow-up days in this period, compared to 2 to 5% in the subsequent period. Similarly, dose reductions occurred more frequently during the initial cycles and decreased subsequently.

CONCLUSIONS: Exploring AE rates over time revealed that these events were most likely to occur in the initial cycles of treatment. Hazard rates declined thereafter, possibly due, in part, to observed dose modifications. Similarly, patients more susceptible to AEs may have discontinued from the study earlier. Further analyses linking AEs to dose modifications are underway.

Figure
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Figure

Month
AEGroup1–34–67–910–1213–1516–1819–21
Neutropenia Len-Dex (Grade 3) 0.038 0.035 0.035 0.021 0.025 0.009 0.011 
 Dex (Grade 3) 0.004 0.002 0.003 0.000 0.002 0.000 0.000 
 Len-Dex (Grade 4) 0.008 0.006 0.001 0.000 0.002 0.000 0.000 
 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
Thrombocytopenia Len-Dex (Grade 3) 0.025 0.007 0.003 0.006 0.002 0.000 0.000 
 Dex (Grade 3) 0.015 0.002 0.000 0.000 0.000 0.000 0.000 
 Len-Dex (Grade 4) 0.001 0.002 0.000 0.000 0.000 0.000 0.005 
 Dex (Grade 4) 0.002 0.000 0.000 0.000 0.000 0.000 0.000 
DVT Len-Dex (Grade 3) 0.013 0.011 0.001 0.004 0.000 0.003 0.000 
 Dex (Grade 3) 0.005 0.006 0.001 0.000 0.000 0.000 0.000 
 Len-Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
Month
AEGroup1–34–67–910–1213–1516–1819–21
Neutropenia Len-Dex (Grade 3) 0.038 0.035 0.035 0.021 0.025 0.009 0.011 
 Dex (Grade 3) 0.004 0.002 0.003 0.000 0.002 0.000 0.000 
 Len-Dex (Grade 4) 0.008 0.006 0.001 0.000 0.002 0.000 0.000 
 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
Thrombocytopenia Len-Dex (Grade 3) 0.025 0.007 0.003 0.006 0.002 0.000 0.000 
 Dex (Grade 3) 0.015 0.002 0.000 0.000 0.000 0.000 0.000 
 Len-Dex (Grade 4) 0.001 0.002 0.000 0.000 0.000 0.000 0.005 
 Dex (Grade 4) 0.002 0.000 0.000 0.000 0.000 0.000 0.000 
DVT Len-Dex (Grade 3) 0.013 0.011 0.001 0.004 0.000 0.003 0.000 
 Dex (Grade 3) 0.005 0.006 0.001 0.000 0.000 0.000 0.000 
 Len-Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 
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Topics:
adverse event, dexamethasone, lenalidomide, deep vein thrombosis, neutropenia, drug holiday, follow-up, thrombocytopenia, reaction time

Disclosures: Ishak:Celgene Corporation: Consultancy. Dimopoulos:Celgene Corporation: Honoraria. Weber:Celgene Corporation: Honoraria. Knight:Celgene Corporation: Employment. Shearer:Celgene Corporation: Employment. Caro:Celgene Corporation: Consultancy.

Author notes

Corresponding author

2008, The American Society of Hematology
2008
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