Declining Rates of Adverse Events and Dose Modifications with Lenalidomide in Combination with Dexamethasone

Abstract

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., NEJM2007, 357:21 and Dimopoulos et. al., NEJM2007, 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 Figure Month AE Group 1–3 4–6 7–9 10–12 13–15 16–18 19–21 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

Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement

“…69 Importantly, the risk of adverse events, including neutropenia, thrombocytopenia and venous thromboembolism (VTE), appears to be highest during the initial cycles of Len/Dex therapy and decreases dramatically thereafter. 70 Clinicians should therefore be particularly vigilant during the initial cycles of Len/Dex in order to prevent or manage any potential adverse events that may arise, so that treatment can continue. It should also be noted that dose adjustments rather than dose discontinuation can often be used to manage adverse events, and thereby ensure that patients are able to receive the benefits of continuous therapy as discussed earlier.…”

“…Grade 3 or higher thrombocytopenia was observed in 13% of patients, 23 but the risk of thrombocytopenia decreased as treatment continued. 12,70 General guidelines are available on the management of neutropenia and thrombocytopenia during treatment with Len/Dex. 19,20 For severe neutropenia (ANC o500 per ml), the panel recommended the suspending lenalidomide therapy and adding G-CSF support to help boost the neutrophil count (Figure 2).…”

A review of the history, properties, and use of the immunomodulatory compound lenalidomide

“…41,42 Furthermore, adverse events mostly occur during early treatment cycles, with the rate decreasing as treatment continues; there is no evidence of cumulative toxicity. 43 The unique adverse events of tumor flare reactions (grade 3/4, 0-8%) and tumor lysis syndrome (any grade, 0-4.4%) have arisen during clinical studies in patients with CLL. [28][29][30] However, careful monitoring and appropriate management can help ensure that patients with CLL achieve maximum therapeutic benefit from lenalidomide therapy.…”

Use of lenalidomide in the management of relapsed or refractory multiple myeloma: expert recommendations in Korea

“…Similarly, the rates of VTE in patients undergoing thromboprophylaxis with aspirin were 0.9% (95% CI, 0.5-1.5) and 0.6% (95% CI, 0.01-2.1), respectively [ 47 ]. The incidence of VTE is highest in the first few months after initiation of lenalidomide/dexamethasone, followed by a reduced incidence [ 48 ].…”

“…Neutropenia and thrombocytopenia are clinically significant and usually occur during the initial lenalidomide/dexamethasone cycles, with a decreasing frequency thereafter [ 48 ]. They are generally predictable and manageable [ 60 ].…”