Managing neutropenia by pegfilgrastim in patients affected by relapsed/refractory multiple myeloma treated with bendamustine-bortezomib-dexamethasone

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From December 2012 to February 2016, 47 patients have been considered (25 male and 22 female) with a median age of 61.3 years (range 37–83) affected by relapsed and refractory MM, treated with several lines of treatments (median 6, r. 2–11), and refractory to the drugs previously received, who were treated with monthly courses of BVD (bendamustine 90 mg/sqm i.v. days 1 and 2; bortezomib 1 mg/sqm s.c. days 1, 4, 8, and 11; and dexamethasone 20 mg per os days 1, 2, 4, 5, 8, 9, 11, and 12, until progression). All treatments were performed in our outpatient unit. Twenty-four consecutive patients received pegfilgrastim (6 mg) subcutaneously with a single administration on day +4, as primary prophlyaxis, and they were compared to a historical group of twenty-three consecutive patients in which filgrastim (5 μg/kg/day for at least 3 days) had been given, as primary prophylaxis “on demand,” if neutrophils count was <1000 × 10 cells/L. All patients performed blood counts twice weekly and received, from day +8 to day +19, considering “day +1” the day in which the chemotherapy protocol starts, prophylactic oral quinolones and anti-fungal drugs. In filgrastim group, twenty-three consecutive patients, previously treated with several lines of treatments (median 6, r. 3–11) with a median age of 60.7 years (r. 37–78) have been considered. Nadir neutropenia was registered after a median of 9.1 days (r.8–15), with maximum duration of 13 days (median 9.4 days, r. 7–13); median of nadir neutrophil count was 1.15 × 10 cells/L (range 0.3–1.5 × 10 cells/L). Median number of filgrastim administrations was 4.2 (r. 3–6). Patients have been evaluated after at least three courses of therapy (r. 3–6). Filgrastim was well tolerated in all patients; main side effects were mild fever and bone pain (6/23, 26 %), treated successfully with paracetamol. Three hospitalizations for pneumonia were needed during filgrastim (median days of hospitalization 15, range 8–19); the patients received intravenous antibiotic treatment with resolution of infectious episodes. Four patients (4/23, 17.3 %) disrupted chemotherapy schedules because of neutropenia. In pegfilgrastim group, twenty-four consecutive patients, previously treated with several lines of treatments (median 6, r. 2–10) with a median age of 62.1 years (r. 43–83) have been considered. Nadir neutropenia, registered at day +11, was 1.484 × 10 cells/L (range 1.04–2.33 × 10 cells/L). During pegfilgrastim, neutropenia, when present, was shorter than during filgrastim treatment, never longer than 8 days (median 5.9 days, r. 4–8), with a consequent reduction of neutropenia-related infections. Only four patients (16.6 %) needed, after pegfilgrastim, a supplement of three administrations of filgrastim. Patients have been evaluated after at least three courses of therapy (r. 3–6). Apart from the advantage of mono-administration, pegfilgrastim was well tolerated in all patients; main side effects were mild fever and bone pain (3/24, 12.5 %), treated successfully with paracetamol. Moreover, no hospitalization was needed during pegfilgrastim. Only two patients (2/24, 8.3 %) disrupted chemotherapy schedules because of neutropenia. In Italy, the cost of filgrastim 30-MU vial is 95.18–127.95 euro (depending from producer), while the cost of pegfilgrastim 6 mg is 1.489.50 euro. However, this cost has to be considered together with that of hospitalizations, antibiotic usage, and disruptions of scheduled chemotherapy treatments. Thus, pegfilgrastim was significantly associated with fewer incidence rate of FN-related chemotherapy disruptions (17.3 % in filgrastim group vs. 8.3 % in pegfilgrastim group, p = 0.3534 by χ2 test), fewer days of hospitalization due to FN (median number 15 days in filgrastim group vs. 0 in the pegfilgrastim group), and fewer G-CSF-related extra-hematological side effects (26 % in filgrastim group vs. 12.5 % in pegfilgrastim group, p = 0.2987 by χ2 test), with consequent improvement of quality of life. However, statistical comparison of the two groups (by χ2 test) was not properly feasible because of the very small sample size. In conclusions, in patients affected by relapsed and refractory MM, treated with bendamustine-bortezomib-dexamethasone, primary prophylaxis with pegfilgrastim seems to reduce the incidence of chemotherapy disruptions due to FN, and the days of hospitalization. Moreover, it is better tolerated and may increase the opportunity to maintain the planned schedule of treatment. These results make pegfilgrastim and advantageous option in most cases, both in terms of cost-effectiveness and of quality of life. These preliminary observations need to be validated by controlled clinical trials, involving a larger number of patients.

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