Long Term Disease Control with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: A Real Life Experience
Authors: Conticello Concetta , Parisi Marina , Leotta Salvatore , Parrinello Nunziatina Laura , Martino Enrica , Calafiore Valeria , Pirosa Maria Cristina , Markovic Urosh , Romano Alessandra , Di Raimondo Francesco 
Published: October 2019

Abstract
Background Pomalidomide is a novel immune-modulatory drug approved in Italy in 2015 for double refractory multiple myeloma patients (RRMM), with drug-related neutropenia as major limitation to treatment.
Aim In lack of real-life data, we retrospectively analyzed RRMM patients treated with pomalidomide and dexamethasone (PomaD) either in real life (N=50), or previously enrolled in an interventional (STRATUS, MM-010, N=15) or enrolled in an observational study (MM-015, N=15) to provide further insights on efficacy, safety, tolerability and clinical advantage of G-CSF prophylaxis..
Methods Between July 2013 and July 2017, 75 RRMM (including 23 double refractory MM) patients received pomalidomide 4 mg daily given orally on days 1-21 of each 28-day cycle, and dexamethasone 40 mg weekly (≤75 years) or 20 mg weekly for patients aged >75 years. Median age was 69 years (range 42-80); median number of prior therapies was 4 (range 2-10). In 9 patients a third agent was added to increase the response: cyclophosphamide (50 mg per day for 10 days/cycle) in 2 fit patients or clarithromycin (500 mg bid for 21 days/cycle) in 7 frail patients. Fifty-six patients with leukocytes count ≤ 2.5· 109/L and neutrophils count ≤ 1.5· 109/L before starting treatment, received also prophylactic subcutaneous filgrastim in order to avoid PomaD induced neutropenia. Phagocytic activity of neuthrophils was also investigated before and after PomaD treatment in the entire series.
Results A median number of 8 (range 1-21) PomaD cycles were given, with an overall treatment duration median of 7.7months.
The regimen was well tolerated with grade 3-4 hematological and non-hematological adverse events in 12 (16%) and 39 (52%) patients respectively. The most frequent grade 3-4 non-hematological AEs included fatigue (15, 20%), pneumonia (16, 13%), diarrhea (9, 12%), glucose metabolism alteration (5, 6%), thromboembolism (3, 4%) and diffuse erythema (3, 4%). In patients who developed serious AE, pomalidomide dose reduction (15, 20%) or discontinuation (18, 24%) were applied. We maintained for 6 cycles a median leukocyte count higher than 3.5· 109/L and median neutrophils count higher than> 1.5 · 109/L, with only 6 (11%) patients hospitalized for pneumonia and infectious disease. Pomalidomide was reduced only in 7/56 (12%), due to anemia or thrombocytopenia. The treatment was temporary interrupted in 12/56 patients (21%) for adverse events.
Before treatment, neutrophils had lower phagocytic activity and oxidative burst together with an increased surface expression of neutrophil activation markers CD64. After 4 cycles of PomaD, CD64 was further increased, and phagocytic activity and oxidative burst recovered completely, improving up to levels comparable to those of healthy subjects, both in patients receiving or not G-CSF.
All patients had a response to treatment that was documented within first two cycles.
The overall response rate was 66%, including 37 (49%) cases of at least partial remission. In 18/77 patients with creatinine clearance lower than 50 ml/min the best outcome obtained was minimal response, with a PFS significantly lower than in those patients with creatinine clearance higher than 50 ml/min (p=0.02). After a median follow-up of 12 months, median PFS and OS for patients were 12.7 and 18.9 months, respectively. In 23 patients (30%) a PFS longer than that obtained with the previous treatment was recorded.
Conclusions Our findings indicate that Poma-D is a safe and well-tolerated regimen also in real-life, with acceptable toxicity. Intensification of G-CSF prophylaxis can reduce frequency of serious adverse events and enable full dosage of pomalidomide. In addition, after four PomaD cycles, neutrophil function improved with recovery of phagocytic activity and oxidative burst. Moreover, PomaD induced six months of disease control in most intensively pre-treated patients and some of them achieved longer PFS than that obtained with the previous treatment.

Disclosures
Conticello: Jansen: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding.