A Randomized Comparison of Low-Dose Cyclophosphamide + G-CSF Versus G-CSF Alone Mobilization after Lenalidomide-Bortezomib-Dexamethasone (RVD) Induction in Multiple Myeloma
Authors: Silvennoinen Raija , Lundan Tuija , Anttila Pekka , Heiskanen Jouni , Säily Marjaana , Siitonen Timo , Kakko Sakari , Ollikainen Hanna , Vanhatalo Seppo , Putkonen Mervi , Terävä Venla , Kutila Anu , Partio Mari , Launonen Kirsi , Räsänen Anu , Sikiö Anu , Suominen Merja , Bazia Piotr , Kananen Kristiina , Kuittinen Taru , Porkka Kimmo , Remes Kari , Jantunen Esa 
Published: October 2019

Abstract

Introduction
Autologous stem cell transplantation (ASCT) is the standard treatment in multiple myeloma (MM) for eligible patients below 70 years of age. The main mobilization treatment in Europe consists of combination of cyclophosphamide (CY) and G-CSF. It is questionable if CY is useful in mobilization. CY as an alkylating agent might also have some negative long-term effects. Bortezomib seems not to have negative impact on autologous stem cell harvesting, but prolonged use of lenalidomide might hamper mobilization. There are only a few studies regarding autologous stem cell mobilization after RVD induction. We designed this randomized study as a substudy of the Finnish Myeloma Group Study (NCT01790737) to compare the results of CY+G-CSF versus G-CSF mobilization in autologous stem cell harvesting. The primary endpoint is the percentage of patients reaching ≥ 3 x 106/kg CD34+ cells (or ≥ 6 x 106/kg for two transplants), with ≤ 2 apheresis after low-dose CY+G-CSF vs. G-CSF mobilization. Secondary endpoints are need for plerixafor, graft cellular composition and engraftment after ASCT.
Patients and methods
This phase 2 study will include 80 patients below 70 years of age with symptomatic MM and eligible for ASCT. At registration the patients are randomized equally to arm A) CY 2 g/m2 + G-CSF 5 μg/kg or arm B) G-CSF 10 μg/kg. Before mobilization three RVD induction cycles are given. Each 3-week RVD cycle includes lenalidomide 25 mg daily on days 1−14, bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, and dexamethasone 160 mg/cycle. By this schedule the first harvest is estimated to be on day +10 in CY + G-CSF and on day +5 in G-CSF group. Apheresis will start with blood CD34+ level >10 x 106/l. The target cell yields for one and two grafts are ≥ 3 and ≥ 6 x 106 CD34+ cells/kg, respectively, and the minimum for one graft ≥ 2 x 106/kg. Plerixafor is given if B-CD34+ cell count is less than 10 x 106/l on days +10 or +5, respectively, or if the first apheresis product contains < 1 x 106/kg CD34+ cells. G-CSF support is used after ASCT if the number of CD34+ cells in the graft is less than 3 x 106/kg. Engraftment will be assessed by blood neutrophil count > 0.5 x 109/l, and unsupported platelets > 20 x 109/l.
Results
Fifty-six patients have been included, and the mobilization data for the first 37 patients are available for analysis. The primary endpoint was reached in 90% of the patients (18/20) in arm A and in 82% (14/17) in arm B (p=NS). The median number of apheresis to reach the goal in arms A and B is one (1-3) and two (1−3), respectively (p=0.03). The median number of harvested cells in the two arms is 6.2 (2.2−12.1) and 4.8 (2.9−7.6) x 106/kg, respectively (p<0.01). All patients achieved the minimum collection target of ≥ 2 x 106/kg CD34+ cells in both arms, and the target yield of ≥ 3 x 106/kg was reached in 95% (19/20) in arm A and in 94% (16/17) in arm B. Plerixafor was used in two (12%) patients in arm B. The median blood CD34+ cell count on the first apheresis day was 55.9 (13.0−118.6) and 35 (16.0−148.5) x 106/l for arms A and B, respectively (p=0.44). The median time from mobilization day 1 to the first apheresis day was 10 (10−13) days in arm A and 5 (5−6) in arm B.
The median number of CD34+ cells transplanted, was 4.1 (2.2−7.3) and 3.2 (2.3−4.7) x 106/kg in arms A and B, respectively (p=0.01). In arm A the median neutrophil engraftment was on day +14 (9−28) (16 patients) and in arm B on day +15 (11−25) (15 patients) (p=0.68). The median platelet engraftment days were +13 (8−22) and +11 (8−21) in arms A and B, respectively (p=0.67). At ASCT the response rates in arm A were ≥ VGPR 65% (13/20), PR 25% (5/20), and 10% (2/20) were progressing, and the respective rates for arm B were 70% (12/17), 18% (3/17),and 12 % (2/17).
Conclusions
Preliminary results of this randomized mobilization substudy with a limited number of patients show no clinically significant differences between the number of harvested CD34+ autologous stem cells. However, in CY+G-CSF group the CD34+ cell target was reached by less aphereses. After short induction course of RVD it seems possible to harvest also for two autografts with G-CSF only mobilization. However, when compared to historical data the CD34+ cell counts in blood and grafts were lower than after bortezomib + dexamethasone induction, and also neutrophil engraftment seemed to be slower after lenalidomide-based induction therapy. We conclude that CY can be omitted in the mobilization regimen for MM patients who have responded to short course of RVD.

Disclosures
Silvennoinen: Janssen-Cilag: Research Funding; Celgene: Research Funding; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding.