Outpatient Stem Cell Mobilization with Low and Intermediate Dose Cyclophosphamide Is a Safe and Effective Procedure in Newly Diagnosed Multiple Myeloma Patients Eligible for Stem Cell Transplantation

Background

Even in the era of new drugs and despite the use of very effective combination regimens, autologous stem cell transplantation (ASCT) remains the gold standard treatment for eligible newly diagnosed multiple myeloma (NDMM) patients (pts) (Attal, NEJM 2017). Pts are usually hospitalized for administration of mobilization chemotherapy (cht) and Cyclophosphamide (CY) at different doses is the most used regimen for collecting peripheral blood stem cells in MM. Clinical trials demonstrated that low (1.5-2 g/m², LD-CY) and intermediate dose CY (3-4 g/m², ID-CY) combined with G-CSF are efficient mobilizing regimens with less toxicity compared with high dose CY (7 g/m², HD-CY) (Fitoussi BMT 2001, Jantunen BMT 2003). On the other hand, hospitalization increases costs and pts discomfort.

Objective

To evaluate the safety of mobilization therapy with LD- and ID-CY administered as outpatient

Methods

We retrospectively reviewed all consecutive patients (n=176) with NDMM undergoing outpatient stem cell mobilization in two centers between 2002 and 2017 with CY 2 (40.3%) or 3-4 g/m2 (59.7%) + G-CSF after induction therapy. Pts characteristics, induction regimens and responses are described in Table 1. Day 0 was defined as the CY infusion day. CY was administered in 2-4 consecutive 1h infusions (depending on total dose). Hyper-hydration, antiemetics and the uroprotectant uromitexan begun IV 1 hour before CY infusion. Subsequently, hyper-hydration and uromitexan were continued IV or orally at home in the next day. G-CSF was started by day +5 and continued until completion of apheresis. Blood count was monitored at day + 4 and daily from day +7. CD34+ cells were counted on peripheral blood by day 7; apheresis was started at leukocyte rise and with a value of at least 20 CD34+/μl. Number of apheresis depended on the number of CD34+ cells collected to obtain at least 3x10⁶ CD34+/Kg. Data about any adverse events (AEs) (type and grade) and/or hospitalization due to AEs were accurately collected.

Results

Median age at diagnosis was 57 y (range 34-68). MM isotype was IgG, IgA, light chain, IgD/IgM/non-secretory respectively in 58.6, 18.2, 20.6 and 2.6%; ISS was 1/2/3 in 58.4/23/18.6%. Bone disease was detectable in 79.9% of pts, with 59.4% having 3 or more osteolysis. Median bone marrow plasma cell was 60%.

Pts received induction with bortezomib (73.4%), IMiDs (5.1%), carfilzomib+IMiDs (12.5%) or cht, mostly VAD (9%). Second line therapy before mobilization was required by 5.1% of pts. Response prior of mobilization was CR/sCR, VGPR, PR, MR/SD/PD respectively in 14, 49.1, 34.5 and 2.4%.

Stem cell collection was successful (at least 3x10⁶/Kg CD34+ cells) in 93.1% of pts, with a median CD34+ cells harvest of 8.7x10⁶/Kg (range 1.8-67.7). Target for 2 ASCT (at least 6x10⁶/Kg CD34+ cells) was reached by 76.3% of pts. Administration of Plerixafor on demand was necessary in 12.1% of pts. After mobilization, 91.3% of pts proceeded to single (52.3%) or double (39%) ASCT.

Cht was very well tolerated with 16.6% of pts having all-grade adverse events (AEs) and only 1.2% grade 3-5 (table 2). Most frequently AEs were nausea and vomiting grade 1-2 (6.8%). 1.7% of pts experienced cystitis (only grade 1-2) and 4% of pts infections (1 pt grade 5 with LD-CY). Other AEs (6.9%) were grade 1-2 and aspecific; only of note a pt presented a sudden appearance of 7^th cranial nerve deficit at the end of ID-CY with negative imaging and resolution in few hours, interpreted as transient ischemic attack not correlated with Cy. Only 5.7% of pts required hospitalization for AEs, mainly infection.

With the limit of retrospective setting, we compared LD and ID-CY with the incidence of AEs overall (14 vs 18%), AEs grade 3-5 (1.5 vs 1%) and hospitalization rate (1.5 vs 8.5%). We evaluated also median harvest (6.6 vs 10.9 x10⁶/Kg CD34+ cells), percentage of pts reaching the target for 1 (87 vs 95%) and 2 (53 vs 89%) ASCT and plerixafor need (21 vs 6%). (Table 3).

Conclusion

In conclusion, outpatient mobilization with L- and ID-CY appears an efficient and safe procedure, with minimal and manageable AEs and low rate of hospitalization. ID respect to LD-CY seems to be associated to a slight increase only in grade 1-2 AEs, however with a better stem cell yield and with a lower need of Plerixafor. Outpatient mobilization could ameliorate quality of life of pts and reduce costs, avoiding or minimizing the hospitalization rate, without compromising the safety profile and the success of PBSC collect.

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