Adding Fludarabine to Cyclophophamide-dexamethason induction therapy impair stem cell harvest in MM: Report from an interim analysis of the NMSG 13/03 randomized placebo controlled phase II trial

BACKGROUND AND OBJECTIVES Recent data have indicated that the myeloma cell hierarchy includes resistant

Recent data have indicated that the myeloma cell hierarchy includes resistant

circulating clonal memory B cells, which differ considerably from the classical end stage plasma cells infiltrating the bone

marrow. The pathophysiological significance of these cells is unknown, but hypothetically they may serve as "sleeping"

myeloma stem cells responsible for and "feeding" post-treatment relapse and disease progression.

The impact of chemotherapy resistant B cells in MM needs to be evaluated by in vivo targeted therapy. A previous open

phase II pilot study has indicated that addition of the DNA repair inhibitor Fludarabine to induction therapy (VAD) was

clinical feasible with only minor toxicity. A beneficial outcome was suggested including a reduction of MRD following the

addition of Fludarabine. Here we report the conclusions from the subsequent phase II randomized, placebo controlled

trial with the main objective to generate data on toxicity, safety and efficacy by adding Fludarabine to the induction with

Cyclophosphamid plus Dexamethason.

DESIGN AND METHODS This was a randomized, placebo controlled, single blinded, phase II study evaluating

This was a randomized, placebo controlled, single blinded, phase II study evaluating

toxicity and safety of Fludarabine added to Cyclophosphamide and Dexamethasone (CyDex) as induction therapy in

younger patients with untreated and treatment demanding newly diagnosed multiple myeloma. The treatment regimen

CyDex as standard induction therapy was documented in NMSG trial #11/01.

Patients were randomized at diagnosis either to CyDex + Placebo (control Arm A) or CyDex + Fludarabine (experimental

Arm B). See Figure 1.

Arm A (Conventional arm): CyDex + placebo, two (three) cycles of CyDex: Cyclophosphamide 1000 mg/m2 IV day 1

and Dexamethasone 40 mg/day PO on day 1 to 4, and 9 to 12 + placebo PO; repeated once day 21.

Arm B (Experimental arm): CyDex plus Fludarabine, two (three) cycles of CyDex: Cyclophosphamide 1000 mg/m2

day 1 IV and Dexamethasone 40 mg/d (or other steroids in equipotent dose) PO on days 1 to 4, and 9 to 12,

combined with Fludarabine 40 mg/m2 PO day 1-3 each cycle; repeated once day 21.

Dosage Adjustments: For patients with creatinine clearance below normal values the dosage of Fludarabine/Placebo

was reduced by 50%. Patients with pre-therapeutic creatinine clearance below 30 ml/min were excluded.

TREATMENT CYCLES DURING INDUCTION All patients in the conventional arm received the scheduled

All patients in the conventional arm received the scheduled

cycles of therapy. However, in the experimental arm this was only the case for 11/17 patients as 6 patients were

stopped before or following the first cycle (Table 1).

TOXICITY AND ADVERSE EVENTS Based on the CTC criteria no difference in severe toxicity was found.

Based on the CTC criteria no difference in severe toxicity was found.

However, analysis of laboratory quantities following the second treatment showed a borderline reduction of

blood lymphocytes from mean 1.12 (SD 0.4) to 0.73 (SD 0.6); p=0.055 and an increased plasma creatinine level

from mean 57.8 (SD 14.2) to mean 124.2 (SD 28.8); p=0.035. All other variables registered were with no difference

including performance score.

RESULTS AND CONCLUSION Fifteen of 17 patients and 12/17 were primed with Cyclophosphamide and

Fifteen of 17 patients and 12/17 were primed with Cyclophosphamide and

rhG-CSF in arm A and B, respectively. Based on an interim toxicity and safety analysis, the trial was stopped

following inclusion of 34 of planned 80 patients due to a reduced number of patients (4/17) actually harvested

in the experimental arm compared to the control arm (11/17; p<0.05).

In conclusion, the scheduled Fludarabine dosage in 2 cycles combined with alkylating therapy impairs stem cell

mobilization and standard therapy in young MM patients and should not be administrated up front