A Prospective Phase 2 Study to Assess Immunophenotypic Remission after Lenalidomide-Based Induction Followed By ASCT and Lenalidomide Maintenance in Patients with Newly Diagnosed Multiple Myeloma

Introduction

ASCT is the standard treatment in MM for eligible patients < 70 years of age. The median OS has improved from 3-4 to 5-6 years with combination of novel drugs and ASCT. In spite of initial response MM will relapse or progress in the majority of patients in 2-3 years and several consolidation and maintenance treatments are under evaluation. We designed this FMG-MM02 study (NCT01790737) to explore the response of lenalidomide, bortezomib and dexamethasone (RVD) induction, followed by single ASCT and lenalidomide maintenance in newly diagnosed MM patients. The primary endpoint of the study is immunophenotypic remission (IR), and molecular response will be assessed from patients with sCR/IR. The secondary endpoints include safety, improvement of responses during lenalidomide maintenance and PFS.

Patients and methods

69 out of 80 included patients proceeded to mobilization after induction with 3 cycles of RVD. Eleven patients (14%) were dropped out due to early toxicity (n=9) or early progression (n=2). The RVD cycle consisted of lenalidomide 25 mg/d po. on days 1-14, bortezomib 1.3 mg/m² sc. on days 1,4,8 and 11 and dexamethasone 20 mg po. on days 1-2, 4-5, 8-9 and 11-12. Additional nine patients were withdrawn before ASCT due to progression, so actually 60 patients received MEL200+ASCT and lenalidomide maintenance was planned to start three months after ASCT, 10 mg/d on days 1-21 in a 28-day cycle. The multiparameter flow cytometry (MFC) was analyzed from all patients with at least PR response. 53/60 patients have achieved the time-point of three months after ASCT and can be analyzed here. Median follow-up time is 52 (1−115) weeks.

Results

Forty-five gr 3-4 SAEs were documented in 39 patients during induction; most common were infections (pneumonia, bronchitis) and gastrointestinal disorders. The nine patients with early drop out due to toxicities had following adverse events: severe liver toxicity, amaurosis fugax, neutropenia, severe sepsis-syndrome with rash, simultaneous diagnosis of adenocarcinoma pulmonum, history of prostate cancer, two patients not eligible to ASCT due to infections and one patient died of hepatorenal syndrome.

The overall response rate for RVD induction was 86% in intention-to-treat. The primary endpoint, IR, measured by 6-10 color MFC, was achieved at ASCT in 22/69 (32%) of patients who actually received the planned RVD induction and in 22/80 (28%) by intention-to-treat (ITT). The median sensitivity of MFC-MRD-negativity was <0.01% (range 0.0046%−0.069%). In MFC-MRD-positive patients the median MRD load was 0.14% (range 0.003%−3.0%).  At least VGPR was achieved in 36/80 (45%) of patients by ITT and in 36/69 (52%) per protocol treated at ASCT.

Three months post-ASCT 24/53 (45%) of evaluable patients had IR with the median sensitivity of MFC-MRD-negativity <0.006% (range 0.003%−0.03%) and in 43% of patients the median MFC-MRD positivity was 0.08% (range 0.003%−0.9%). 12% of patients can not be assessed yet. So far samples of 10 patients in sCR/IR have been analyzed by ASO RQ-PCR and 7/10 were also PCR-MRD negative with the median sensitivity of <0.0006% (<0.0004%−0.02%).

The achievement of at least VGPR response or IR at ASCT predicts better outcome with estimated PFS of 23.8 months compared to 15.2 months of patients response worse than VGPR (p=0.001) and the respective figures for IR and non-IR are 24.7 and 17.2 months (p=0.016). Patients with t(4;14), t(14;16), n=9, had shorter median PFS (shorter than patients with del 17p), 12.8 months, compared to estimated 20.8 months of other patients (p=0.053).

Conclusion

One third (28%) of patients achieved an IR after RVD induction, which contrasts with only 14% of serological CR/sCR. This discrepancy most probably results from the rather slow kinetics of paraprotein disappearance. Thus, subsequential samples and sufficient follow-up time are mandatory in evaluation of paraprotein responses. The IR was still predicting favorable outcome and only one of these MFC-MRD negative but paraprotein positive patients has so far relapsed. In spite of quite high initial IR rate the patients with high-risk cytogenetics relapse quite soon. RVD regimen seems not to overcome their poor prognosis, and these patients clearly need more individual treatment choices.