A Phase II Multi-Center Study of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RsqVD) in Newly Diagnosed Multiple Myeloma - Ctrial-IE (ICORG) 13-17 Study

Introduction: Lenalidomide, bortezomib and dexamethasone (RVD) is considered a new standard of care regimen for patients with newly diagnosed multiple myeloma. A previous phase I/II study of RVD in front-line myeloma enrolled 66 patients and achieved a partial response rate or better of 100%, overall and a CR/nCR rate of 52% in the phase 2 portion of the study with encouraging tolerability, but high rates of peripheral neuropathy (PN), albeit mainly mild to moderate grade (Richardson et al, Blood 2010). Subcutaneous (SQ) administration of single agent bortezomib has been shown to be non-inferior to IV bortezomib and led to lower rates of PN, a common treatment-related toxicity (Moreau et al, Lancet Oncol 2011). Herein we present preliminary results of the RsqVD Study, a multi-center, open-label single arm phase II trial, incorporating SQ bortezomib with lenalidomide and dexamethasone and including patients who were considered either transplant eligible or ineligible. All patients subsequently received maintenance therapy with lenalidomide until progression, plus the addition of subcutaneous bortezomib twice monthly in high risk patients (ISS stage II or III and/or high risk cytogenetics features, t(4;14, t(14;16) and del17p). The primary endpoint was overall response rate (ORR) after 4 cycles of induction therapy (PR or better). Secondary endpoints include: rate and severity of PN, safety, time to progression, progression-free survival, duration of response and overall survival.

Methods: Planned treatment was 4 cycles of lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m²as SQ injection on days 1, 4, 8 and 11 of a 21-day cycle. Thromboprophylaxis with aspirin 75 mg/day or higher was mandatory and HSV prophylaxis was as per institutional standard. Following 4 cycles, patients were planned to proceed with stem cell mobilization and autologous stem cell transplant (ASCT) or further induction therapy up to a total of 8 cycles. Following completion of ASCT or induction therapy, all patients were scheduled to receive lenalidomide maintenance in 28 - day cycle until progression, unacceptable toxicity or withdrawal of consent. Patients with high-risk features received SQ bortezomib on days 1 and 15 during maintenance phase. Response was investigator-assessed as per IMWG criteria. Sample size (n=42) was determined to provide 80% power to test an acceptable ORR of >70% versus an unacceptable ORR of <50% (1-sided alpha=0.05) including an estimated drop-out rate of 10%.

Results: Between November 2014 and February 2016, 42 patients were enrolled across 8 sites in Ireland. Baseline demographic factors include: 64% males, 36% females; median age of 64 years (45-79 years); 41% ISS stage I, 59% ISS stage II/III. FISH analysis detected t(4;14) in 18% of patients (7/40), t(14;16) in 3% of patients (1/36) and del17p in 10% of patients (4/40). 64% (27/42) patients proceeded to stem cell mobilization and 60% (25/42) to ASCT. The median number of induction cycles completed was 4 (1 to 8 cycles). 40 of a total of 42 patients were considered evaluable for the primary endpoint of ORR. A preliminary analysis of ORR following 4 cycles of induction therapy indicates that 98% (39/40) of patients achieved partial response or better. PN of any grade has been reported by sites in 43% (18/42) of patients to date.

Conclusion: RsqVD is a highly effective regimen in newly diagnosed multiple myeloma producing a very high ORR following initial induction therapy, with a lower overall rate of PN described by sites than expected. Full analyses of response and safety data for induction treatment and follow up will be presented, as well as preliminary evaluation of response to subsequent therapy.