Weekly CyborD-DARA Is a Safe and Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Preliminary Results of the Early Phase 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study

Introduction: Daratumumab (DARA) is a human IgG1k monoclonal antibody licenced for second line use as monotherapy or in combination with either lenalidomide or bortezomib (Bor) plus dexamethasone (D) for patients (pts) who have received at least one prior therapy. There are no published data on front line use of DARA in combination regimens. CyBorD is considered a safe and effective induction regimen for patients with newly diagnosed MM eligible for transplantation. Up to 60% of patients achieve very good partial response (VGPR) or better following 4 cycles of induction (Reeder CB et al, Blood 2010). Since our pre-clinical data showed enhanced antibody dependent cellular phagocytosis (ADCP) following Cyclophosphamide (Cy) exposure (Rigalou et al, ASH 2016), we set out to explore the feasibility of combining DARA with weekly CyBorD in newly diagnosed transplant eligible MM patients. We aim to demonstrate safety, efficacy, convenience and cost-effectiveness in a Phase 1b clinical trial of newly diagnosed patients with MM.

Methods: This ongoing phase Ib, open-label, single arm, dose escalation study has recruited 12 patients from November 2016 to June 2017 across 3 sites in Ireland (3 pts in DL 1, 3 pts in DL 2 and 6 pts in DL 3). Baseline demographic factors include: 75% males, 25% females; median age of 57.5 years (35-66 years); 83% ISS stage I, 17% ISS stage II/III. FISH analysis detected t(4;14) in 0% of pts (0/12), t(14;16) in 0% of pts (0/12) and del17p in 17% of pts (2/12). The study is designed to assess the safety and efficacy of 4 cycles of induction therapy with Cy and Bor on days 1, 8, 15 and 22, D 20/mg/day on days 1, 2, 8, 9, 15, 16, 22 and 23 and DARA 16mg/kg on days 1, 8, 15 and 22 for cycles 1 and 2 and on days 1 and 15 for cycles 3 and 4. Following the induction therapy, patients proceed with stem cell mobilization and high dose Melphalan 200mg/m² autologous stem cell transplant (ASCT). Following SCT 2 cycles of consolidation therapy with Cy and Bor on days 1, 8, 15 and 22, D 20/mg/day on days 1, 2, 8, 9, 15, 16, 22 and 23 and DARA 16mg/kg on days 1 and 15 were administered. After consolidation therapy, all patients are scheduled to receive DARA maintenance on day 1 every 4 weeks until progression, unacceptable toxicity or withdrawal of consent (limited to a maximum duration of 2 years). Patients with high-risk features receive subcutaneous (SQ) Bor on days 1 and 15 during maintenance phase. We used a standard 3+3 design in sequential cohorts (3 dose levels (DL) of Cy and Bor: DL 1: Cy 150mg/m² and Bor 1.3mg/m², DL 2: Cy 300mg/m² and Bor 1.3mg/m² and DL 3: Cy 300mg/m² and Bor 1.5mg/m²; and a DL -1: Cy 100mg/m² and Bor 1.3mg/m². Six additional patients will be enrolled in an expansion cohort as the maximum tolerated dose (MTD) has been determined as DL 3. The primary endpoints are the incidence of dose limiting toxicity (DLT) within the first cycle of combination at each dose level and complete response (CR) rate post ASCT. Secondary endpoints include: safety, CR rates at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Response will be investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810.

Results: We report the safety data from interim analysis following completion of the dose escalation phase of CyBorD-DARA trial. The most common adverse events (AE) of grade 3 severity or higher were thrombocytopenia, postoperative wound infection, urinary tract infection, hyponatraemia, back pain, bone pain. Five serious adverse events (SAE) were reported but none related to the study treatment. No DLT occurred in any group. To date all pts continue on treatment and enrolment is ongoing. Although follow up is still short, the combination shows a promising response rate. Following 4 cycles of induction therapy the first 6 patients enrolled (at DL1 and DL2) have achieved VGPR or better. Safety and efficacy data will be updated at ASH meeting.

Conclusion: DARA can be safely combined with weekly CyBorD. MTD/RP2D is Cy 300mg/m² and Bor 1.5mg/m² in combination with D and DARA and early analysis demonstrates promising efficacy.