Page 165 - 2018_12-Haematologica-web

Subgroup analyses of D-Rd vs. Rd in POLLUX
lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P<0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs. 10.2 months; hazard ratio, 0.53; 95% confi- dence interval, 0.25-1.13; P=0.0921) and patients with treatment-free intervals of >12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free sur- vival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identi- fier: 02076009.
Introduction
Novel therapeutics approved during the last decade for relapsed or refractory multiple myeloma (RRMM), includ- ing proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), are now standard of care treatments.1-3 However, patients eventually relapse and subpopulations such as those with high-risk cytogenetic abnormalities may not achieve the same benefits as standard-risk patients.4 Treatment choices must be based on patient fac- tors (comorbidities, frailty, preferences), disease factors (burden, molecular risk), and treatment factors (prior ther- apies, refractoriness, and toxicity).
Daratumumab is a human monoclonal antibody target- ing CD38, a cell surface receptor highly expressed on mul- tiple myeloma (MM) cells,5,6 that exerts its effects via direct on-tumor and immunomodulatory mechanisms of action.7-11 Daratumumab is approved in many countries as monotherapy for patients with heavily treated RRMM.12,13 In combination with standard of care regimens, including bortezomib/dexamethasone (Vd; CASTOR study)14 and lenalidomide/dexamethasone (Rd; POLLUX study),15 dara- tumumab significantly prolonged progression-free sur- vival (PFS) and deepened responses in patients with RRMM. This led to regulatory approval in many countries for patients with ≥1 prior line of therapy.16
In the prespecified interim analysis of POLLUX, after a median follow up of 13.5 months, daratumumab in com- bination with Rd (D-Rd) resulted in a 63% reduction in the risk of disease progression or death, significantly high- er overall response rates (ORRs; 92.9% vs. 76.4%), and significantly higher minimal residual disease (MRD)-nega- tivity rates at multiple sensitivity thresholds versus Rd.15
To identify patients who may benefit more from D-Rd treatment, we conducted subgroup analyses of POLLUX after a longer follow up of 25.4 months. The efficacy of D-Rd versus Rd was compared according to the number of prior lines of therapy received, prior IMiD exposure, bortezomib refractoriness, treatment-free interval after previous treatment line, and cytogenetic risk. We also assessed the ability of daratumumab to drive deep clinical responses beyond complete responses (CRs) through assessment of MRD.
Methods
Study Design
POLLUX is an ongoing randomized, open-label, multicenter, phase 3 study conducted in patients with RRMM (clinicaltrials.gov identifier: 02076009). An independent ethics committee or institu- tional review board at each site approved the trial. The study pro-
tocol was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study design and primary results have been previously published.15 Briefly, eligible patients had progressive disease according to International Myeloma Working Group (IMWG) criteria18,19 dur- ing or after their last regimen and had received and responded to ≥1 line of prior therapy; lenalidomide-refractory patients were ineligible. Patients were randomized 1:1 to Rd (lenalidomide: 25 mg orally on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg orally weekly) with or without daratumumab (16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks) until progression.
Endpoints and Assessments
The primary efficacy endpoint was PFS, and secondary efficacy endpoints included ORR, rates of very good partial response (VGPR) or better and CR or better, MRD, time to response, and overall survival.
This exploratory, post hoc, secondary analysis examined patient populations according to prior lines of therapy received (1, 2-3, 1-3), prior treatment exposure (bortezomib, lenalidomide, and thalidomide), refractoriness to bortezomib, time since last therapy (>12 months, ≤12 months, >6 months, and ≤6 months prior to ran- domization), and cytogenetic risk. Numbers of prior lines of ther- apy were determined by investigators according to the IMWG consensus guidelines.19 Treatment-free interval was defined as the duration between the end date of the last line of prior therapy and randomization. Cytogenetic abnormalities were determined with CD138+ selected cells at the screening visit prior to randomization by centralized next-generation sequencing. The presence of 1 or more of t(4;14), t(14;16), or del17p (utilizing >50% deletion cut- off) defined a patient as high risk. Standard-risk cytogenetic status was assigned to those not meeting the high-risk criteria. Due to limitations with sample quality or quantity, and because cytoge- netic evaluation was mandated mid-study, cytogenetic risk was not evaluated in all patients. PFS, ORR, and MRD negativity at sensitivity thresholds of 10–5 and 10–6 were assessed for each sub- group. PFS based on MRD and cytogenetic risk status was also examined. Health-related quality of life (HRQoL) was assessed using the EuroQol 5-Dimension Questionnaire (EQ-5D-5L) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30).
Minimal Residual Disease
MRD was assessed (blinded to treatment group) at the time of suspected CR (i.e., CR/stringent CR or VGPR with suspected interference20,21), and at 3 and 6 months after suspected CR for patients who maintained this response. The MRD-negativity rate per treatment arm was determined as the proportion of patients with negative MRD at any time point after the first dose and com- pared using the likelihood-ratio test.
haematologica | 2018; 103(12)
2089