Daratumumab, lenalidomide, and dexamethasone in East Asian patients with relapsed or refractory multiple myeloma: subgroup analyses of the phase 3 POLLUX study

In the phase 3 POLLUX study, daratumumab plus lenalidomide and dexamethasone (DRd) significantly reduced the risk of progression/death and induced deeper responses vs. lenalidomide and dexamethasone alone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM). We report a subgroup analysis of East Asian (Japanese, Korean, and Taiwanese) patients from POLLUX based on a longer follow-up of 24.7 months. Median progression-free survival was not reached (NR) for DRd vs. 13.8 months for Rd (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.23–0.76), and overall response rates were higher for DRd vs. Rd (90.2 vs. 72.1%). DRd extended the median duration of response vs. Rd (NR vs. 20.2 months), and minimal residual disease–negative rates at the 10–5 sensitivity threshold were 21.2 vs. 9.1% for DRd vs. Rd. No new safety signals were observed. Similar efficacy and safety were observed in the smaller subgroup of Japanese patients treated with DRd vs. Rd. These results demonstrate favorable efficacy and safety of DRd vs. Rd in East Asian patients and also in the Japanese-only patient subgroup that are consistent with findings in the overall patient population of POLLUX.


Introduction
Daratumumab, a human IgG1κ monoclonal antibody that targets the cell surface protein CD38, demonstrates on-tumor and immunomodulatory mechanisms of action in multiple myeloma (MM) [1][2][3][4][5][6] . Daratumumab exerts its antimyeloma activity via multiple mechanisms, including direct apoptosis induction, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and modulation of the enzymatic activities of CD38 [1][2][3][4]6 . Daratumumab also binds CD38 on immunosuppressive regulatory cells, triggering the expansion and activation of cytotoxic T-cells and elevation in T-cell clonality, which may provide additional antimyeloma effects 5 . Based on the results of single-agent and combination therapy studies, daratumumab was approved as a monotherapy and in combination with standard of care regimens across many countries in patients with relapsed and/or refractory multiple myeloma (RRMM) [7][8][9][10][11][12] . Recently, daratumumab in combination with lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone was approved for treatment of adults with RRMM in Japan 13 .
The POLLUX study compared the efficacy and safety of daratumumab in combination with Rd (DRd) vs. Rd alone in patients with RRMM who received at least one prior line of therapy 9 . The addition of daratumumab to Rd significantly prolonged progression-free survival (PFS; median, not reached (NR) vs. 18.4 months; hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.27-0.52; P < 0.001) and increased the overall response rate (ORR; 92.9 vs. 76.4%; P < 0.001). A novel aspect of the POLLUX study was a prospective analysis of minimal residual disease (MRD) in RRMM patients. At a sensitivity threshold of one tumor cell per 100,000 white cells (10 -5 ), 22.4% of patients treated with DRd were below this threshold compared with 4.6% in the control group, highlighting the very deep responses induced by daratumumab-based treatment 9 . The adverse event profile was clinically manageable and was consistent with those of daratumumab and Rd alone 9 .
The efficacy and safety profiles of targeted anticancer therapies in East Asian patients may differ from those of the overall study populations in clinical trials 14,15 . To understand the impact of DRd vs. Rd in the East Asian patient population, we performed subanalyses of POL-LUX data to evaluate the efficacy and safety of DRd vs. Rd in East Asian (Japanese, Korean, and Taiwanese) patients as well as in only Japanese patients.

Patients
A total of 96 East Asian patients from the phase 3 POLLUX clinical trial (ClinicalTrials.gov identifier: NCT02076009) were included in this analysis. A separate subanalysis of the 36 Japanese patients alone was also conducted. Study design, patient eligibility, treatment schedule, and statistical analyses were previously published 9 . In brief, eligible patients had documented MM, measurable disease at screening, and progressive disease during or after receiving their last regimen, and had received and responded to one or more previous lines of therapy. Measurable disease was defined according to serum or urine M-protein levels or serum-free light chain levels and abnormal serum immunoglobulin-free light chain ratios (kappa:lambda light chains). Progressive disease was defined according to International Myeloma Working Group (IMWG) criteria 16 . Patients with lenalidomide-refractory disease or who had discontinued previous lenalidomide treatment due to adverse events were excluded from the study.

Dosing
Patients were randomized (1:1) to receive 28-day cycles of DRd or Rd alone until disease progression, unacceptable toxicity, withdrawal of consent, or death. Daratumumab was administered at 16 mg/kg intravenously once weekly during Cycles 1 and 2, every 2 weeks during Cycles 3-6, and every 4 weeks thereafter. Patients with creatinine clearance >60 ml/min received 25 mg lenalidomide orally on Days 1-21 of each cycle; patients with creatinine clearance of 30-60 ml/min received 10 mg lenalidomide daily. Dexamethasone was administered at 40 mg weekly. Patients in the DRd group received a split dose of dexamethasone on weeks when daratumumab was administered: 20 mg of dexamethasone before the daratumumab infusion and 20 mg the day after the daratumumab infusion. Patients aged >75 years or with a body mass index <18.5 kg/m 2 received a reduced dose of dexamethasone (20 mg) weekly at the physician's discretion.

Evaluation and statistical analyses
Responses were evaluated based on IMWG criteria 16,17 . The Kaplan-Meier method was used to evaluate PFS, overall survival (OS), and duration of response. A Cox regression model was used to estimate 95% CIs. MRD status was assessed by next-generation sequencing (NGS) using bone marrow obtained from patients who had a suspected complete response (CR) and was measured at three sensitivity thresholds: 10 -4 , 10 -5 , and 10 -6 , corresponding to one tumor cell per 10 4 , 10 5 , and 10 6 white blood cells, respectively. The MRD-negative rate was defined as the proportion of subjects who achieved MRD negativity at any time after their first dose of daratumumab. In our MRD analysis, patients in the intentto-treat population who did not undergo MRD assessment were considered to be MRD-positive. Cytogenetic risk status was assessed by fluorescence in situ hybridization or karyotype testing. Patients were considered high risk if they had at least one of the following cytogenetic abnormalities: del(17p), t(4;14), or t(14;16); patients lacking all three of these abnormalities were considered standard risk.

Patients and treatment
Patients in POLLUX were randomized between June 2014 and July 2015, and the clinical cutoff date for this analysis was 7 March 2017. East Asian patients comprised 16.9% (96/569) of the overall population of patients in POLLUX, with Japanese patients constituting 6.3% (36/ 569) of the POLLUX study population. Fifty-two East Asian (21 Japanese) patients were randomized to the DRd group, and 44 East Asian (15 Japanese) patients were randomized to the Rd group ( Table 1). The median (range) age was 64 (34-85) years for East Asian patients and 68 (45-81) years for Japanese patients. The median (range) time since diagnosis was 3.3 (0.8-27.0) years for East Asian patients and 3.0 (0.9-27.0) years for Japanese patients.
Among East Asian patients, 22 (43.1%) patients in the DRd group and 32 (72.7%) patients in the Rd group discontinued treatment. The most common reasons for discontinuation for DRd vs. Rd were progressive disease

Safety
The most common treatment-emergent adverse events (TEAEs; >20% of patients in any group) are listed in Table  3. Consistent with the overall patient population 9 (Table 3).
The most common grade 3 or 4 TEAEs (>5% of patients in any group) are summarized in Table 4 Among East Asian patients, serious TEAEs were observed in 26 (51.0%) patients in the DRd group vs. 19 (43.2%) patients in the Rd group; among Japanese patients, they were observed in 10 (50.0%) vs. 4 (26.7%), respectively. The most common serious TEAE in the DRd group was pneumonia, which occurred in 7 (13.7%) East Asian patients treated with DRd and 5 (11.4%) treated with Rd, and in 2 (10.0%) Japanese patients treated with DRd and 1 (6.7%) treated with Rd.
TEAEs led to discontinuation of study treatment in 8 (15.7%) East Asian patients and 3 (15.0%) Japanese patients in the DRd group, and in 2 (4.5%) East Asian patients in the Rd group. No Japanese patients in the Rd group discontinued study treatment due to TEAEs. Among patients in the DRd group who discontinued study treatment due to TEAEs, four East Asian patients (including one Japanese patient) discontinued due to TEAEs possibly or probably related to daratumumab; these TEAEs were grade 3 Epstein-Barr virus-associated lymphoproliferative disorder, grade 3 diarrhea, grade 3 pneumonia, and grade 5 multiple organ dysfunction syndrome. Pneumonia was the most common TEAE leading to discontinuation of study treatment and was observed in 3 (5.9%) East Asian patients and 1 (5.0%) Japanese patient in the DRd group and in 1 (2.3%) East Asian patient and none of the Japanese patients in the Rd group.
In East Asian patients, the median (range) duration of infusion was 7.1 (6.0-14.5) h for the first infusion  Infusion-related reactions (IRRs) among daratumumabtreated patients occurred in 25 (49.0%) East Asian patients and 7 (35.0%) Japanese patients. Most occurred during the first infusion and were grade 1 or 2 in severity. Grade 3 IRRs occurred in 6 (11.8%) East Asian patients and 1 (5.0%) Japanese patient, and no grade 4 IRRs were observed. The most common IRR was dyspnea, which occurred in 5 (9.8%) East Asian patients and 2 (10.0%) Japanese patients. No patients discontinued treatment due to IRRs.
In the overall POLLUX population, the rates of second primary malignancies were low and were balanced between the two treatment groups (6% in both treatment groups) 18 . Among patients in the East Asian and Japanese subgroups, second primary malignancies were reported in 3 patients in the DRd group: 1 Korean patient (right flank skin site metastatic adenocarcinoma) and 2 Japanese patients (worsening of Bowen's disease in 1 patient and EBV-positive lymphoproliferative disorder in another   DRd daratumumab/lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone a Patients from Japan, Korea, and Taiwan   Table 4 Most common (>5%) grade 3 or 4 treatmentemergent adverse events in the safety population DRd daratumumab/lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone a Patients from Japan, Korea, and Taiwan total of 7 platelet transfusions). Among Japanese patients, 2 (10.0%) patients in the DRd group received a total of 10 blood transfusions (all were packed red blood cell transfusions), and 2 (13.3%) patients in the Rd group received a total of 8 blood transfusions (2 [13.3%] patients received a total of 6 packed red blood cell transfusions and 1 [6.7%] patient received 2 platelet transfusions).
USA. 11 Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan