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lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival 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 6 and ≤6 months. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses . Novel therapeutics approved during the last decade for relapsed or refractory multiple myeloma (RRMM), including proteasome inhibitors (PIs) and immunomodulatory drugs (IMi Ds), are now standard of care treatments.31 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 factors (comorbidities, frailty, preferences), disease factors (burden, molecular risk), and treatment factors (prior therapies, refractoriness, and toxicity).

Daratumumab is a human monoclonal antibody targeting CD38, a cell surface receptor highly expressed on multiple myeloma (MM) cells,65 that exerts its effects via direct on-tumor and immunomodulatory mechanisms of action.117 Daratumumab is approved in many countries as monotherapy for patients with heavily treated RRMM.1312 In combination with standard of care regimens, including bortezomib/dexamethasone (Vd; CASTOR study)14 and lenalidomide/dexamethasone (Rd; POLLUX study),15 daratumumab significantly prolonged progression-free survival (PFS) and deepened responses in patients with RRMM. This led to regulatory approval in many countries for patients with ≥1 prior line of therapy.1716In the prespecified interim analysis of POLLUX, after a median follow up of 13.5 months, daratumumab in combination with Rd (D-Rd) resulted in a 63% reduction in the risk of disease progression or death, significantly higher overall response rates (ORRs; 92.9% vs. 76.4%), and significantly higher minimal residual disease (MRD)-negativity rates at multiple sensitivity thresholds versus Rd.15To 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 IMi D 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. POLLUX is an ongoing randomized, open-label, multicenter, phase 3 study conducted in patients with RRMM (identifier: 02076009).

An independent ethics committee or institutional 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) criteria1918 during 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. 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.

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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 (6 months, and ≤6 months prior to randomization), and cytogenetic risk. Numbers of prior lines of therapy 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 cutoff) defined a patient as high risk. Standard-risk cytogenetic status was assigned to those not meeting the high-risk criteria.   PFS, ORR, and MRD negativity at sensitivity thresholds of 10 and 10 were assessed for each subgroup.  

PFS based on MRD and cytogenetic risk status was also examined. Health-related quality of life (HRQo L) was assessed using the Euro Qol 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).

MRD was assessed (blinded to treatment group) at the time of suspected CR (i.e., CR/stringent CR or VGPR with suspected interference2120), 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 compared using the likelihood-ratio test. Additional details on assessments for safety, MRD, cytogenetic risk, and HRQo L and statistical analyses are provided in the Appendix.

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Of 569 enrolled patients in POLLUX, 286 were assigned to D-Rd and 283 to Rd (Appendix Figure 1). Baseline patient demographics and prior treatment history were generally balanced and have been previously reported.15 Additional baseline clinical and cytogenetic characteristics are summarized in Table 1. The median (range) duration of study treatment was 24.5 (0-32.7) months in the D-Rd group and 16.0 (0.20-32.2) months in the Rd group. At the clinical cut-off on March 7, 2017, the median (range) duration of follow up was 25.4 (0-32.7) months. Consistent with the primary analysis, D-Rd improved PFS compared with Rd (median not reached [NR] vs. 17.5 months; hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.31-0.53; P(A) PFS in the ITT population and (B) a forest plot summary of PFS HRs in subgroups by prior lines, prior therapies, treatment-free intervals. Kaplan-Meier analysis of PFS among patients in the ITT population.

Standard-risk patients had an absence of high-risk abnormalities. PFS: progression-free survival; ITT: intent-to-treat; HR: hazard ratio; D-Rd: daratumumab/lenalidomide/dex amethasone; Rd: lenalidomide/dexamethasone; CI: confidence interval; NR: not reached; TFI: treatment-free interval; std: standard.