Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma

The combination of pomalidomide and dexamethasone (Pd) represents an important advance in the treatment of relapsed/refractory multiple myeloma, with an overall response rate (ORR) of 32·6% and median progression-free survival (PFS) of 4·6 months (San Miguel et al, 2013; Dimopoulos et al, 2016). The addition of daratumumab to the Pd backbone (DaraPd) represented a further advance for patients with relapsed and refractory multiple myeloma (Chari et al, 2017), with an ORR of 60%, but the optimal treatment of patients with pomalidomide and daratumumab-refractory disease is unknown. Pomalidomide inhibits T-regulatory cells and stimulates proliferation and activity of cytotoxic T and Natural Killer cells (Davies et al, 2001; Gorgun et al, 2010), while daratumumab depletes levels of CD38-expressing myeloid-derived suppressor cells, and T- and B-regulatory cells, thereby stimulating clonal expansion of helper and cytotoxic T cells (Krejcik et al, 2016; Mahaweni et al, 2018). Thus, pomalidomide and daratumumab could potentiate clinical efficacy even when the disease has developed resistance to the cytotoxic activity of the individual agents (van der Veer et al, 2011). We therefore evaluated our experience with DaraPd in patients with pomalidomide and/or daratumumab-refractory disease. Nineteen patients treated with DaraPd between January 2016 and January 2017 were identified, 11 were refractory to either daratumumab or pomalidomide (Dara or Pom-refractory) and 8 were refractory to both daratumumab and pomalidomide (Dara and Pom-refractory) in separate lines of therapy. Refractoriness and responses were defined using International Myeloma Working Group uniform response criteria. Baseline demographic, clinical and cytogenetic characteristics were collected, along with prior regimen details. Statistical analyses were performed as outlined in Data S1. The study was approved by the Institutional Review Board and conducted in accordance with the Declaration of Helsinki. DaraPd was administered according to the approved dosing schedule (Chari et al, 2017). For patients with disease progression on daratumumab monotherapy as their last line of therapy prior to DaraPd, the schedule of daratumumab administration was either kept the same or escalated as outlined below. Pomalidomide was given over a range of 1–4 mg and dexamethasone at 12–40 mg weekly or on days of daratumumab infusion only. Baseline demographic, disease and treatment characteristics are outlined in Tables SI and SII. Eighty-three percent of the patients were lenalidomide refractory, 79·0% bortezomib refractory and 75·0% carfilzomib refractory. Of the 11 patients in the Dara or Pom-refractory cohort, 8 were pomalidomide refractory and 3 were daratumumab refractory. All patients were refractory to daratumumab or pomalidomide in their most recent line of therapy. Median follow-up was 17·3 and 13·8 months for the Dara or Pom- and Dara and Pom-refractory cohorts, respectively. The ORR was 36·8% and clinical benefit rate (CBR; ORR + minimal response [MR]) was 57·9% (Table 1). The ORR and CBR were 54·6% and 63·6% for the Dara or Pom-refractory cohort and 12·5% and 50·0% for the Dara and Pom-refractory cohort. The median duration of clinical benefit (DoCB; time from ≥MR to disease progression) was 5·1 months (range: 0·4–17·3 months; 95% confidence interval [CI]: 0·6–9·6 months) with only one patient maintaining a response at the time of data lock. The DoCB stratified by cohort is shown in Fig 1A. For the 7 patients achieving ≥MR in the Dara or Pom-refractory cohort, 5 had no escalation of the dose or schedule of the agent to which they were refractory, pomalidomide was increased from 2 to 4 mg in one patient and the information was not available in another. Of the 4 patients who achieved an MR or better in the Dara and Pom-refractory cohort, the daratumumab schedule was escalated and pomalidomide dose unchanged in 1 patient, the pomalidomide dose increased and daratumumab dose schedule unchanged in 1 patient, and the daratumumab schedule and pomalidomide dose unchanged in 2 patients. The median PFS was 3·9 months (95% CI: 1·4–7·8 months); 3·9 months for Dara or Pom-refractory disease (95% CI: 0·7–8·1 months), 4·4 months for Dara and Pom-refractory disease (Fig 1B; hazard ratio [HR] 0·94; 95% CI: 0·9–8·5 months; P = 0·899). The median overall survival for all 19 patients was 15·9 months (95% CI: 5·0 months–not reached); 9·0 months for those with Dara or Pom-refractory disease (95% CI 1·0 month–not reached) and not reached for those with Dara and Pom-refractory disease (Fig 1C; HR 3·45; 95% CI 1·8 months–not reached; P = 0·102). Our observations are in line with those reported by Nooka et al (2016). In their hands, the ORR with DaraPd was 36·8% in patients with Dara or Pom-refractory disease and 33·3% for those with Dara and Pom-refractory disease (Nooka et al, 2016). This would support the hypothesis that the DaraPd combination has the potential to overcome resistance to the individual agents, at least in some cases. There are limitations to our analysis that must be acknowledged. First, this is a single institution, retrospective analysis, leaving the potential for significant selection bias. Additionally, we cannot exclude the possibility that some of the responses that we re-captured were influenced by utilization of a higher dose of pomalidomide, re-incorporation of corticosteroids or re-escalation of the daratumumab schedule. Nonetheless, Gavriatopoulou et al (2018) recently reported their experience with lenalidomide or pomalidomide in combination with daratumumab in lenalidomide/pomalidomide and daratumumab-refractory disease. Importantly, they utilized the same immunomodulatory drug to which the disease was refractory, kept the dose the same as it was at the time of documented resistance to the agent and maintained the same daratumumab dose schedule that was used at the time of documented daratumumab resistance. Despite no escalation of the lenalidomide/pomalidomide dose or daratumumab schedule, 4 out of the 6 patients achieved at least a partial response (Gavriatopoulou et al, 2018). These results are in line with our experience and would suggest that the activity of the regimen is largely driven by the synergistic immune-stimulatory properties of daratumumab and pomalidomide. Our observations, and those of others, support the pursuit of prospective studies of DaraPd in patients with Pomalidomide and/or daratumumab -refractory disease. However, given the modest median PFS and DoCB observed to date, further studies into pomalidomide and/or daratumumab resistance are needed to help inform future studies of novel combinations utilizing the DaraPd backbone. MH, SU and PV contributed to the research design and acquisition and interpretation of the data. IH and JA assisted with the acquisition of the data and MR and JS with analysis. MB, SA, RF and MP-R contributed to the acquisition and interpretation of the data. MH and PV wrote the manuscript. All authors were involved in the drafting and critical revision of the manuscript and approved the final submitted product. This work was supported through the Carolinas Myeloma Research Fund. MH, MR, IH, JA, MP-R and JS have no competing interests. MB has received consulting fees from Amgen and research funding from Janssen, MedImmune and Prothena. SA has received consulting fees from Amgen, BMS, Celgene and Takeda. RF has received consulting fees from Amgen and Takeda. SU has received consulting fees from Abbvie, Amgen, BMS, Celgene, EdoPharma, GSK, Janssen, Sanofi, Seattle Genetics, Skyline Dx, Takeda and TeneoBio and research funding from Amgen, Array Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Prothena, Sanofi, Seattle Genetics, Skyline Dx and Takeda. PV has received consulting fees from Amgen, BMS, Celgene, Janssen, Novartis, Oncopeptides, Takeda and TeneoBio. Data S1. Methods. Table SI. Characteristics of the study population at initiation of DaraPd. Table SII. Previous lines of therapies in patients receiving daratumumab, pomalidomide and dexamethasone (DaraPd). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.