Pooled analysis of the reports of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma

Purpose The purpose of this study was to better understand the efficacy and safety of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma(R/RMM). Methods We retrieved and reviewed published reports including carfilzomib, panobinostat, and elotuzumab combination regimens for patients with R/RMM. Results We identified 20 prospective studies that evaluated 2220 patients. Carfilzomib combination regimens produced an overall response rate (ORR ≥ PR) of 61 % in the 1211 relapsed/refractory patients. At least very good partial response (VGPR) was 29 % in patients with carfilzomib combinations. Finally, 49 % of the 597 patients achieved ORR in patients receiving panobinostat-containing combinations. At least VGPR was 16 % in patients with panobinostat combinations. Three hundred twenty-eight of these 449 patients (73 %) receiving elotuzumab-containing combinations achieved ORR. And at least VGPR was 37 %. And, the vital nonhematologic adverse events (AEs) were cardiac events and pneumonia. Conclusion Carfilzomib, panobinostat, and elotuzumab combination regimens produced clinical benefits in patients with R/RMM.

Abbreviations: R/RMM, Refractory/relapsed multiple myeloma; ORR, Overall response rate; VGPR, Very good partial response rate; CBR, Clinical benefit rate; SDR, Stable disease rate; PDR, Progressive disease rate; CFZ, Carfilzomib; PAN, Panobinostat; ELO, Elotuzumab; DEX, Dexamethasone; BOR, Bortezomib; LEN, Lenalidomide To the editor Relapsed myeloma disease is characterized by increasingly lower remission rate even following salvage therapy [1]. So, there is still an urgent need for new treatments to improve the outcomes of such patients. Carfilzomib (CFZ; a selective proteasome inhibitor), panobinostat (PAN; a pan-deacetylase inhibitor), and elotuzumab (ELO; a fully humanized monoclonal antibody against CS1 with significant anti-myeloma activity) are potent anti-myeloma agents with different mechanisms of action [2][3][4]. We conducted a pooled analysis to determine the efficacy and safety of carfilzomib, panobinostat, and elotuzumab combination regimens in these patients with relapsed/refractory multiple myeloma (R/RMM). The primary outcomes of the analysis were the overall response rate (ORR ≥ PR), at least very good partial response (VGPR), clinical benefit rate (CBR ≥ MR), stable disease rate (SDR), and progressive disease rate (PDR). Statistical analysis method has been shown in Appendix 1.
Sensitivity analyses shown that the combination of panobinostat and melphalan regimen [19] differed much from the others, which contribute most to the heterogeneity. In order to strengthen the reliability of this pooled analysis, we exclude this trial. When excluding this trial, as shown in Fig. 1b, 49 % of the 597 evaluable R/RMM patients treated with panobinostat-containing combination regimens achieved an ORR, at least VGPR was achieved by 16 %, CBR by 66 %, the SDR was 28 %, and the PDR was 17 %. In those 504 response evaluable patients, the ORR of 48 % derived from PBD (PAN/ BOR/DEX) regimen seems to be higher than that of bortezomib (BOR)-containing therapy in a similar population [25]. Furthermore, the addition of panobinostat to bortezomib and dexamethasone could reduce the risk of disease progression by 37 % [20]. As shown in Fig. 1c, four trials enrolling a total of 449 patients evaluated the response rate of elotuzumabcontaining combination regimens for those patients with R/RMM. Three hundred twenty-eight of 449 patients (73 %) achieved ORR. And at least VGPR was 37 %, and CBR was 74 %. In the 422 response evaluable patients, the ORRs of 80 % derived from ERD (ELO/ LEN/DEX) was encouraging, which compared favorably with that of 60 to 61 % reported in the two trials of RD (LEN/DEX) [26,27].
In the pooled analysis, the most common adverse events (AEs) consisted primarily of myelosuppression (Fig. 2). And the vital nonhematologic AEs were cardiac events and pneumonia (Fig. 3). Notably, neuropathy was generally mild and infrequent in most carfilzomib trials. But 1 % of 589 patients with baseline grade 1-2 peripheral neuropathy increased to grade 3 before resolving.
When interpreting our results, there are some limitations that should be considered. The first and major problem is that we used abstracted data. A meta-analysis of individual patient data might more clearly define the treatment benefits of these agents and allow time-toevent analyses of progression-free and overall survival. Secondly, as is often the case with meta-analysis, the effect of heterogeneity needs to be taken into account. Finally, the quality of a meta-analysis is always subject to the quality of included studies. Eighteen of the 20 trials included in this pooled analysis were no-RCTs. And, three of them reported interim analyses, and it is unclear whether these results would change when their final analyses are conducted.
In conclusion, the results presented here show that carfilzomib, panobinostat, and elotuzumab combination regimens produced clinical benefits in patients with R/ RMM and had acceptable safety profile.

Literature search strategy
Medline, Embase, the Cochrane controlled trials register, the Science Citation Index, Conference proceedings from the American Society of Hematology(ASH), the European Hematology association (EHA) and the American Society of Clinical Oncology were searched for prospective trials using the medical subject headings "myeloma," "carfilzomib," "panobinostat," and "elotuzumab." Reference lists from studies selected for this review and from other published systematic reviews and practice guidelines were also hand-searched.

Selection of studies
Studies were eligible for inclusion in the meta-analysis if they met all the following criteria: (1) they were published Fig. 1 Meta-analysis of the response rate of carfilzomib (a), panobinostat (b), and elotuzumab (c) combination regimens in patients with relapsed and refractory multiple myeloma. n number of the enrolled patients, CI 95 % confidence interval, Random random effects model up to February, 2016, and written in English, (2) they dealt only with patients with refractory or relapsed multiple myeloma, (3) study selection included the setting of these trials: carfilzomib, panobinostat, and elotuzumab combinations, and (4) we included studies that provided sufficient information to allow the calculation of response rate. Multiple reports of a single study were considered as one publication, and only the most recent or complete article was examined. All potentially relevant articles were reviewed by two independent investigators (L.D.W and L.P.L).

Statistical analysis
All analyses were conducted using a random effects model, which could give a more conservative evaluation of treatment effect. The heterogeneity of between-study and between-subgroup were tested using the Cochrane χ 2 test. We also undertook subgroup analyses to seek the source of heterogeneity. We used a visual inspection of the funnel plot and trim and fill analyses to evaluate the influence of publication bias on the pooled RR. All meta-analyses were conducted with Stata ver.12.0 software and Review Manager version 5.1. Fig. 2 Meta-analysis of hematologic adverse events (AEs) with variable carfilzomib/panobinostat/elotuzumab-containing combination regimens in patients with multiple myeloma. a ≥Grade 3 hematologic AEs with carfilzomib combination regimens in patients with relapsed and refractory multiple myeloma. b All grades hematologic AEs with carfilzomib combination regimens in patients with relapsed and refractory multiple myeloma. c ≥Grade 3 hematologic AEs with panobinostat combination regimens in patients with relapsed and refractory multiple myeloma. d All grades hematologic AEs panobinostat combination regimens in patients with relapsed and refractory multiple myeloma. e ≥Grade 3 hematologic AEs with elotuzumab combination regimens in patients with relapsed and refractory multiple myeloma. f All grades hematologic AEs with elotuzumab combination regimens in patients with relapsed and refractory multiple myeloma. N number of the included trials, CI 95 % confidence interval, Random random effects model Fig. 3 Meta-analysis of nonhematologic adverse events (AEs) with variable carfilzomib/panobinostat/elotuzumab-containing combination regimens in patients with multiple myeloma. a ≥Grade 3 nonhematologic AEs with carfilzomib combination regimens in patients with relapsed and refractory multiple myeloma. b All grades nonhematologic AEs with carfilzomib combination regimens in patients with relapsed and refractory multiple myeloma. c ≥Grade 3 nonhematologic AEs with panobinostat combination regimens in patients with relapsed and refractory multiple myeloma. d All grades nonhematologic AEs panobinostat combination regimens in patients with relapsed and refractory multiple myeloma. e ≥Grade 3 nonhematologic AEs with elotuzumab combination regimens in patients with relapsed and refractory multiple myeloma. f All grades nonhematologic AEs with elotuzumab combination regimens in patients with relapsed and refractory multiple myeloma. N number of the included trials, CI 95 % confidence interval, Random random effects model