Combinative Regimens For The Treatment Of Relapsed Or Refractory Multiple Myeloma And Waldenstr?m Macroglobulinemia: Evaluations Based On Meta-analysis

Part 1 Monoclonal antibodies versus histone deacetylase inhibitors in combination with bortezomib or lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: an indirect-comparison meta-analysis of randomized controlled trialsObjective: Agents with novel mechanisms of action,such as monoclonal antibodies(MAb)and histone deacetylase inhibitors(HDACis)have been applied to treat relapsed or refractory multiple myeloma(RRMM).However,the treatment outcomes of MAb versus HDACi in combination with bortezomib or lenalidomide plus dexamethasone remain unknown.We conducted this meta-analysis to compare indirectly the efficacy and safety of MAbs and HDACis in combination with bortezomib or lenalidomide plus dexamethasone.Methods: We searched for relevant studies in the database of Pubmed,Embase(OVID),The Cochrane Library and Web of Science.By performing an indirect comparison meta-analysis between two subgroups of MAb and HDACis,we synthesized hazard ratios(HRs)for progression-free survival(PFS)and overall survival(OS)to compare the survival outcomes.While synthesized relative risks(RR)for complete response(CR),very good partial response(VGPR),overall response(OR),progressive disease plus stable disease(PD+SD)and common at least grade 3 adverse events were utilized to compare the treatment response status and adverse events incidence.Results: Six trials(eight articles)were included with 3270 RRMM patients enrolled.The indirect-comparison results indicated that MAb group might improve PFS when compared wtih HDACi group,yielding pooled HR 0.83(95%CI 0.66-0.98),which represented a 17% lower risk of progression or death in the MAb group than in the HDACi group.After removing all the trials about elotuzumab,the indirect-comparison results showed that daratumumab group might significantly improve PFS in comparison with HDACi group,yielding pooled HR 0.55(95%CI 0.40-0.74),which suggested that daratumumab group dramatically reduced the risk of disease progression or death by 45% compared with HDACi group.In terms of OS,the indirect-comparison results indicated that elotuzumab group did not gain an advantage over HDACi group on OS,generating pooled HR of 0.87(95%CI 0.65-1.15).When talked about the response rate,the indirect-comparison of MAb group versus HDACi group generated pooled RR 1.04(95%CI 0.91-1.18)for OR,0.83(95%CI 0.44-1.57)for VGPR,0.85(95%CI 0.23-3.12)for CR and 0.80(95%CI 0.65-0.94)for PD plus SD.As for adverse effect,there were fewer incidences of at least grade 3 neutropenia(RR 0.70,95%CI 0.51-0.96),thrombocytopenia(RR 0.35,95%CI 0.23-0.53)in the MAb group than in the HDACi group when combined with bortezomib or lenalidomide plus dexamethasone,while equivalent frequencies of at least grade 3 anemia(RR 0.79,95%CI 0.59-1.07)were observed between the two groups.Fewer incidences of at least grade 3 sense of fatigue were found in the MAb group than in the HDACi group,giving RR 0.37(95%CI0.17-0.82).There existed no significant difference in the incidence of other common grade 3 or 4 adverse events such as nausea or vomiting,peripheral neuropathy,pyrexia,constipation,diarrhea and upper respiratory tract infection between the MAb group and the HDACi group.Conclusions: Our meta-analysis indicates that among patients with RRMM,MAb in combination with bortezomib or lenalidomide plus dexamethasone is associated with significant longer PFS,lower incidence of PD+SD and lower incidence of at least grade 3 thrombocytopenia,neutropenia and sense of fatigue as compared with HDACis in combination with bortezomib or lenalidomide plus dexamethasone.In other words,MAb may be superior to HDACis in achieving longer progression-free survival and better tolerated when used in combination therapy with bortezomib or lenalidomide plus dexamethasone.Part2 Rituximab-based combination therapy in patients with Waldenstr?m macroglobulinemia: a systematic review and meta-analysisObjective: To evaluate the efficacy and safety of rituximab-based combination therapy for Waldenstr?m macroglobulinemia(WM),we conducted this meta-analysis by pooling the rate of overall response,major response,complete response and grade 3 or higher hematological adverse events.Materials and methods: We searched for relevant studies in the database of Pubmed,Web of Science,Embase and The Cochrane Library.Qualitative assessment for all the included articles was conducted by reference to the Newcastle-Ottawa scale.A random-effect model was selected to perform all pooled analyses.Results: We identified altogether 22 studies with a total of 806 symptomatic WM patients enrolled.Pooled analysis indicated that rituximab-based combination therapy achieved overall response rate(ORR)of 84%(95%CI 81%-87%),major response rate(MRR)of 71%(95%CI 66%-75%)and complete response rate(CRR)of 7%(95%CI 5%-10%).Rituximab plus conventional alkylating agents-containing chemotherapy(subgroup A)yielded ORR of 86%(95%CI 81%-89%),MRR of 74%(95%CI 69%-79%)and CRR of 8%(95%CI 4%-14%).Rituximab plus purine analogue(subgroup B)resulted in ORR of 85%(95%CI 79%-89%),MRR of 74%(95%CI 66%-81%)and CRR of 9%(95%CI 4%-15%).Rituximab plus proteasome inhibitor(subgroup C)resulted in ORR of 86%(95%CI,81%-90%),MRR of 68%(95%CI 58%-77%)and CRR of 7%(95%CI 3%-11%).Rituximab plus immunomodulatory drug(subgroup D)attained relatively lower response rate,with ORR of 67%(95%CI 51%-81%),MRR of 56%(95%CI 27%-83%)and CRR of 5%(95%CI 1%-12%).Common grade 3 or higher hematological adverse events consisted of neutropenia(33%,95%CI 17%-52%),thrombocytopenia(7%,95%CI 3%-11%)and anemia(5%,95%CI 3%-9%).Conclusion: Rituximab in combination with alkylating agent,purine analogue or proteasome inhibitor is highly effective with tolerable hematological toxicities for WM.