A Comparison of the Efficacy of Immunomodulatory-containing Regimens in Relapsed/Refractory Multiple Myeloma: A Network Meta-analysis

Background

Previous network meta-analyses combined studies of immunomodulatory drug (IMiD)–containing and IMiD-free regimens, despite a lack of head-to-head randomized controlled trials to robustly link them. However, patients with relapsed or refractory multiple myeloma (RRMM) treated with IMiD-containing regimens differ from those treated with IMiD-free regimens, especially relating to treatment history, which is an important treatment-effect modifier requiring clinical consideration when evaluating the most appropriate subsequent treatment options. A need exists to separately assess the efficacy of treatment regimens for patients who are suitable candidates for IMiD-containing and IMiD-free regimens. The presented analyses will enable clinicians to assess the best regimens to use in patients suitable for IMiD-containing regimens.

Efficacy and Safety of Inotuzumab Ozogamicin (CMC-544) for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis

IntroductionThe purpose of this systematic review and meta-analysis was to evaluate the efficacy and safety of inotuzumab ozogamicin (INO) in patients with relapsed/refractory acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL).Materials and MethodsDatabases (PubMed, EMBASE, and Cochrane databases) were searched through April 4, 2020. Outcome measures of efficacy covered complete remission (CR) rates and minimal residual disease response rates. Safety was evaluated by hepatic venous obstructive disease/sinus obstructive syndrome and grade ≥ 3 hematologic adverse events. We also evaluated the quality of enrolled studies by the Newcastle-Ottawa Quality Assessment Scale.ResultsA total of 12 studies involving 644 patients were included. The summary estimates of the CR and minimal residual disease response rates for patients with ALL were 67% (95% confidence interval [CI], 61%-73%) and 45% (95% CI, 37%-53%) of patients with NHL. The pooled CR rate was 28% (95% CI, 15%-47%). Thrombocytopenia and neutropenia were the most common adverse events. In patients receiving INO, venous obstructive disease/sinus obstructive syndrome, grade ≥ 3 thrombocytopenic events, grade ≥ 3 neutropenic events of the pooled estimated incidence were 8% (95% CI, 5%-14%), 29% (95% CI, 20%-39%), and 48% (95% CI, 38%-57%).ConclusionsAccording to our study, INO was effective in the treatment of relapsed/refractory ALL and NHL with limited adverse effects. High-quality randomized controlled trials and extensive follow-up are pending to confirm and update the results of this analysis in the future.     

Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma

BackgroundConcern has been increasing in oncology regarding randomized clinical trial (RCT) eligibility limiting the generalizability of the findings to real-world populations. Using a large US electronic health record database, we investigated the real-world generalizability of the findings from recent RCTs for relapsed and/or refractory multiple myeloma (RRMM).Patients and MethodsPatients with RRMM initiating second-to fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as “RCT eligible” or “RCT ineligible” according to the eligibility criteria: (1) Rd (lenalidomide, dexamethasone)—ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2; and (2) Vd (bortezomib, dexamethasone)—CASTOR and ENDEAVOR. Predictors of RCT ineligibility and overall survival were analyzed using logistic regression and Cox regression analysis.ResultsVariations in the individual trial ineligibility rates were noted, with up to 72.3% (range, 47.9%-72.3%) of patients not meeting the eligibility criteria for 1 of the 6 hallmark RCTs (n = 788 for Rd; n = 477 for Vd). Other malignancies, cardiovascular disease, acute infection, and renal dysfunction were the common reasons for ineligibility. Advanced age, Charlson comorbidity score of ≥ 2, later therapy lines (3-4), and refractory status to the previous line were independently predictive of RCT ineligibility. RCT-ineligible versus RCT-eligible patients had a significantly greater mortality risk (hazard ratio, Rd, 1.46; Vd, 1.51).ConclusionMost real-world patients with RRMM were ineligible for the hallmark RCTs. The eligibility rates varied across the RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. Overall survival was significantly affected by the inability to meet the criteria, highlighting the limited generalizability of the RCT results. Greater efforts are required to broaden the eligibility criteria to reflect real-world clinical characteristics and narrow the gap between RCT efficacy and the observed effectiveness in real-world patients with RRMM.     

Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review

Multiple myeloma is the second most common hematologic malignancy and remains incurable. Patients who fail multiple lines of therapy typically have a poor prognosis despite recent advances in myeloma treatment. Chimeric antigen receptor T (CAR T) cell treatment has emerged as a promising therapy for many hematologic malignancies, including recently approved and emerging applications for myeloma treatment. A systematic review of the available clinical trial data for CAR T therapies in multiple myeloma was undertaken. All multiple myeloma trials registered at ClinicalTrials.gov were reviewed and studies mentioning CAR T and studying relapsed/refractory multiple myeloma (R/R MM) were included. PubMed, Google Scholar, and conference proceedings were also reviewed to determine which trials had reported data. Twenty-seven registered clinical trials in humans with published data were identified as of March 10, 2021. The majority of these trials were CAR T cells targeting B-cell maturation antigen (BCMA), and many were Phase I studies. Data demonstrated promising short-term (<12 months) efficacy with low incidence of grade 3 or higher toxicities. CAR T cell therapy in R/R MM remains a promising treatment modality. While one biologic has recently received FDA-approval, the majority of products remain investigational and in early-phase trials. More investigation is needed to determine which CAR T constructs and combination therapies optimize patient outcomes.     

Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma

The oral proteasome inhibitor ixazomib (Ninlaro^®) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study). A significantly longer time to progression and favourable hazard ratios for PFS were observed across all prespecified subgroups, including patients with high cytogenetic risk. Overall response was achieved in a significantly higher proportion of patients receiving ixazomib- than placebo-based treatment. Ixazomib had a manageable tolerability profile in patients with MM. Ixazomib is the first orally-administered proteasome inhibitor approved for patients with MM, and in combination with lenalidomide and dexamethasone represents an important new option for use in patients with relapsed and/or refractory MM who have previously received at least one prior therapy.

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复发难治性多发性骨髓瘤治疗的现状与挑战

多发性骨髓瘤是一种无法治愈的恶性血液病，近年来众多药物的应用改善了患者的生存和生活质量，然而疾病最终会进展为复发难治性多发性骨髓瘤，新药的基础研究和临床应用变得至关重要。本文评估了复发难治性多发性骨髓瘤治疗试验中的数据，列举了目前的治疗进展。此外，多发性骨髓瘤与基因组异常、免疫正常化、蛋白质稳态密切相关，以这三个方面为靶点进行研究将进一步指导精准治疗的发展。     

MPV方案治疗难治性复发性多发性骨髓瘤18例临床观察

目的评估MPV方案治疗难治性复发性多发性骨髓瘤（MM）的疗效。方法18例难治性复发性MM患者,均给予MPV方案化疗,治疗4个周期观察疗效。观察项目包括血清M蛋白、肝肾功能、尿蛋白、骨髓像、血像等。结果经4个周期治疗,7例完全缓解,8例部分缓解,总有效率为83．33％。结论MPV方案是治疗难治性复发性MM较好的选择。     

Treatment Options for Patients With Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.     

来那度胺为主的联合化疗方案治疗复发难治性多发性骨髓瘤的临床观察

[目的]观察来那度胺(lenalidomide)为主的联合化疗方案治疗复发难治性多发性骨髓瘤(multiple myeloma,MM)的临床疗效及不良反应.[方法]22例复发难治性MM患者中,来那度胺联合马法兰和地塞米松治疗者14例,来那度胺联合地塞米松治疗者7例,来那度胺联合亚砷酸和地塞米松治疗者1例.所有患者于2个疗程后评价疗效及不良反应.[结果] 22例患者中完全缓解(CR)2例(9.1％);非常好的部分缓解(VGPR)5例(22.7％);部分缓解(PR)12例(54.5％);无效以及死亡3例(13.7％),总有效率为86.3％.不良反应主要包括中性粒细胞减少(54.5％)、血小板减少(72.7％)、乏力(100％)以及继发感染(36.4％).[结论]以来那度胺为主的联合化疗是治疗复发难治性MM的合适治疗方案,近期疗效显著,患者耐受性好.     

Modern Treatments and Future Directions for Relapsed/Refractory Multiple Myeloma Patients

Since the introduction of proteasome inhibitors, immunomodulators, and monoclonal antibodies, the longevity of a patient with multiple myeloma has greatly improved. Although prognosis is improving, multiple myeloma remains an incurable disease and most patients will inevitably relapse. With new studies and prospective trials being published every few months, the landscape of multiple myeloma treatment is changing and sequencing treatments remains complex. In this review, we discuss the current data and approaches to treating a patient with relapsed/refractory multiple myeloma.     

Real-World Treatment of Patients With Relapsed/Refractory Myeloma

The continuous advances in the treatment landscape of multiple myeloma has led to the approval of several novel agents and their combinations that significantly improved patient outcomes. Despite their undoubtful effectiveness in the context of clinical trials, their impact on real-world (RW) clinical practice remains debatable. RW data on the role of novel agents and their combinations among patients with relapsed/refractory multiple myeloma have confirmed the efficacy of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. However, the magnitude of the benefit and the safety profile may differ among RW studies and between RW and pivotal clinical trials. Several variables may pertain to these observations and include patient selection, ethnicity, age, comorbidities, disease stage at diagnosis and at relapse, number of prior lines of therapy, disease subtype, presence of renal impairment, extramedullary disease, and cytogenetic abnormalities. All these contribute to a varying degree of disease and patient heterogeneity among the studies that may result in a differential treatment effect. The expertise of each medical center and the treatment setting in terms of availability and drug access are particularly important as well. Interestingly, RW observations may serve as proof of concept for designing novel clinical trials, as is the case with retreatment studies. In conclusion, clinical trial and RW data are complementary, and they should be considered to improve both clinical trial design and clinical practice.     

Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: A Case Series Illustrating Utility in Clinical Practice

IntroductionIncreasing numbers of patients are presenting with relapsed/refractory multiple myeloma (MM) following treatment with bortezomib. Therefore, there is a need for effective and well-tolerated treatment strategies after failure of bortezomib-based regimens. Vorinostat, a histone deacetylase inhibitor, has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM. Preliminary results from ongoing phase I trials have demonstrated the clinical activity of vorinostat in combination with bortezomib in patients with MM. This case series reports our experience of combined vorinostat and bortezomib in 6 patients with relapsed/refractory MM after previous bortezomib.Materials and MethodsPatients received oral vorinostat 300 mg or 400 mg once daily (days 1-14) and bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 in a 21-day cycle.ResultsAll patients derived clinical benefit from combined vorinostat and bortezomib, with objective response observed in 5 of the 6 patients (≥ minimal response), including 1 very good partial response; stable disease was observed in the remaining patient. Patients remained on therapy until disease progression. Combined vorinostat and bortezomib therapy was well tolerated: grade 2 nausea and diarrhea were the only adverse events reported. No patients discontinued therapy because of toxicity, and no dose adjustments were required for either agent.ConclusionThese results suggest that combined vorinostat and bortezomib therapy is effective in patients with relapsed/refractory MM after failure of previous bortezomib-based regimens and support further evaluation of this combination in randomized trials.     

Real World Treatment of Patients with Relapsed/Refractory Myeloma

Translating clinical trial results into robust treatment options remains an important issue for patients with relapsed/refractory multiple myeloma (RRMM). The availability of different treatment regimens in different countries, the heterogeneous patient population among clinical trials versus real-world data (i.e. the under-representation of frail patients or patients with severe renal impairment in several clinical trials) and the clinical practice setting contribute to discrepant results

Causes for Discrepancies between Clinical Trial and RW Data

The most easily identifiable factor for discrepancies between clinical trials and RW data is patient selection. Eligibility criteria delineate a study population that may be substantially different from the general RW population with RRMM. Thus, extrapolating the clinical trials results is cautious by principle.¹ Frail patients with comorbidities are usually excluded from clinical trials; however, they represent the most challenging patient group in clinical practice. Furthermore, the

RW Data in RRMM Patients

The prospective, non-interventional EMMOS study has revealed several approaches in the RW treatment of RRMM, depending on the treatment setting and the availability of novel agents. Bortezomib, thalidomide and lenalidomide remain important backbone regimens, whereas prior autologous transplantation improves outcomes in the subsequent lines of therapy.¹⁴ In the RW, RRMM patients present with an unmet need for a more effective therapeutic approach inducing deep and durable responses in the

Conclusion

RW data on the role of novel agents and their combinations among patients with RRMM have confirmed their contribution in the significant improvement in patient outcomes and the prolongation of survival. RW evidence is valuable, which is reflected on the conduction of large multicenter RW studies such as the EMMOS and the INSIGHT studies.^14,30 Clinical trial and RW data are complementary and they should be considered as important feedback to improve both the clinical trial designs and our

References

• 1.Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375:2293-2297.
• 2.Combest AJ, Reitsma DJ, Moseley A, et al. Adult participation in oncology clinical trials by indication, race, and age. J. Clin. Oncol. 2013;31(15 suppl):e17586.
• 3.Myeloma, U. K. Myeloma Patient Experience Report 2016. Myeloma, UK, 2016.
• 4.Richardson PG, San Miguel JF, Moreau P, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the

     

Role of Proteasome Inhibitors in Relapsed and/or Refractory Multiple Myeloma

Proteasome inhibition is an established treatment strategy for patients with multiple myeloma as proteasome inhibitors (PIs) selectively target and disrupt the protein metabolism of aberrant plasma cells. Since the introduction of the first-in-class PIs bortezomib, the therapeutic landscape for multiple myeloma has shifted with the development of next-generation PIs (carfilzomib and ixazomib) and new classes of agents. Treatment with modern combination therapies has been shown to result in deep responses and improved outcomes, and these potent regimens are increasingly used as frontline therapy. As patients continue to live longer with modern frontline therapy, there will be an increased need for effective regimens after initial treatment failure. Several recent studies have shown that treatment with combination therapy incorporating PIs induces deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this review, we review pivotal data and discuss the role of PIs-based doublet and triplet regimens for the management of relapsed/refractory multiple myeloma in the era of modern combination therapy.     

Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States

Background

In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival.