A Noninterventional,Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide

IntroductionLenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting.Patients and MethodsPatients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator’s routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration.ResultsIn total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively.ConclusionNo new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials.     

Optimal Supportive Care With Selinexor Improves Outcomes in Patients With Relapsed/Refractory Multiple Myeloma

BackgroundSupportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-in-class, oral, selective exportin 1 inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased utilization of supportive care measures in a sub-cohort of the STORM study prolonged treatment duration with- and improved efficacy of- selinexor.Materials and MethodsThe STORM protocol included specific recommendations for dose modifications and supportive care to mitigate selinexor most common adverse events (AEs) including nausea, fatigue, and thrombocytopenia. The Tisch Cancer Center at Mount Sinai School of Medicine (MSSM) incorporated additional supportive care strategies within the framework of the STORM protocol.ResultsOf 123 patients enrolled in STORM, 28 were enrolled at MSSM. The overall response rate was 26.2% in the overall STORM population and 53.6% in the MSSM cohort. Moreover, duration of response, progression free survival, and overall survival were longer in the MSSM cohort. AEs and dose modification events were similar in the 2 groups. The MSSM cohort had more dose reductions (67.9% vs. 50.5%), and higher use of multiple antiemetic agents (71.4% vs. 50.1%) and romiplostim (32.1% vs. 6.3%), but less discontinuations due to treatment-related AEs (3.6% vs. 25.3%).ConclusionThese results suggests that in addition to more frequent dose reductions, prompter and more aggressive supportive care may have contributed to the low discontinuation rate, longer duration therapy, and greater efficacy rates observed in the MSSM cohort. (ClinicalTrials.gov NCT02336815).     

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.     

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.     

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。     

Blood Transfusion Management and Transfusion-Related Outcomes in Daratumumab-Treated Patients With Relapsed or Refractory Multiple Myeloma

Introduction

Daratumumab, a human CD38 monoclonal antibody approved for multiple myeloma (MM) treatment, binds red blood cells (RBCs), resulting in panagglutination in compatibility tests. Published mitigation methods avoid additional testing, ensuring timely release of blood products. Blood transfusion management and transfusion-related outcomes of daratumumab-treated patients in the SIRIUS study are reported, with emphasis on 2 clinical sites.

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.     

Modified HyperCVAD Versus Bortezomib-HyperCAD in Patients With Relapsed/Refractory Multiple Myeloma

Introduction

Multiple myeloma (MM) is an incurable plasma cell malignancy, in which aggressive relapses might require salvage cytotoxic infusional chemotherapy. Several clinical trials that reported the efficacy of bortezomib led to institutional practice changes in which vincristine was replaced with bortezomib in the modified hyperCVAD regimen, creating a new treatment regimen, named “bortezomib-hyperCAD.”

Patterns of Relapse or Progression After Bortezomib-Based Salvage Therapy in Patients With Relapsed/Refractory Multiple Myeloma

IntroductionBortezomib-based therapy is commonly used in treatment for relapsed or refractory multiple myeloma (MM). Unfortunately, many patients show relapse or progression in heterogeneous patterns.Patients and MethodsIn this study, we retrospectively evaluated patterns of relapse or progression after bortezomib-based salvage therapy in patients with MM and analyzed prognostic significance according to patterns of relapse or progression. One hundred forty-eight patients were treated with bortezomib-based therapy between November 2004 and April 2012. Of these patients, 104 (70.3%) patients relapsed or progressed after bortezomib-based salvage therapy. We divided the patterns of relapse or progression to the 2 groups: (1) the isoform relapse or progression (group A) in 89 (85.6%) patients as disease findings at initiation of bortezomib-based therapy; and (2) transformed relapse or progression (group B) in 15 (14.4%) patients (plasmacytoma, n = 7; light chain escape, n = 6; and plasma cell leukemia, n = 2) different from initial disease findings.ResultsMedian overall survival in group A and group B were 32.7 months (95% confidence interval [CI], 21.3-44.1) and 10.7 months (95% CI, 2.0-19.4) (P < .001), respectively.ConclusionMM patients who relapsed or progressed as the transformed pattern for bortezomib-based salvage therapy have an extremely poor prognosis and might require new innovative approaches.     

Gemcitabine in Treating Patients with Refractory or Relapsed Multiple Myeloma

Background: Patients with refractory or relapsed multiple myeloma are considered to have a very poorprognosis, and new regimens are needed to improve the outcome. Gemcitabine, a nucleoside antimetabolite, isan analog of deoxycytidine which mainly inhibits DNA synthesis through interfering with DNA chain elongationand depleting deoxynucleotide stores, resulting in gemcitabine-induced cell death. Here we performed a systemicanalysis to evaluate gemcitabine based chemotherapy as salvage treatment for patients with refractory andrelapsed multiple myeloma. Methods: Clinical studies evaluating the impact of gemcitabine based regimenson response and safety for patients with refractory and relapsed multiple myeloma were identified by using apredefined search strategy. Pooled response rate (RR) of treatment were calculated. Results: In gemcitabine basedregimens, 3 clinical studies which including 57 patients with refractory and relapsed multiple myeloma wereconsidered eligible for inclusion. Systemic analysis suggested that, in all patients, pooled RR was 15.7% (9/57)in gemcitabine based regimens. Major adverse effects were hematologic toxicity, including grade 3 or 4 anemia,leucopenia and thrombocytopenia i. No treatment related death occurred with gemcitabine based treatment.Conclusion: This systemic analysis suggests that gemcitabine based regimens are associated with mild activitywith good tolerability in treating patients with refractory or relapsed multiple myeloma.     

Oprozomib,pomalidomide, and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

IntroductionThis phase Ib study evaluated oprozomib, an oral proteasome inhibitor, plus pomalidomide-dexamethasone in relapsed/refractory multiple myeloma (RRMM).Patients and MethodsPatients received oprozomib once-daily on days 1 to 5 and 15 to 19 (5/14 schedule; 150 mg/day starting dose) or on 2 consecutive days weekly (2/7 schedule; 210 mg/day starting dose) of 28-day cycles, pomalidomide on days 1 to 21 (4 mg/day starting dose), and dexamethasone 20 mg on 2 consecutive days weekly. A 3 + 3 dose-escalation schema was used to determine the maximum tolerated dose.ResultsThirty-one patients were treated (5/14, n = 4; 2/7, n = 27). Oprozomib maximum tolerated dose was not defined. The 2/7 schedule (oprozomib 210 mg/day, pomalidomide 4 mg/day) was selected for dose expansion based on overall safety (n = 17). In this group, the most common adverse events (AEs) were gastrointestinal (diarrhea [88.2%], nausea [58.8%], and vomiting [58.8%]); grade ≥ 3 gastrointestinal AEs were uncommon. The most common grade ≥ 3 AEs were hematologic (anemia [47.1%], neutropenia [35.3%], and thrombocytopenia [29.4%]). One dose-limiting toxicity (gastric hemorrhage) occurred; 3 patients discontinued owing to AEs. The overall response rate was 70.6%.ConclusionSafety and pharmacokinetic profiles were concerns with the oprozomib formulation used in this study and need to be improved. Oprozomib-pomalidomide-dexamethasone (2/7 schedule) had encouraging efficacy, supporting an ongoing phase Ib study evaluating new oprozomib formulations for this combination in relapsed/refractory multiple myeloma.     

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study

IntroductionCiltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation.MethodsQualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study.ResultsPatients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments.ConclusionOverall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.     

Outcomes of VD-PACE With Immunomodulatory Agent as a Salvage Therapy for Relapsed/Refractory Multiple Myeloma

BackgroundAggressive relapsed/refractory multiple myeloma (RRMM) often requires salvage cytotoxic chemotherapy. We evaluated the efficacy and toxicity of VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) with an immunomodulatory agent (IMiD) in RRMM.Patients and MethodsWe retrospectively reviewed the effectiveness and tolerability among 30 patients with RRMM receiving ≥ 1 cycle of VD-PACE + IMiD between January 2012 to April 2019.ResultsOf 30 patients, 26 (86%) had myeloma double refractory to protease inhibitors and IMiDs, and had received a median of 3 lines prior of therapy. The overall response rate was 67.7%, 13% patients experienced complete remission or better, and 13% experienced very good partial response. Median progression-free and median overall survival were 11 and 26 months, respectively. The most common grade 3 or higher adverse events were hematologic events, which were manageable.ConclusionVD-PACE + IMiD is an effective and tolerable salvage treatment for RRMM, with an impressive response rate in pretreated RRMM.     

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。     

Belantamab in Combination with Dexamethasone in Patients with Triple-class Relapsed/Refractory Multiple Myeloma

BackgroundTriple-class relapsed/refractory multiple myeloma (RRMM) has a poor prognosis. This study analyzed the clinical outcomes of Belantamab mafadotin in combination with dexamethasone (Bd) in triple-class RRMM.MethodsWe identified 35 patients with triple-class RRMM who received Bd at the University of Kansas from October 2019 to November 2021.ResultsThe median age was 66 years (42-85) and the median prior lines of therapy was 5 (3-15). Nineteen (54%) patients had R-ISS stage III disease, 15 (43%) patients had high-risk cytogenetics, and 15 patients (43%) had extramedullary disease (EMD). Eight patients received prior BCMA-targeted therapy. Overall response rate (ORR) was 43%, with 23% achieving very good partial response and better. At a median follow up of 10.7 months, the median progression-free survival and survival were 4.9 and 10.7 months, respectively. The most common adverse event was keratopathy, which occurred in 30 (86%) patients. Twenty-four patients required dose reduction or delay due to keratopathy. Other common toxicities included anemia (83%), thrombocytopenia (80%), neutropenia (34%), and elevated liver function tests (51%).ConclusionOur analysis shows Bd has good activity in triple-class RRMM. Keratopathy remains a challenging AE and the leading cause of dose reduction, delay and treatment cessation.