Search

Clinical Practice Points • Selinexor may be active even in the dire situation of early relapse after allogeneic stem cell transplantation. • Selinexor retains activity in patients who are proteasome, immunomodulatory drug, and daratumumab refractory. • Selinexor has the potential to be combined effectively with multiple standard anti-myeloma agents, including carfilzomib.

A 66-year-old man with refractory multiple myeloma presented with acute severe aortic insufficiency leading to cardiogenic shock and multiorgan failure. After comprehensive heart team evaluation, he underwent successful JenaValve transcatheter aortic valve (JenaValve Technology, Inc., Irvine, California) implantation resulting in resolution of his aortic insufficiency and improvement in his clinical status. (Level of Difficulty: Advanced.), Central Illustration

na

The number and type of therapeutic options available to treat patients with multiple myeloma has risen dramatically over recent years, offering exciting opportunities to significantly improve the future management of this currently incurable disease. Some of the latest advances in the settings of newly diagnosed and relapsed/refractory multiple myeloma were presented at the 61st Annual Meeting of the American Society of Hematology (Orlando, Florida, December 7 to 10, 2019) and are reviewed in this article with accompanying expert commentary. Presentations covered the use of registry-generated real-world data to define the characteristics of 'functional' high-risk patients in order to enable early therapeutic intervention for this poor-prognosis subset; studies that reported impressive new and updated data with novel combinations of targeted agents across different settings, including biomarker-specific subgroups; and promising early-phase data with novel immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor T-cell B-cell maturation antigen-directed therapies. This review offers insights into how these latest developments may fit within the rapidly evolving treatment landscape. The adoption and optimal use of novel therapies may be impacted by logistical challenges such as limited funding and access to necessary infrastructure to provide these treatments. In this manuscript, we focus particularly on Asia-Pacific regions and identify areas for development, such as establishment of robust national registries, promotion of investigator-initiated trials, compassionate-use treatment programs, and collaboration between jurisdictions with similar patterns of care. The hope is that such efforts will augment research outputs and ultimately translate into improved patient outcomes in the real world.

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.

Purpose Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting. Patients and methods Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DR MM) were included to the Polish Myeloma Group observational study. Results The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events. Conclusion Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable remission rates in patients with relapsed and refractory acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), and refractory multiple myeloma (MM). However, objective responses to adoptive T cell therapy remain suboptimal in patients with solid tumors. A major obstacle for adoptive T cell therapy for solid tumors is the intrinsic ability of tumors to evolve and to develop mechanisms that inhibit the immune system’s innate ability to recognize and kill tumor cells. This review delineates some of the major immunosuppressive barriers within the tumor microenvironment (TME) that ultimately neutralize the anti-tumor function of adoptively transferred T cells. Recent advances in engineering strategies have been applied to T cells in order to survive and overcome the hostile TME.

Daratumumab is a monoclonal antibody that targets CD38. It has an anti-tumor action on the myeloma cell and an immunomodulatory action. For relapsing and/or refractory myeloma patients, daratumumab is effective both alone and in combination and significantly improves progression-free survival. Daratumumab has been approved in 2016 in France for treatment of relapses or refractory multiple myeloma.

Context Belamaf is a B-cell maturation antigen-targeting antibody-drug conjugate approved in the US and EU for the treatment of RRMM. Ocular events (OEs) during the DREAMM-2 trial (NCT03525678) included corneal exam findings (punctate keratopathy and microcyst-like epithelial changes), BCVA changes, and ocular symptoms. Dose reductions or delays based on corneal exam findings and BCVA were used to manage OEs. Objective To study relationships between exam findings, BCVA changes, and patient-reported ocular symptoms in a post hoc analysis to explore if BCVA changes and symptoms alone could guide dosing. Methods Patients receiving single-agent belamaf (2.5 mg/kg) had eye evaluations (including a corneal exam and BCVA assessment of Snellen visual acuity) performed by ophthalmologists at baseline and prior to each dose. Changes in the corneal epithelium (Ker) and BCVA were assessed per protocol-defined criteria and assessment of grade was based on the worse eye. BCVA grading was relative to baseline. Patient-reported ocular symptoms were reported per the Common Terminology Criteria for Adverse Events. Results In 12.5% of eye evaluations Grade 3–4 Ker was associated with minimal or no (Grade ≤1) BCVA changes. When patient-reported ocular symptoms were also considered, only 7.5% of evaluations found Grade 3–4 Ker with Grade ≤1 BCVA changes or ocular symptoms. Mild or no (Grade ≤2) Ker was associated with Grade ≤1 BCVA changes in 59.5% of evaluations, or in 38.8% of evaluations with no ocular symptoms reported. Overall, Grade 3–4 Ker were found in 24.9% of evaluations; by contrast, patients had Grade 2–4 BCVA changes or ocular symptoms in 53.7% of evaluations. Conclusions BCVA changes and ocular symptoms should be further investigated to determine if they can be used as alternatives (e.g., frequency of eye examinations based on symptoms) for the management of belamaf dosing to potentially reduce the burden on patients and healthcare professionals. Funding GlaxoSmithKline (205678; NCT03525678). Drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.

Context As the treatment landscape for RRMM evolves, it is becoming increasingly important to understand how treatments differ in terms of benefits, risks, and convenience, as these factors may influence patients’ preferences for treatment. Understanding these preferences can aid in shared treatment decision-making between patients and physicians. Objective To understand patients’ experiences with RRMM and their preferences related to treatment. Methods This is the qualitative interview phase of a two-part study designed to better understand the experiences and treatment preferences of patients with RRMM. Interview questions were informed by a literature review that extracted relevant attributes and clinical data of interest. Sixty-minute, semi-structured interviews were conducted with patients in the United States, United Kingdom, France, and Germany. The interview consisted of two main sections, within which patients were asked to select and rank features related to (1) disease and symptoms and (2) treatment experiences and expectations. Results A total of 19 patients participated in this study; 63% (n=12) had used 4 or more prior lines of therapy. Mean age was 56 years (range: 41–75) and 79% (n=15) of patients were female. Sixty-three percent (n=12) of patients were not working, 37% (n=7) due to disability/sick leave; 26% were retired (n=5). Forty-two percent (n=8) of patients were in remission. Disease symptoms often impacted patients’ abilities to perform daily tasks (84% [n=16]), which was also the most bothersome impact of the disease (32% [n=6]). Patients reported increased life expectancy as the most important treatment benefit (79% [n=15]). Frequent side effects after starting treatment included blood-related side effects (89%, [n=17]), fatigue (89% [n=17]), and bone pain (74% [n=14]). The side effects that patients ranked as most important to avoid included fatigue (16% [n=3]), peripheral neuropathy (16%, [n=3]), and blood-related side effects (11% [n=2]). Treatment frequency (79% [n=15]) and mode of administration (74% [n=14]) were also important to patients. Conclusions Patients reported a number of RRMM symptoms and impacts. Patients desired treatment that prolonged overall survival; whilst administration was important, this was often contingent on efficacy and risks. These results will inform a discrete choice experiment to elicit patients’ preferences for RRMM treatments. Funding GlaxoSmithKline (212408).

Carfilzomib is a proteasome inhibitor that is approved for use as a single agent in patients with relapsed and refractory multiple myeloma and when used in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma (1-3 prior lines of therapy). Cardiac and cardiopulmonary adverse events have been reported to be associated with carfilzomib-based treatment regimens. This article discusses the cardiac-related adverse events that have been reported in clinical studies of carfilzomib and presents a single institution perspective on the prevention and management of cardiac adverse events following treatment with this agent.

LNA-i-miR-221, a 13-mer oligonucleotide, has proved favorable efficacy and safety profiles in the preclinical studies, leading to being approved for use in clinical trials by regulatory authorities. The objective of this study was to develop and validate LC-MS/MS methods to quantify LNA-i-miR-221 in human plasma and urine. Chromatographic separation was performed with a gradient system on HALO C18 column using hexafluoro-2-propanol/triethylamine buffer and methanol as mobile phase. LNA-i-miR-221 was detected on tandem mass spectrometer with electrospray ionization source in negative ion mode. The methods showed good linearity within the calibration range of 50-25000 ng/mL and 50-50000 ng/mL for human plasma and urine, respectively. The methods proved to be accurate, precise and selective in both human matrices. These validated methods are reliable and are currently in use to support a first-in-human clinical trial of LNA-i-miR-221 in patients affected by refractory multiple myeloma and advanced solid tumors.

Proteosome inhibitors (PI) are standard therapies for relapsed and/or refractory multiple myeloma (RRMM). Carfilzomib (CAR), an irreversible PI, is associated with greater risk of cardiovascular adverse events (CVAE) compared to bortezomib (BOR), a reversible PI. Whether PIs induce changes in

We have performed a face to face comparison of all-oral triplet ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS).

New treatment options for patients with myeloma have helped to change the natural history of this disease, even in the context of relapsed disease. For standard-risk patients, doublet-based therapy may offer benefit, whereas for patients with aggressive or genetically high-risk disease combinations of agents are needed for adequate disease control. Second-generation agents offer significant activity for patients with refractory myeloma, and new categories of agents provide new targets for future study and clinical use. Combinations of these agents in selected patient populations represent the next stage in the quest to cure myeloma.

Background The phase 3 ICARIA study demonstrated that isatuximab (Isa) plus pomalidomide and dexamethasone (Pd) significantly improved progression free survival (PFS) compared with Pd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (HR = 0.596, 95%CI 0.44-0.81, P = 0.001). We evaluated the efficacy/safety of Isa-Pd in the East Asian pts (13 Japanese, 9 Korean and 14 Taiwanese pts) of ICARIA. Methods RRMM pts who had received ≥2 prior lines of therapies, including lenalidomide (len) and at least a proteasome inhibitor (PI), and were refractory to their last therapy were enrolled. Pts were randomized into either Isa-Pd arm who received Isa 10 mg/kg IV weekly for the first 4 weeks (wks) followed by biweekly or Pd arm, and all pts received Pom (4mg PO days 1-21) and dex (40mg [20mg if older than 75 yrs] PO or IV weekly) in 28 day cycle until disease progression or unacceptable toxicity. Results Data from 36 East Asian pts (21 Isa-Pd, 15 Pd) including Japanese pts (9 Isa-Pd, 4 Pd) were analyzed. Patient’s characteristics were similar in the East Asian subgroup and the entire population of ICARIA study (n = 307). Of these pts, median age: 65 (range, 41-85) yrs; median prior lines of therapy: 3 (range, 2-7); 91.7% and 69.4% were refractory to len and PI, respectively; and 13.9% had high-risk cytogenetics. After median follow-up of 11.6 months, median PFS was not reached yet in Isa-Pd arm and was 7.9 months in Pd arm (HR 0.517 [95% CI 0.19-1.39]). ORR (≥PR) was 71.4% in Isa-Pd arm 60% in Pd arm. The VGPR rate or better was 61.9% and 13.3% in Isa-Pd and Pd arm, respectively. Median time to first response was 32 days and 59 days for Isa-Pd and Pd arm, respectively. Grade ≥3 AEs were observed in 90.5% and 73.3% pts in Isa-Pd and Pd arm, respectively and which caused 9.5% pts in the Isa-Pd arm and 0 % in Pd arm to discontinue their treatment. Infusion associated reactions were reported in 57.1% pts receiving Isa-Pd but none of them were grade 3-4. Conclusions This subgroup analysis of ICARIA demonstrates that the efficacy and safety of Isa-Pd in East Asian population, including Japanese pts, are comparable with the entire population of ICARIA. Isa-Pd is a novel treatment option for East Asian pts with RRMM. Clinical trial identification Clinical trial information: NCT02990338. Legal entity responsible for the study Sanofi. Funding Sanofi. Disclosure K. Sunami: Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: GlaxoSmithKline; Speaker Bureau / Expert testimony: Janssen Pharmaceutical. M. Matsumoto: Speaker Bureau / Expert testimony: Celgene Co., LTD; Speaker Bureau / Expert testimony: Janssen Pharmaceutical Co., LTD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., LTD. C. Shimazaki: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Celgen Co. Ltd.; Speaker Bureau / Expert testimony: Fujimoto Pharmaceutical Co. Ltd. F. Campana: Full / Part-time employment: Sanofi. K. Tada: Full / Part-time employment: Sanofi. S. Iida: Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Daiichi-Sankyo; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AbbVie. K. Suzuki: Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Fujimoto; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sumitomo Dainippon ; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Sanofi. All other authors have declared no conflicts of interest.