Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring.

BACKGROUND: Carfilzomib is a selective proteasome inhibitor approved in the United States in 2012 for the treatment of relapsed and refractory multiple myeloma. Although cardiopulmonary and vascular events have been reported infrequently, they can be potentially serious complications, and their incidence and pathophysiology following carfilzomib treatment remain poorly characterized in a real-world patient population. METHODS: We retrospectively reviewed the records of 67 patients with relapsed and/or refractory multiple myeloma treated at our institution. RESULTS: We describe 12 patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib-based treatment (median age, 59 years [range, 49-77]). Nine patients had prior autologous stem cell transplant, and three had prior anthracycline exposure. Detailed case reports are provided for five representative patients: (1) systemic hypertension in a 65-year-old Caucasian female with a history of hypertension, hypothyroidism, and stage III chronic kidney disease; (2) pulmonary hypertension in a 72-year-old Caucasian male with a history of recurrent respiratory infections and chronic right lower extremity deep venous thrombosis; (3) acute renal insufficiency with increased blood pressure in a 50-year-old Caucasian male with a history of hypertension and stage IV chronic kidney disease; (4) heart failure in a 64-year-old African American female with a history of hypertension; and (5) dyspnea and lung disease in a 58-year-old Asian American male with a history significant for hepatitis B virus infection. CONCLUSIONS: While cardiac and vascular-related adverse events were reported in patients with relapsed and/or refractory multiple myeloma who were treated with carfilzomib, most patients had a history of the specific cardiac or vascular adverse event they exhibited and demonstrated an improvement or resolution in symptoms after the discontinuation of therapy. Appropriate screening and monitoring could potentially allow at-risk patients to benefit fully from treatment with carfilzomib

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM

Proteasome inhibition and its therapeutic potential in multiple myeloma

Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches.

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM

Bispecifics, trispecifics, and other novel immune treatments in myeloma.

Despite recent advances in treatment, relapses in multiple myeloma (MM) are inevitable. Off-the-shelf immunotherapeutics represent a promising avenue for research, with various classes of agents under development and several demonstrating deep and durable responses in patients who have exhausted all available therapies. Antibody-drug conjugates (ADCs) seek to improve on naked monoclonal antibodies by delivering a cytotoxic payload directly to tumor cells while largely limiting systemic effects. Belantamab mafodotin, a B-cell maturation antigen (BCMA)-targeted ADC, has shown response rates >30% in a phase 2 trial of highly refractory patients and is being investigated in a variety of settings and combinations. Several other ADCs are in earlier stages of development that target cell surface antigens that are internalized, including BCMA, CD38, CD46, CD56, CD74, and CD138. Bispecifics are designed to bring cytotoxic immune effector cells into proximity with tumor cells, and several agents have shown high response rates in early trials. Current targets include BCMA, CD38, GPRC5d, and FCRH5, and all of these seek to engage T cells through CD3. Bispecifics targeting natural killer (NK) cells through CD16 are still in preclinical development. Trispecific antibodies may represent an advance over bispecifics by providing a T-cell costimulatory signal such as CD28, or alternatively, dual MM antigens to increase specificity of NK or T-cell targeting. This is an area of active preclinical research at this time. Lastly, designed ankyrin repeat proteins, which are small antibody-mimetic proteins with high target-binding affinity, have the potential to block multiple pathways at once and provide stimulatory signals to the immune system

Selinexor in relapsed/refractory multiple myeloma.

Multiple myeloma (MM) represents an incurable hematologic malignancy. Despite significant advances over the past decade, with the advent of multiple new classes of anti-myeloma agents, including immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, patients ultimately relapse. Selinexor is a first-in-class exportin-1 inhibitor with activity in these multiply relapsed and refractory patients. Although the current Food and Drug Administration (FDA) approval is for the doublet of Selinexor in combination with dexamethasone, ongoing clinical trials are evaluating a number of combination regimens. These triplet and quadruplet, selinexor-based, regimens are showing significant activity in triple-class refractory patients. With appropriate combination drug choice, drug dosing, and supportive measures, patients with previously no viable options for therapy, now have multiple potential regimens to control their disease

Management and outcomes of proteasome inhibitor associated chalazia and blepharitis: a case series.

BACKGROUND: The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management strategies, and to propose a treatment algorithm for eyelid complications in this patient population. METHODS: This retrospective case series included sixteen patients found to have chalazia and/or blepharitis while receiving proteasome inhibitors for plasma cell disorders at Mount Sinai Hospital in New York, NY from January 2010 through January 2017. Main outcomes were complete resolution of eyelid complications and time to resolution. Students t-test was used to compare average values and Fishers exact test was used to compare proportions. RESULTS: Fourteen patients had chalazia and 10 had blepharitis. Chalazia averaged 5.4 mm, and 11 patients with chalazia experienced two or more lesions. Median follow-up time was 17 months. Average time from bortezomib exposure to onset of first eyelid complication was 3.4 months. Chalazia episodes were more likely to completely resolve than blepharitis episodes (p = 0.03). Ocular therapy alone was trialed for an average of 1.8 months before proceeding to bortezomib omission. Average time to eyelid complication resolution using ocular therapy alone was 1.8 months versus 3.1 months after bortezomib omission. In this series, the combination of ocular therapy and bortezomib omission led to complete resolution of eyelid complications more often than ocular therapy alone. CONCLUSION: Proteasome inhibitor associated eyelid complications were identified in sixteen patients with plasma cell disorders. Eyelid complications may be treated with a 2-month trial of conservative ocular therapies alone, followed by continuation of ocular therapy in combination with bortezomib omission if eyelid signs persist

Duration of frontline therapy and impact on clinical outcomes in newly diagnosed multiple myeloma patients not receiving frontline stem cell transplant.

BACKGROUND: Extended first-line therapy (1LT) has improved clinical outcomes in newly diagnosed multiple myeloma (NDMM). This retrospective study of NDMM patients evaluated the relationship between dose-attenuation of 1LT and duration of therapy (DOT) and DOT on outcomes. METHODS: Adults with NDMM not undergoing stem cell transplant (SCT) from January 1, 2012 toMarch 31, 2018 from the Integrated Oncology Network were included; 300 were randomly selected for chart review. 1LT DOT, time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Marginal structural models evaluated relationships between DOT and TTNT, PFS, and OS at 2 years accounting for confounders and survival bias from the time-dependent nature of DOT. RESULTS: Of 300 chart-reviewed patients, 93 were excluded for incomplete data or meeting exclusion criteria. Among 207 NDMM patients, median age was 74 years; 146 (70.5%) did not receive dose-attenuation during 1LT. Patients with short DOT were older, frailer, with a higher comorbidity burden, and a significantly lower proportion had an Eastern Cooperative Oncology Group PS = 0. As DOT increased, more patients underwent dose-attenuation (p < 0.0001). The median 1LT DOT was 20.9 (95% confidence interval [CI]: 13.9, 26.4) versus 4.2 months (95% CI: 3.2, 4.9) for patients receiving versus not receiving dose-attenuation, respectively (p < 0.0001). After accounting for survival bias, confounder-adjusted TTNT was prolonged with each additional month of 1LT (odds ratio [OR]: 0.76 [95% CI: 0.75, 0.78]); likelihoods of risks of disease progression (OR: 0.87 [95% CI: 0.86, 0.88]) and death at 2 years (OR: 0.72 [95% CI: 0.70, 0.74]) were reduced with each month of 1LT (p < 0.0001 for all outcomes). CONCLUSIONS: Dose-attenuated 1LT was associated with longer DOT among patients with non-SCT NDMM. Each additional month of 1LT was associated with a reduced adjusted likelihood of disease progression and death at 2 years. Dose-attenuation of 1LT can extend DOT; longer DOT may improve clinical outcomes

Patient-Reported Factors in Treatment Satisfaction in Patients with Relapsed/Refractory Multiple Myeloma (RRMM).

BACKGROUND: Therapy choices in relapsed/refractory multiple myeloma (RRMM) should consider patient satisfaction with treatment, because it is associated with adherence to therapy, health outcomes, and medical safety. The primary objective of this pilot cross-sectional observational study was to ascertain factors associated with patient-reported treatment satisfaction in RRMM. PATIENTS AND METHODS: Patients with a self-reported diagnosis of RRMM recruited from PatientsLikeMe, MyelomaCrowd, and Facebook were administered an electronic survey that included questions on demographics and clinical history, treatment experience, economic burden, and standardized patient-reported outcome measures, including the Treatment Satisfaction Questionnaire for Medication, Eastern Cooperative Oncology Group performance status (ECOG PS) measure, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem V2.0. Univariable and multivariable analyses were used to identify predictors of patient-perceived treatment satisfaction. RESULTS: One hundred sixty patients with RRMM participated in the study, with a median of two prior relapses and 66.3% reporting the most recent relapse within the last 12 months. ECOG PS ≥2 was associated with lower patient-reported global satisfaction and perceived effectiveness of current treatment. In addition to shorter time spent receiving therapy, orally administered treatment was the strongest predictor of higher satisfaction with treatment convenience. For patients receiving an injectable drug-containing regimen versus an all-oral regimen, respectively, time spent receiving multiple myeloma-directed therapy was higher (12.6 vs. 4.0 hours per month), and total monthly indirect costs were $1,033 and$241. CONCLUSION: Poor ECOG PS was linked to reduced treatment satisfaction and perceived effectiveness of current therapy, whereas an all-oral regimen was associated with increased treatment convenience satisfaction. IMPLICATIONS FOR PRACTICE: This study suggests that attributes including better Eastern Cooperative Oncology Group performance status, less time spent receiving treatment, and oral route of treatment administration lead to higher patient-perceived satisfaction with relapsed/refractory multiple myeloma (RRMM) treatment. Oral route of administration was also associated with less time spent receiving treatment and reduced economic burden for patients. Increased attention to these factors in shared treatment decision making is warranted to help identify individual patient needs, preferences, and expectations for RRMM treatments, to resolve dissatisfaction issues, and to improve the experience of patients with RRMM

Risk stratification of smoldering multiple myeloma: predictive value of free light chains and group-based trajectory modeling.

We investigated the predictive role for serum free light chain ratio (FLCr) ≥100, bone marrow plasma cell (BMPC) ≥60%, and evolving biomarkers through group-based trajectory modeling (GBTM) as high-risk defining events in 273 smoldering multiple myeloma (SMM) patients with a median follow-up of 74 months. FLCr ≥100 was confirmed as a marker for high-risk progression with a median time to progression (TTP) of 40 months with a 44% risk of progression of disease (PD) at 2 years; however, 44% of FLCr ≥100 also did not progress during follow-up. For patients with BMPC ≥60% by core biopsy, the median TTP was 31 months with a 2-year PD of 41%. GBTM established high-risk trajectories for evolving hemoglobin (eHb; characterized as a 1.57 g/dL decrease in hemoglobin), evolving m-protein (eMP; 64% increase in m-protein), and evolving differences in FLC (edFLC; 169% increase in dFLC) within 1 year of diagnosis associated with a decreased median TTP and an increased 2 year rate of PD. Of all the variables examined, we identify a model where immunoparesis, eHb, eMP, and edFLC were significant predictors for ultra-high-risk progression with a median TTP of only 13 months with 3 or more variables present. Our results not only confirm a more modest 2 year PD associated with FLCr ≥100 and BMPC ≥60 but also suggest that eHb, eMP, and edFLC may help identify an ultra-high-risk SMM group