Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma

Over the past two decades, the improvement in our understanding of the biology of MM and the introduction of new drug classes, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (MoAb), have significantly improved outcomes. The first IMiD introduced to treat MM was thalidomide. The side effects observed during treatment with thalidomide initiated work on the synthesis of IMiD analogs. Subsequently, lenalidomide and pomalidomide were developed, both with different safety profiles, and they have better tolerability than thalidomide. In 2010, the cereblon (CRBN) protein was discovered as a direct target of IMiDs. By binding to CRBN, IMiDs change the substrate specificity of the CRBN E3 ubiquitin ligase complex, which results in the breakdown of internal Ikaros and Aiolos proteins. Most clinical trials conducted, both in newly diagnosed, post-transplant maintenance and relapsed/refractory MM, report a beneficial effect of IMiDs on the extension of progression-free survival and overall survival in patients with MM. Due to side effects, thalidomide is used less frequently. Currently, lenalidomide is used at every phase of MM treatment. Lenalidomide is used in conjunction with other agents such as PIs and MoAb as induction and relapsed therapy. Pomalidomide is currently used to treat relapsed/refractory MM, also with PIs and monoclonal antibodies. Current clinical trials are evaluating the efficacy of IMiD derivatives, the CRBN E3 ligase modulators (CELMoDs). This review focuses on the impact of IMiDs for the treatment of MM.

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Autoimmunity associated with immunotherapy of cancer

Blood ◽

10.1182/blood-2011-01-325266 ◽

2011 ◽

Vol 118 (3) ◽

pp. 499-509 ◽

Cited By ~ 105

Author(s):

Sally M. Amos ◽

Connie P. M. Duong ◽

Jennifer A. Westwood ◽

David S. Ritchie ◽

Richard P. Junghans ◽

...

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Side Effects ◽

Cell Transfer ◽

Serious Adverse Events ◽

Normal Tissues ◽

Immune Mediated ◽

Organ Systems ◽

Immunotherapy Of Cancer ◽

Future Potential

Abstract In this age of promise of new therapies for cancer, immunotherapy is emerging as an exciting treatment option for patients. Vaccines and cytokines are being tested extensively in clinical trials, and strategies using monoclonal antibodies and cell transfer are mediating dramatic regression of tumors in patients with certain malignancies. However, although initially advocated as being more specific for cancer and having fewer side effects than conventional therapies, it is becoming increasingly clear that many immunotherapies can lead to immune reactions against normal tissues. Immunotoxicities resulting from treatment can range from relatively minor conditions, such as skin depigmentation, to severe toxicities against crucial organ systems, such as liver, bowel, and lung. Treatment-related toxicity has correlated with better responses in some cases, and it is probable that serious adverse events from immune-mediated reactions will increase in frequency and severity as immunotherapeutic approaches become more effective. This review introduces immunotherapeutic approaches to cancer treatment, provides details of toxicities arising from therapy, and discusses future potential ways to avoid or circumvent these side effects.

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Meta Analysis of Grade 3 and/or 4 Toxicities in Low-Grade Non-Hodgkin Lymphoma (LG-NHL) Patients Receiving Maintenance Rituximab (MR) Therapy: Impact of Schedule on Toxicity

Blood ◽

10.1182/blood.v118.21.2704.2704 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2704-2704

Author(s):

Chadi Nabhan ◽

Dana Villines ◽

Tina V. Valdez ◽

Michele Ghielmini ◽

Shu-Fang Hsu Schmitz ◽

...

Keyword(s):

Clinical Trials ◽

Research Funding ◽

Meta Analysis ◽

Statistical Significance ◽

Comparative Trial ◽

Progression Free Survival ◽

Low Grade ◽

Front Line ◽

Grade 3 ◽

The Impact

Abstract Abstract 2704 Background: MR has improved the outcome and progression-free survival (PFS) in patients with follicular lymphoma (FL) in front-line and relapsed settings. However, maintenance schedules have been empirically designed based on either B-cell depletion kinetics or rituximab levels, with no consensus on the optimal regimen. Overall, toxicities have been predictable and tolerable but the impact of MR schedule on toxicities has not been previously reported and could influence selection of maintenance regimens. Methods: Using PubMed, prospective clinical trials employing MR were identified. Data presented in abstract form or at meetings were deemed incomplete and thus excluded. Data were analyzed from published manuscripts as percentages of subjects experiencing an adverse event (AE). Percentages were considered as the unit of analysis as this adjusted for the uneven sample sizes. Data were collected for overall Grade 3 and/or Grade 4 toxicity (AE reported at any phase of treatment) and was further categorized as AE occurring during initial treatment or during MR. Grade 1 and 2 toxicities were excluded from meta-analysis, given lack of consistent reporting. No grade 5 toxicities were reported. The incidence, severity, and type of toxicity was analyzed by type of induction (Rituximab (R) vs. R plus chemotherapy), histology (FL vs. FL plus other LG-NHL), setting (front-line vs. relapsed), and MR schedule (one dose every 2 months vs. one dose every 3 months vs. 4 doses every 6 months). Results: Nine clinical trials involving 1,928 patients were included in this Meta analysis (4 of which were randomized controlled in the MR phase). Of those, 1,004 patients received MR. The mean percentage of Grade 3/4 toxicities during any phase of treatment was 26% (95% CI = 0.12–51.88) but when restricted to the MR phase; it was 12.88% (95% CI = 6.50–19.26). Toxicities were numerically higher in patients receiving R induction plus chemotherapy versus R induction alone and in patients receiving MR for relapsed disease versus newly diagnosed patients, but did not reach statistical significance (P = 0.661 and 0.517, respectively). However, patients receiving MR every 2 months were significantly more likely to develop grade 3 and 4 toxicities compared to patients receiving MR every 6 months (P = 0.005). No statistical differences were demonstrated between the 2 vs. 3 months schedules or when comparing the 3 vs. 6 months schedules (P = 0.342 and 0.267, respectively) (Table 1). Statistically significant differences were also found in studies restricted to FL versus others allowing non-FL histologies (P = 0.025) with the FL patients experiencing more toxicity than others. The most frequently reported toxicities were neutropenia and infections. There were no treatment-related deaths in any of the arms. Conclusions: Approximately 13% of patients receiving MR experience grade 3 and/or 4 toxicities, mainly consisting of neutropenia and infections. MR given every 6 months appears to provide the least grade 3 and 4 toxicities. There is a suggestion of increased toxicity in FL histologies. It is important to note that this meta-analysis did not address efficacy and only a true comparative trial can definitively establish the relative risk/benefit ratios amongst MR schedules. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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The impact of kidney function on the efficacy and safety of pazopanib in metastatic renal cell carcinoma (mRCC) patients: CORE-URO-01 study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16063 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16063-e16063

Author(s):

Maria Giuseppa Vitale ◽

Cristina Masini ◽

Giuseppe Procopio ◽

Ugo De Giorgi ◽

Sebastiano Buti ◽

...

Keyword(s):

Renal Function ◽

Side Effects ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Therapy Initiation ◽

Frequent Monitoring ◽

Group 2 ◽

Grade 3 ◽

The Impact ◽

Group 1

e16063 Background: Pazopanibhas been approved for treatment of patients (pts) with mRCC based on the prospective randomized trial that enrolled only pts with adequate renal parameters. There are no data on the toxicity profile and efficacy of pazopanib in pts with renal insufficiency (RI).The aim of this study is to investigate the effect of renal function on treatment outcomes in pts treated with pazopanib for mRCC. Methods: We retrospectively analyzed the data of the mRCC pts treated with pazopanib with respect to renal function in eleven Italian institutions from January 2010 to June 2016. Baseline glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula at the time of therapy initiation. Pts with MDRD < 60 mL/min/1.73 m2 (group 1) were compared with pts with MDRD ≥60 mL/min/1.73 m2(group 2) in terms of response rates, progression free survival (PFS), overall survival (OS) and side effects. Results: One hundred and twenty-ninepts with mRCC were included in this study: 70 pts in group 1 and 59 pts in group 2. 67% of pts were male, median age was 66 years (34-83) and median CrCl was 49 ml/min (6.3-59.5) in group 1. In group 2, 64% of pts were male, median age was 65 years (38-80), and median CrCl was 64 ml/min (58.1-137.1) Pts with MDRD < 60 were more likely to have had a previous nephrectomy (84.3% vs 79.7%). No difference between the 2 groups was observed in terms of outcomes: PFS was 9.6 months (0.6–56.9) and 9.0 months (0.4–60.1), OS was 16.1 months (1.3–56.9) and 17.0 months (1.2–60.1), for MDRD < 60 group and MDRD ≥60 respectively. The disease control rate was 85.8% in group 1, and 72.9% in group 2. About grade 1-2 toxicity, no difference between the 2 groups was reported (67.1% vs 67.8%) while a higher incidence of grade 3-4 toxicity was evident in the group 1 (25.7% vs 18.6%). Conclusions: RI was commonly observed in pts with mRCC. Renal function at therapy initiation does not adversely affect the efficacy and safety of pazopanib. More frequent monitoring of side-effects in patients with RI is recommended.

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Molecularly Targeted Therapies in Multiple Myeloma

Leukemia Research and Treatment ◽

10.1155/2014/976567 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Pilar de la Puente ◽

Barbara Muz ◽

Feda Azab ◽

Micah Luderer ◽

Abdel Kareem Azab

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Tumor Microenvironment ◽

Cell Signaling ◽

Targeted Therapies ◽

Proteasome Inhibitors ◽

Novel Agents ◽

Immunomodulatory Drugs ◽

Therapeutic Outcomes

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

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How I manage the toxicities of myeloma drugs

Blood ◽

10.1182/blood-2017-01-725705 ◽

2017 ◽

Vol 129 (17) ◽

pp. 2359-2367 ◽

Cited By ~ 21

Author(s):

Michel Delforge ◽

Heinz Ludwig

Keyword(s):

Monoclonal Antibodies ◽

Side Effects ◽

Adverse Events ◽

Day Treatment ◽

A Priori ◽

Proteasome Inhibitors ◽

Real Life ◽

Treatment Decision ◽

Short Term Treatment ◽

Treatment Regimens

AbstractThe treatment of multiple myeloma is considered a continuously evolving paradigm as a result of the growing availability of new and highly effective drugs, including first- and second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Clinical trials advocate long-term rather than short-term treatment schedules with combinations of these new anti–myeloma drug classes. Although the overall toxicity profile of the recommended regimens can be considered favorable, their increasing complexity and prolonged use warrant a heightened vigilance for early and late side effects, a priori because real-life patients can be more frail or present with 1 or more comorbidities. The treatment decision process, at diagnosis and at relapse, therefore requires myeloma physicians to carefully balance efficacy and toxicity profiles for each individual patient. Early and/or unnecessary tapering or treatment discontinuation for drug-related adverse events may not only reduce patients’ quality of life, but also negatively impact their outcome. Accurate knowledge in recognizing and managing the potential side effects of present-day treatment regimens is therefore a cornerstone in myeloma care. Using 5 case vignettes, we discuss how to prevent and manage the most common nonhematological adverse events of anti–myeloma treatment regimens containing proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.

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Minimal residual disease (MRD) status pre- and post- high-dose therapy/autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8605 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8605-8605

Author(s):

Adetola Kassim ◽

Jeremy Scott McDuffie ◽

Claudio A Mosse ◽

Bipin N. Savani ◽

John P. Greer ◽

...

Keyword(s):

Residual Disease ◽

Prognostic Significance ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Novel Agents ◽

Disease Stage ◽

High Dose ◽

Free Survival ◽

Depth Of Response ◽

The Impact

8605 Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples pre- HDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (+) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.

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Inhibition of the HDM-2 E3 Ligase Induces Types I and II Cell Death in Wild-Type and Mutant p53 Models of Multiple Myeloma, and Acts Synergistically in Both with ABT-737.

Blood ◽

10.1182/blood.v120.21.2940.2940 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2940-2940

Author(s):

Dongmin Gu ◽

Richard Julian Jones ◽

Hua Wang ◽

Lance Leopold ◽

Robert Z. Orlowski

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Therapeutic Target ◽

Proteasome Inhibitors ◽

E3 Ligase ◽

Standards Of Care ◽

Type I ◽

Wild Type ◽

E3 Ligases ◽

The Impact

Abstract Abstract 2940 Background: The ubiquitin-proteasome pathway has been validated as a therapeutic target for multiple myeloma by the incorporation of proteasome inhibitors such as bortezomib and carfilzomib into our standards of care against this disease. A minority of patients achieve complete remission with single-agent therapy, however, and proteasome inhibitors may induce on- and off-target anti-apoptotic effects and clinical toxicities that limit their utility. Unlike proteasome inhibitors, which have a broad impact on intracellular proteolysis, E3 ligases are responsible for ubiquitination of only a small subset of proteins. Our hypothesis proposed that inhibition of the Human double minute (HDM)-2 E3 ligase, which in part is responsible for p53 ubiquitination, could be a more rational therapeutic target for myeloma, where p53 mutations are less common than is the case in solid tumors. Methods: We used Nutlin-3a and MI-63, which bind to the p53 binding pocket of HDM-2, as prototypic agents, and studied their activity against both wild-type (wt) and mutant (mut) p53 cell line models of multiple myeloma. These studies were supported by the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: Inhibition of HDM-2 in wt p53 (MM1.S, H929, MOLP-8) cells with Nutlin-3a or MI-63 reduced viability, with a median inhibitory concentration (IC50) in the 0.5–2 μM range. In wt cells, genomic and proteomic studies showed that MI-63 induced transcription of downstream gene targets including p21, PUMA and Bax, and promoted accumulation of p53, p21, p27, and Bax. This was accompanied by cell cycle arrest at G1, and induction of apoptosis as demonstrated by Annexin V staining and caspase activation. Interestingly, these agents also showed activity against mut p53 cells such as RPMI 8226 and U266, though with higher IC50's of 30–40 μM. Knockdown of HDM-2 sensitized mut p53 myeloma cells to MI-63, suggesting that this agent was inducing cell death in an on-target manner. In p53 mutant cells, MI-63 induced both type I cell death and type II, autophagic cell death, as determined by conversion of microtubule-associated protein 1 light chain 3, and activation of transcription of autophagy (ATG) genes ATG3 and 5. Since autophagy can be a mechanism of cell survival or cell death, we tested the impact of the autophagy inhibitors chloroquine and 3-methyladenine, and found that they reduced the impact of MI-63 on viability. Moreover, knockdown of ATG5 helped rescue cells as well, supporting the possibility that autophagic activation was a mechanism of cell death in these myeloma models. Synergistic anti-myeloma effects were seen when MI-63 was combined with the BH3 mimetic ABT-737, with decreased viability and enhanced apoptosis, accompanied by increased Bax activation and caspase cleavage. Notably, ABT-737 also enhanced the effects of MI-63 on mut p53 myeloma models, where increased levels of both type I and II programmed cell death were seen. Conclusions: Together, our findings support the possibility that HDM-2 is a promising therapeutic target for multiple myeloma, and also provide a rationale for translation of HDM-2 inhibitors alone, and in combination with ABT-737, to the clinic. Disclosures: Leopold: Ascenta Therapeutics: Employment, Equity Ownership.

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Daratumumab in untreated newly diagnosed multiple myeloma

Therapeutic Advances in Hematology ◽

10.1177/2040620719894871 ◽

2019 ◽

Vol 10 ◽

pp. 204062071989487 ◽

Cited By ~ 8

Author(s):

Nadine Abdallah ◽

Shaji K. Kumar

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Clinical Trials ◽

High Risk ◽

Human Monoclonal Antibody ◽

Proteasome Inhibitors ◽

Immunomodulatory Drugs ◽

Newly Diagnosed ◽

Infusion Reactions

The treatment of multiple myeloma has evolved markedly in the last decade, but mortality remains high, emphasizing the need for more effective therapies. Daratumumab, a fully human monoclonal antibody targeting CD38, has shown clinical efficacy in relapsed/refractory multiple myeloma both as monotherapy and in combination with other drugs, including novel agents. More recently, promising results have been reported in patients with untreated newly diagnosed multiple myeloma (NDMM). Clinical trials thus far have shown enhanced efficacy and tolerability of several daratumumab-based combinations in both transplant ineligible and eligible patients, without compromising transplant ability. However, benefit in high-risk subpopulations is still unclear. A subcutaneous formulation of daratumumab has been introduced to decrease the risk of infusion reactions, with preliminary results showing non-inferior efficacy. The antimyeloma activity of daratumumab is achieved through multiple mechanisms including direct, Fc-dependent, and immunomodulatory mechanisms. Enhanced efficacy of daratumumab in combination with immunomodulatory drugs and proteasome inhibitors is supported by preclinical data showing synergism. This review will focus on the role of daratumumab in untreated NDMM patients, highlighting the results of major clinical trials, and listing ongoing trials that are evaluating various daratumumab-based combinations in this setting.

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Practical Considerations for Antibodies in Myeloma

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_205443 ◽

2018 ◽

pp. 667-674 ◽

Cited By ~ 3

Author(s):

Jacob P. Laubach ◽

Niels van de Donk ◽

Faith E. Davies ◽

Joseph Mikhael

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Patient Outcomes ◽

Great Improvement ◽

Treatment Options ◽

Proteasome Inhibitors ◽

Drug Combinations ◽

Therapeutic Antibodies ◽

Immunomodulatory Drugs ◽

Favorable Safety

The development of the monoclonal antibodies daratumumab and elotuzumab has expanded treatment options for multiple myeloma and led to great improvement in patient outcomes. These agents have favorable safety profiles and synergize effectively with established agents used in the management of myeloma, namely immunomodulatory drugs and proteasome inhibitors. This article reviews the rationale for use of monoclonal antibodies in myeloma, current approved indications for daratumumab and elotuzumab, the manner in which these agents are used in the overall management of myeloma, and specific challenges associated with their use in the clinic. It also highlights other, emerging drug combinations that incorporate daratumumab or elotuzumab and profiles new therapeutic antibodies currently under development.

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Patient-Reported Outcomes in Online Communications on Statins, Memory, and Cognition: Qualitative Analysis Using Online Communities (Preprint)

10.2196/preprints.14809 ◽

2019 ◽

Author(s):

Farris Timimi ◽

Sara Ray ◽

Erik Jones ◽

Lee Aase ◽

Kathleen Hoffman

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Online Communities ◽

Side Effect ◽

Online Communication ◽

Linguistic Analysis ◽

Control Group ◽

Patient Reported ◽

Hands On ◽

The Impact

BACKGROUND In drug development clinical trials, there is a need for balance between restricting variables by setting eligibility criteria and representing the broader patient population that may use a product once it is approved. Similarly, although recent policy initiatives focusing on the inclusion of historically underrepresented groups are being implemented, barriers still remain. These limitations of clinical trials may mask potential product benefits and side effects. To bridge these gaps, online communication in health communities may serve as an additional population signal for drug side effects. OBJECTIVE The aim of this study was to employ a nontraditional dataset to identify drug side-effect signals. The study was designed to apply both natural language processing (NLP) technology and hands-on linguistic analysis to a set of online posts from known statin users to (1) identify any underlying crossover between the use of statins and impairment of memory or cognition and (2) obtain patient lexicon in their descriptions of experiences with statin medications and memory changes. METHODS Researchers utilized user-generated content on Inspire, looking at over 11 million posts across Inspire. Posts were written by patients and caregivers belonging to a variety of communities on Inspire. After identifying these posts, researchers used NLP and hands-on linguistic analysis to draw and expand upon correlations among statin use, memory, and cognition. RESULTS NLP analysis of posts identified statistical correlations between statin users and the discussion of memory impairment, which were not observed in control groups. NLP found that, out of all members on Inspire, 3.1% had posted about memory or cognition. In a control group of those who had posted about TNF inhibitors, 6.2% had also posted about memory and cognition. In comparison, of all those who had posted about a statin medication, 22.6% (<italic>P</italic><.001) also posted about memory and cognition. Furthermore, linguistic analysis of a sample of posts provided themes and context to these statistical findings. By looking at posts from statin users about memory, four key themes were found and described in detail in the data: memory loss, aphasia, cognitive impairment, and emotional change. CONCLUSIONS Correlations from this study point to a need for further research on the impact of statins on memory and cognition. Furthermore, when using nontraditional datasets, such as online communities, NLP and linguistic methodologies broaden the population for identifying side-effect signals. For side effects such as those on memory and cognition, where self-reporting may be unreliable, these methods can provide another avenue to inform patients, providers, and the Food and Drug Administration.

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