Trial Summary
What is the purpose of this trial?
This pilot clinical trial studies whether using high throughput drug sensitivity and genomics data is feasible in developing individualized treatment in patients with multiple myeloma or plasma cell leukemia that has come back or does not respond to treatment. High throughput screen tests many different drugs that kill multiple myeloma cells in individual chambers at the same time. Matching a drug or drug combination to a patient using high throughput screen and genetic information may improve the ability to help patients by choosing drugs that work well for their disease.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop your current medications. However, you cannot have had previous treatments for multiple myeloma within 2 weeks of starting the study treatment.
What data supports the idea that Individualized Treatment Plans for Multiple Myeloma is an effective treatment?
The available research shows that Individualized Treatment Plans for Multiple Myeloma, like the Ex vivo Mathematical Myeloma Advisor (EMMA), can accurately predict how patients will respond to different drugs. In a study with 52 patients, EMMA correctly identified 96% of responders and non-responders. Another study used a 7-gene signature to predict which patients would benefit most from specific drug combinations, leading to better survival outcomes. These personalized approaches help choose the most effective treatments, improving patient outcomes compared to standard treatments.12345
What safety data exists for individualized treatment plans for multiple myeloma?
The safety data for individualized treatment plans for multiple myeloma includes information from various studies and reports. The FDA's boxed warnings impact adverse drug reactions reporting rates for multiple myeloma drugs, highlighting the importance of monitoring these reactions. Novel agents have specific side effect profiles, and guidelines exist for managing these adverse events. Post-marketing safety data from the FDA's Adverse Event Reporting System shows that immunomodulatory drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide have significant adverse event signals, including cardiac, gastrointestinal, and respiratory disorders. Real-world data indicates that treatment decisions should consider efficacy, safety, tolerability, and quality of life, as many patients do not meet clinical trial criteria. Patient-reported outcomes and physician-patient concordance on side effects are also important for understanding treatment impact.678910
Is High Throughput Screening a promising treatment for multiple myeloma?
Yes, High Throughput Screening is a promising treatment for multiple myeloma because it helps doctors predict how well a patient will respond to different drugs, allowing for personalized treatment plans. This approach can lead to better treatment outcomes by identifying the most effective drugs for each individual patient.1351112
Eligibility Criteria
This trial is for adults with relapsed or refractory multiple myeloma or plasma cell leukemia who have tried at least three prior treatments, including an IMiD and a PI. They must be able to consent, practice birth control if applicable, have adequate organ function, and measurable disease. Excluded are those with HIV/hepatitis B/C, recent major treatments like SCT within 12 weeks, active infections requiring antibiotics within 7 days of study start.Inclusion Criteria
Your blood test shows high levels of a specific protein called free light chain and an abnormal ratio of certain proteins in your blood.
A sample from my bone marrow or tissue with enough cells for testing has been collected.
You have a disease that can be measured by specific criteria.
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Exclusion Criteria
I have another cancer that is expected to affect my life for less than a year.
Pregnant or breast feeding women
Any medical conditions that would impose excessive risk to the patient, or would adversely affect his/her participation in the study
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Treatment Details
Interventions
- High Throughput Screening (Other)
Trial OverviewThe trial tests the feasibility of using high throughput drug sensitivity screening alongside genomics data to personalize treatment for patients whose multiple myeloma or plasma cell leukemia has returned after treatment or is resistant. It involves collecting samples from patients and testing many drugs simultaneously to find effective ones based on genetic information.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Device feasibility (high-throughput assay, sequencing)Experimental Treatment3 Interventions
Patients undergo collection of bone marrow aspirate and blood for high-throughput drug sensitivity assay and mutational analysis using next generation sequencing. Patients and their treating physicians receive the results of the tests. Treatment decisions are then made by the patients and their treating physicians.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fred Hutch/University of Washington Cancer ConsortiumSeattle, WA
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Who Is Running the Clinical Trial?
University of WashingtonLead Sponsor
References
An Ex Vivo Platform for the Prediction of Clinical Response in Multiple Myeloma. [2021]Multiple myeloma remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, Ex vivo Mathematical Myeloma Advisor (EMMA), consisting of patient-specific mathematical models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of chemosensitivity of primary cells from multiple myeloma patients, allowing us to predict clinical response to up to 31 drugs within 5 days after bone marrow biopsy. From a cohort of 52 multiple myeloma patients, EMMA correctly classified 96% as responders/nonresponders and correctly classified 79% according to International Myeloma Working Group stratification of level of response. We also observed a significant correlation between predicted and actual tumor burden measurements (Pearson r = 0.5658, P < 0.0001). Preliminary estimates indicate that, among the patients enrolled in this study, 60% were treated with at least one ineffective agent from their therapy combination regimen, whereas 30% would have responded better if treated with another available drug or combination. Two in silico clinical trials with experimental agents ricolinostat and venetoclax, in a cohort of 19 multiple myeloma patient samples, yielded consistent results with recent phase I/II trials, suggesting that EMMA is a feasible platform for estimating clinical efficacy of drugs and inclusion criteria screening. This unique platform, specifically designed to predict therapeutic response in multiple myeloma patients within a clinically actionable time frame, has shown high predictive accuracy in patients treated with combinations of different classes of drugs. The accuracy, reproducibility, short turnaround time, and high-throughput potential of this platform demonstrate EMMA's promise as a decision support system for therapeutic management of multiple myeloma. Cancer Res; 77(12); 3336-51. ©2017 AACR.
RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature. [2023]Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.
Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma. [2023]Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
"Direct to Drug" screening as a precision medicine tool in multiple myeloma. [2021]Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.
High-Throughput Drug Screening and Multi-Omic Analysis to Guide Individualized Treatment for Multiple Myeloma. [2023]Multiple myeloma (MM) is a genetically heterogeneous malignancy characterized by variable treatment responses. Although numerous drugs have been approved in recent years, the ability to predict treatment response and tailor individual therapy is limited by the absence of robust predictive biomarkers. The goal of this clinical trial was to use ex vivo, high-throughput screening (HTS) of 170 compounds to predict response among patients with relapsed or refractory MM and inform the next treatment decisions. Additionally, we integrated HTS with multi-omic analysis to uncover novel associations between in vitro drug sensitivity and gene expression and mutation profiles.
Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs. [2021]To determine the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDA's Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs.
Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network. [2023]During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
Post-marketing safety of immunomodulatory drugs in multiple myeloma: A pharmacovigilance investigation based on the FDA adverse event reporting system. [2022]Objective: In recent years, the emergence of immunomodulatory drugs (IMiDs) has significantly improved clinical outcomes in patients with multiple myeloma (MM); however, serious adverse events (AEs) have hindered their safe clinical application. This study aimed to characterize the safety profiles and differences in IMiDs through a disproportionality analysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing surveillance database. Methods: This study filtered reports of thalidomide, lenalidomide, and pomalidomide as primary suspect drugs in FAERS files from January 2013 to December 2021. AEs in the reports were retrieved according to the preferred terms (PTs) of the Medical Dictionary for Regulatory Activities. Furthermore, we detected safety signals using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian belief propagation neural network (BCPNN). When all three algorithms showed an association between the target drug and the AE, a positive signal was generated. Results: We extracted 9,968 thalidomide, 231,926 lenalidomide, and 55,066 pomalidomide AE reports. AEs were more common in male patients and in those >44 years old. Important safety signals were detected based on the system organ classes (SOC), including thalidomide (cardiac disorders: ROR, 2.87; PRR, 2.79; IC 1.22), lenalidomide (gastrointestinal disorders: ROR, 2.38; PRR, 2.27; IC 0.75), and pomalidomide (respiratory, thoracic, and mediastinal disorders: ROR, 2.14; PRR, 2.09; IC 0.85). Within the PT level, we identified novel risk signals: the thalidomide-induced second primary malignancy (SPM) signal was significant; lenalidomide reduced the success rate of hematopoietic stem cell collection; and three IMiDs may cause human chorionic gonadotropin increase, but this needs to be proven by clinical data. Pneumonia, sepsis, and renal failure are common risk factors for death due to IMiDs. Compared with thalidomide and lenalidomide, pomalidomide has a lower risk of venous thromboembolism (VTE) and is beneficial to patients with renal insufficiency. Conclusion: Mining data from FAERS resulted in novel AE signals, including adenocarcinoma of colon, harvest failure of blood stem cells, and increased levels of human chorionic gonadotropin. Further investigation is required to verify the significance of these signals. Moreover, IMiDs showed differences in safety reports, which should be emphasized by clinicians.
Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life. [2021]Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.
Real-world patient-reported outcomes and concordance between patient and physician reporting of side effects across lines of therapy in multiple myeloma within the USA. [2023]We aimed to explore patient-reported outcomes (PROs) and patient and physician concordance of side effects perception across lines of therapy (LOT) in multiple myeloma (MM) within the United States of America (USA).
Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation. [2019]Multiple myeloma (MM) has benefited from significant advancements in treatment that have improved outcomes and reduced morbidity. However, the disease remains incurable and is characterized by high rates of drug resistance and relapse. Consequently, methods to select the most efficacious therapy are of great interest. Here we utilize a functional assay to assess the ex vivo drug sensitivity of single multiple myeloma cells based on measuring their mass accumulation rate (MAR). We show that MAR accurately and rapidly defines therapeutic susceptibility across human multiple myeloma cell lines to a gamut of standard-of-care therapies. Finally, we demonstrate that our MAR assay, without the need for extended culture ex vivo, correctly defines the response of nine patients to standard-of-care drugs according to their clinical diagnoses. This data highlights the MAR assay in both research and clinical applications as a promising tool for predicting therapeutic response using clinical samples.
A preclinical assay for chemosensitivity in multiple myeloma. [2021]Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma, an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating three-dimensional extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used to convert experimental data into dose-exposure-response "surfaces," which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical multiple myeloma treatments, in three multiple myeloma cell lines and seven patient-derived primary multiple myeloma cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology.