Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life

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Abstract

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.

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Implementation of Patient-Reported Outcomes in Routine Medical Care

Ethan Basch, Lisa Barbera, Carolyn L Kerrigan … (2018)

There is increasing interest to integrate collection of patient-reported outcomes (PROs) in routine practice to enhance clinical care. Multiple studies show that systematic monitoring of patients using PROs improves patient-clinician communication, clinician awareness of symptoms, symptom management, patient satisfaction, quality of life, and overall survival. The general approach includes a brief electronic survey, administered via the Web or an app or an automated telephone system, with alerts to clinicians for concerning or worsening issues. Patients have generally been asked to self-report on a regular basis (remotely between visits and/or at visits), with reminders prompting patients to self-report that are sent via email, text, or automated phone message. More recently, care management pathways for patients and clinicians have been triggered by PRO system alerts. PRO systems may be free-standing, integrated into electronic health record systems or patient portals, or native functionality of an electronic health record. Despite potential benefits, there are challenges with integrating PROs into practice for monitoring patient status, as there are with any modifications to existing clinical processes. These challenges range from administrative to technical to workflow. A session at the 2018 ASCO Annual Meeting was dedicated to the implementation of PROs in clinical practice. The session focused on practical examples of PRO implementations, with honest reflections on barriers and strategies that may be generalizable to other systems looking to implement PROs. Panelists for that session are the authors of this paper, which describes their respective experiences implementing PROs in practice settings.

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Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

Graham Jackson, Faith Davies, Charlotte Pawlyn … (2019)

Summary Background Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1–21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Findings Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18–50), median progression-free survival was 39 months (95% CI 36–42) with lenalidomide and 20 months (18–22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41–0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6–81·6) in the lenalidomide group and 75·8% (72·4–79·2) in the observation group (HR 0·87 [95% CI 0·73–1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3–90·7) in the lenalidomide group and 80·2% (76·0–84·4) in the observation group (HR 0·69 [95% CI 0·52–0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6–72·1) in the lenalidomide group and 69·8% (64·4–75·2) in the observation group (1·02 [0·80–1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0–90·9) in the lenalidomide group compared with 81·3% (74·2–86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8–81·9) in the lenalidomide group compared with 63·7% (52·8–72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0–75·8) compared with 43·5% (22·2–63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. Interpretation Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. Funding Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.

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Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.

Antonio Palumbo, Sara Bringhen, Maria-Victoria Mateos … (2015)

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).

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Author and article information

Contributors

Evangelos Terpos:

ORCID: http://orcid.org/0000-0001-5133-1422

eterpos@hotmail.com

Journal

Journal ID (nlm-ta): Blood Cancer J

Journal ID (iso-abbrev): Blood Cancer J

Title: Blood Cancer Journal

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2044-5385

Publication date (Electronic): 18 February 2021

Publication date PMC-release: 18 February 2021

Publication date Collection: February 2021

Volume: 11

Issue: 2

Electronic Location Identifier: 40

Affiliations

[1 ]GRID grid.5216.0, ISNI 0000 0001 2155 0800, Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, , National and Kapodistrian University of Athens, School of Medicine, ; Athens, Greece

[2 ]GRID grid.250942.8, ISNI 0000 0004 0507 3225, Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute, City of Hope Cancer Center, ; Phoenix, AZ USA

[3 ]Department of Hemato-Oncology, University Hospital Ostrava, and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic

[4 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, ; New York, NY USA

[5 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Department of Hematology, Cancer Center Amsterdam, , Amsterdam University Medical Center, VU University Amsterdam, ; Amsterdam, The Netherlands

[6 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Lymphoma and Myeloma, MD Anderson Cancer Center, ; Houston, TX USA

[7 ]GRID grid.411258.b, Department of Hematology, , University Hospital of Salamanca, IBSAL, CIC, IBMCC (USAL-CSIC), ; Salamanca, Spain

[8 ]GRID grid.7605.4, ISNI 0000 0001 2336 6580, Myeloma Unit, Division of Hematology, , University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, ; Torino, Italy

[9 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Haematology, , Oxford University Hospitals NHS Foundation Trust, RDM, Oxford University, NIHR BRC Blood Theme, ; Oxford, UK

[10 ]Department of Haematology, The Royal Marsden Hospital, and Division of Molecular Pathology, The Institute of Cancer Research (ICR), London, UK

[11 ]GRID grid.415967.8, ISNI 0000 0000 9965 1030, Leeds Cancer Centre, Leeds Teaching Hospitals Trust, ; Leeds, UK

[12 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[13 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Medicine, Division of Blood and Marrow Transplantation, Moores Cancer Center, , University of California San Diego, ; La Jolla, CA USA

[14 ]GRID grid.419849.9, ISNI 0000 0004 0447 7762, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, ; Cambridge, MA USA

[15 ]GRID grid.468189.a, Department of Hematologic Oncology and Blood Disorders, , Levine Cancer Institute, ; Charlotte, NC USA

Author information

Evangelos Terpos http://orcid.org/0000-0001-5133-1422

Roman Hajek http://orcid.org/0000-0001-6955-6267

María-Victoria Mateos http://orcid.org/0000-0003-2390-1218

Alessandra Larocca http://orcid.org/0000-0002-2070-3702

Martin Kaiser http://orcid.org/0000-0002-3677-4804

Katja C. Weisel http://orcid.org/0000-0001-9422-6614

Antonio Palumbo http://orcid.org/0000-0002-1763-6609

Article

Publisher ID: 432

DOI: 10.1038/s41408-021-00432-4

PMC ID: 7891472

PubMed ID: 33602913

SO-VID: 4f2fa46c-0597-4b78-aecf-5bebc165c340

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 November 2020

Date revision received : 22 January 2021

Date accepted : 28 January 2021

Funding

Funded by: FundRef https://doi.org/10.13039/100007723, Takeda Pharmaceuticals U.S.A. (Takeda Pharmaceuticals U.S.A., Inc.);

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: myeloma,quality of life,adverse effects,cancer therapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: myeloma, quality of life, adverse effects, cancer therapy

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