Oral Antimyeloma Therapy: Barriers to Patient Adherence and Tips for Improvement
Karen Sweiss, PharmD BCOP
Clinical Pharmacist and Clinical Assistant Professor
Hematology and Bone Marrow Transplant
University of Illinois at Chicago
Multiple myeloma (MM) is a plasma cell disorder characterized by uncontrolled clonal plasma cell proliferation in the bone marrow, production of monoclonal protein in the blood or urine, and associated organ dysfunction.1,2 As the second most common hematologic malignancy, MM is an important area of focus for clinical pharmacists. Fortunately, outcomes for MM patients have greatly improved recently with the explosion of novel agents such as immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies.1-4
Novel agents pose unique challenges to clinicians. In particular, many drugs currently being prescribed in MM treatment are oral.5 Furthermore, continuous treatment has been a paradigm shift in MM, allowing for ongoing disease suppression, deeper responses, and improved progression-free survival.6 But these changes are also associated with substantial burdens, such as treatment-related toxicities, financial toxicity, and decreased patient adherence because of complex dosing schedules.
What Is Adherence?
Adherence is defined as the “extent to which a patient’s behavior coincides with instructions from a healthcare provider.”7 Nonadherence is associated with suboptimal drug efficacy, resulting in poor clinical outcomes and increased healthcare costs.7 Medication nonadherence is identified as the largest driver of avoidable U.S. healthcare costs, accounting for more than $200 billion annually.8-9 Because of the significant clinical and economic impact of nonadherence to oral therapies, it is vital that healthcare providers acknowledge and address adherence, especially in a disease that tends to follow a chronic disease trajectory where treatment is continuous. Unfortunately, data for understanding adherence rates among patients with MM and the impact of nonadherence on long-term patient outcomes are lacking. A recent article aimed to explain how medication adherence affects the burden of MM. An online survey was administered to 162 adult patients with MM. Better medication adherence was related to less impairment to work productivity and functioning, lower out-of-pocket costs, and fewer office visits.10
What Are the Barriers to Adherence, and How Can They Be Overcome?
Several oral drugs, including thalidomide, lenalidomide, pomalidomide, ixazomib, and panobinostat, are currently approved for use in treating MM.4,11-18 These agents play an active role in both the upfront treatment of MM and the treatment of relapsed or refractory MM. In addition, in accordance with guidelines, patients are frequently prescribed supportive care medications that are important in preventing disease- and treatment-related complications.19-23 These include oral anticoagulants, calcium and Vitamin D supplements, and antivirals. The addition of supportive care medications represents an essential component of treatment, which adds further complexity to the treatment regimen.
Multiple barriers to optimal adherence in MM patients exist (Table 1 – see PDF ). The reasons for adherent behavior may differ according to the patient’s situation and stage of myeloma treatment. Barriers to medication adherence are treatment-, patient-, physician-, and environment-related.24
Oral regimens including supportive care add significantly to the pill burden of patients. This issue is particularly relevant for older patients (the median age of onset of MM is 70 years) who may have multiple comorbid illnesses.4 Increasing pill burden has been linked to worse adherence in other disease states.25 Additionally, the incorporation of oral therapies has caused a shift in medication responsibility. Although healthcare providers are traditionally responsible for the administration of intravenous medications, this burden has now shifted to patients, creating new challenges for healthcare professionals seeking to maintain medication adherence and ongoing clinical and laboratory monitoring.26-28
In addition, current treatment regimens are highly complex, and oral chemotherapy regimens require from patients a high degree of understanding. Chemotherapy doses and schedules are not consistent or linear and can be very hard for patients to understand. Initiation of treatment is often delayed significantly because many of these oral drugs are part of a risk evaluation and mitigation strategy (REMS) program, are primarily dispensed through a specialty pharmacy, and often require prior authorization. They are also expensive and place a financial burden on the patient.
Patient-related factors may include the patient’s age and sex, a poor understanding of the disease and associated risks, a perception of being cured or having asymptomatic disease, a lack of belief in treatment benefits, cognitive impairment (e.g., forgetfulness), comorbid conditions, polypharmacy, and reluctance to change behaviors.26,28-30 Although a cure for myeloma does not exist, it is important to understand how patients perceive their response to treatment because it may affect their attitude toward continued treatment.
Treatment-related factors, such as medication side effects and drug-drug interactions, can result in medication nonadherence when the patient is unprepared or unable to manage his or her symptoms. Patient education, both initial and ongoing, by the healthcare team—specifically, by a specialized pharmacist—could provide patients better guidance on recognizing these side effects and preparing strategies to both prevent and treat them. Many of the oral drugs we prescribe have unique adverse effects that the patient must be able to recognize at home and communicate to the healthcare team. For example, the immunomodulator drug class (including thalidomide, lenalidomide, and pomalidomide) can cause myelosuppression, peripheral neuropathy, gastrointestinal disturbances (such as diarrhea), rash, venous thromboembolism, and increased susceptibility to infection.
Physician-related barriers include poor patient-provider communication, lack of positive reinforcement from the healthcare provider, insufficient educational measures on the medication regimen or importance of adherence, and infrequent follow-up. This may hold true especially during the maintenance phase, when patients are seen only monthly.
Socioeconomic factors, such as lack of health insurance, medication cost, limited access to healthcare facilities or pharmacies, social lifestyle, lack of family or social support network, and inadequate supervision, are also strong determinants of medication nonadherence.
Because of these logistic, perceptual, physiologic, and social barriers to treatment, it is important that healthcare providers identify individual barriers to oral therapy and work with individual patients to isolate strategies that will enable them to take their medications as prescribed. In providing patient-centered oncology care, it is important to perform ongoing assessments of medication adherence to oral therapies. Direct methods include directly observed therapy, and indirect methods include use of patient questionnaires, patient self-report, and patient diaries or logs.31
Using pill containers with a microelectronic monitoring system allows for tracking of the opening of the pill container but can be expensive. Assessing prescription filling and insurance records is considered to provide the most accurate estimate of actual medication use over a period of time. However, prescription filling does not necessarily translate to pill consumption or provide information about whether the patient is taking the medication as prescribed. In addition, oral therapy for myeloma is often withheld because of treatment or disease complications, but the suspension of treatment may not necessarily be captured by this method.
It is well accepted that improving patient adherence requires a multifaceted approach and cannot rely on one method. Typically, models of adherence interventions are based on the key elements of patient education, behavioral interventions, and affective support, which may include symptom management, simplifying medication regimens, improving patient-provider communication, and relying on other specialized experts (e.g., pharmacists) to increase patients’ knowledge and organize strategies to increase adherence rates. Lifestyle differences among patients mean that identifying individual barriers and tailoring adherence interventions to their individual needs is critical.
The frequency of monitoring and follow-up that are appropriate for the patient and the agent prescribed must be determined and defined in the treatment plan. It is recommended that an office visit be scheduled once per cycle for an assessment, and follow-up visits, calls, e-mails, or text-message reminders must be used as opportunities to reiterate the importance of adherence. During these follow-up visits, medication adherence must be assessed, and any identified barriers dealt with. Patients should be encouraged to use adherence aids and reminder cues to improve adherence outcomes. Reminders that can be used to improve patients’ adherence to their oral therapies include pillboxes, pill diaries, and treatment calendars. Phone or text-message reminders based on the dosing schedule are popular methods. Calendars, checklists, and medication charts may be used as refill reminders so that patients have an adequate supply of medications.
What Is the Role of the Clinical Pharmacist in Oncology Care?
Strategies for incorporating the services of a clinical pharmacist directly into oncology care delivery have been published.32-34 For example, pharmacists have been integrated into hematology-oncology clinics with the aims of improving supportive care, enhancing the education of patients receiving chemotherapy, and improving efficiency in the chemotherapy infusion unit.15 Additional areas of study include the assessment of pain, nausea, and vomiting; management of treatment-related side effects; palliative care; programs dedicated to monitoring oral anticancer regimens; and follow-up of patients undergoing hematopoietic stem cell transplantation.32,34-38 The pharmacist who is integrated into the healthcare team can be involved with providing patient education, monitoring adverse effects of therapy, evaluating adherence to oral antimyeloma medication schedules, ensuring provision of drugs in a timely fashion, and assessing the appropriateness of supportive care in the overall treatment of the patient.
How Have We Sought to Improve Adherence in Multiple Myeloma Patients?
At the University of Illinois at Chicago (UIC), we hypothesized that a multidisciplinary collaborative physician-pharmacist MM clinic would improve patients’ adherence to treatment and supportive care guidelines, managing treatment-related side effects, and navigating issues involving access to oral specialty medications (a collaborative clinic). Outcome measures were retrospectively compared to those of patients being treated by the same physician during the previous year, where ad-hoc pharmacist consultation was available upon request (a traditional clinic).
The collaborative clinic led to significant improvements in patients’ adherence to supportive medications such as bisphosphonates (96% vs. 68%, p = .0002), calcium and vitamin D (100% vs. 41%, p < .001), acyclovir (100% vs. 58%, p = .0009), and Pneumocystis jirovecii pneumonia (PJP) prophylaxis (100% vs. 50%, p < .0001). Appropriate venous thromboembolism (VTE) prophylaxis in immunomodulatory agent (IMiD)-treated patients was prescribed in 100% versus 83% of patients (p = .0035). The median time to initiation of bisphosphonate (5.5 vs. 97.5 days (p < .001) and PJP prophylaxis after autologous transplant was shortened in the collaborative clinic (11 days vs. 40.5 days, p < .0001). Furthermore, the number (85% vs. 21%, p <.0001) and duration (7 days vs. 15 days, p = .002) of delays in obtaining IMiD therapy were also significantly reduced. Our collaborative clinic model could potentially be applied in other practice sites to improve the management of MM patients.
Myeloma is a complex disease, and patients must adhere to difficult treatment regimens. Integrating the clinical pharmacist—who can focus on providing patient education and improving patient-related symptoms, while helping patients avoid additional side effects and drug interactions with the antimyeloma treatment—into the healthcare team is important. Future studies of myeloma treatment should focus on patient adherence and evaluate the long-term effects of nonadherence on disease- and patient-related outcomes.
- Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128.
- SEER Cancer Stat Facts: Myeloma. National Cancer Institute. Bethesda, MD. Accessed from: https://seer.cancer.gov/statfacts/html/mulmy.html
- Dimopoulos MA, Richardson PG, Moreau P, Anderson KC. Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol. 2015;12(1):42-54.
- Kumar SK, Callander NS, Alsina M, et al. NCCN Guidelines Insights: multiple myeloma, Version 3.2018. J Natl Compr Canc Netw. 2018;16(1):11-20.
- Kumar SK, Vij R, Noga SJ, et al. Treating multiple myeloma patients with oral therapies. Clin Lymphoma Myeloma Leuk. 2017;17(5):243-251.
- Palumbo A, Gay F, Cavallo F, et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol. 2015;33:3459-3466.
- Zafar SY. Financial toxicity of cancer care: it’s time to intervene. J Natl Cancer Inst. 2015;108(5):1-4
- Iuga AO, McGuire MJ. Adherence and health care costs. Risk Manag Healthc Policy. 2014;7:35-44..
- Vander Stichele R. Measurement of patient compliance and the interpretation of randomized clinical trials. Eur J Clin Pharmacol. 1991;41(1):27-35.
- Gupta S, Abouzaid S, Liebert R, Parikh K, Ung B, Rosenberg AS. Assessing the effect of adherence on patient-reported outcomes and out of pocket costs among patients with multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(3):210-218.
- Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
- Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934-1939.
- Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-631.
- Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.
- Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634.
- Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
- Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.
- Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
- Terpos E, Morgan G, Dimopoulos MA, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31:2347-2357.
- Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.
- Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238.
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- Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32:587-600.
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- Jacobs JM, Pensak NA, Sporn NJ, et al. Treatment satisfaction and adherence to oral chemotherapy in patients with cancer. J Oncol Pract. 2017;13:e474-e485.
- Muluneh B, Deal A, Alexander MD, et al. Patient perspectives on the barriers associated with medication adherence to oral chemotherapy. J Oncol Pharm Pract. 2018;24(2):98-109.
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