Oral Therapies for Multiple Myeloma Continuum

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Oral Therapies for Multiple Myeloma

Changing Patient Perceptions to Promote Adherence to Oral Antimyeloma Oncolytics

Sabby Muneer, PhD 

The management of multiple myeloma (MM) is undergoing a seismic shift from acute treatment to a chronic care model that requires long-term treatment. This trend is fueled by the availability of an increasing number of novel oral oncolytic therapies for patients with MM, including thalidomide (Thal­omid), lenalidomide (Revlimid), pomalidomide (Pomalyst), panobinostat (Farydak), ixazomib (Ninlaro), and many more in the pipeline.1 MM therapy has traditionally been delivered in the controlled environment of an infusion suite in a hospital or a clinic, where the administration and monitoring is effectively managed by the healthcare team. However, the advent of oral oncolytics has changed the dynamics of MM care delivery, and shifted the burden of medication administration to the patients. Patients are now responsible for self-administering often complex dosing regimens at home, monitoring their symptoms, managing their side effects, and making dose adjustments. Although the majority of patients prefer oral therapies because of their flexibility, convenience, better quality of life, and sense of empowerment, oral oncolytics have also created new and unique challenges for the oncology care team.2

Of primary concern is the significant potential for nonadherence to oral oncolytics; this gains particular relevance in the chronic care setting, which is where the MM field is heading toward. Moreover, whereas healthcare professionals in chronic diseases (eg, diabetes, hypertension, asthma) may be more experienced with managing patient nonadherence to prescription medication, their oncology counterparts may be less familiar with adherence measures, largely because of the predominant use of intravenous oncology treatments.3 It is imperative that healthcare professionals, particularly oncology nurses and nurse navigators, are educated on the complex issue of adherence, including patient barriers to adherence, adherence assessments, and intervention strategies to improve patient outcomes. In particular, oncology care teams must be mindful of the importance of educating and communicating to patients that nonadherence to oral oncolytic therapy is associated with serious consequences so they may change patient beliefs, and, therefore, facilitate adherent behavior.

Consequences of Nonadherence

According to the World Health Organization (WHO), adherence is defined as “the extent to which a person’s behavior—taking medication, following a diet, and/or executing lifestyle changes-corresponds with agreed recommendations from a healthcare provider.”4 The WHO estimates that only approximately 50% of patients globally take their medicines as prescribed; as a result, the WHO has labeled nonadherence as a “worldwide problem of striking magnitude.” The nonadherence rate was found to be disturbingly higher in the United States. A survey commissioned by the National Community Pharmacists Association reported that a staggering 75% of participants had not taken their prescription as directed.5 Moreover, 49% of those surveyed stated that they had forgotten to take a prescribed medication, 31% had not filled a prescription, 29% had stopped taking a medicine before their supply ran out, and approximately 24% had taken less than the recommended dosage.4,5

Although the bulk of available data on medication nonadherence exists in the chronic disease setting, current evidence indicates that it also applies to patients with cancer. In contrast to the assumption that patients with cancer are more adherent to their medications owing to the seriousness of their disease, nonadherence to prescription medications occurs in 20% to 100% of patients with cancer.3 In the Adherence Assessment with Gleevec: Indicators and Outcomes study of 169 patients with chronic myelogenous leukemia on imatinib (Gleevec) therapy, only 14% were fully adherent, approximately 33% missed ≥1 doses or did not take it on time (delay of >2 hours), and the majority took less medication than prescribed.6

These data highlight the magnitude and scope of poor medication adherence in the United States, and underscore the importance of changing patient beliefs about the severity of their disease and treatment benefit with oral oncolytic therapy through effective communication and education to achieve adherent behavior. Oncology healthcare professionals must communicate that the consequences of deviating from the prescribed oral treatment are manifold and grave, with severe economic and medical implications. Medication nonadherence across all health conditions, including cancer, was identified as the largest contributor of avoidable US healthcare costs, accounting for more than $200 billion annually.7

In terms of clinical significance, medication adherence was found to be associated with worse treatment outcomes and mortality. It was estimated that medication nonadherence results in 125,000 deaths annually in the United States.8 Moreover, poor adherence is a strong determinant of disease progression, increased disease complications, lower quality of life, frequent physician visits, and higher rates of hospitalization, which is attributable to considerably lower medication effectiveness. This is largely because many oral oncolytics have a limited half-life, and operate effectively within a narrow therapeutic window, greatly impacting the extent of nonadherence that can be tolerated without compromising outcomes.3 For example, in a retrospective cohort study of women with breast cancer who were treated with tamoxifen (Nolvadex) as adjuvant therapy, an adherence rate of <80% significantly impacted mortality rate; patients with adherence lower than the 80% threshold had a 10% increase in their risk for death.9

Notably, medication nonadherence can obscure the clinician’s assessment of a medication’s therapeutic effectiveness.3 For example, a clinician may incorrectly attribute lack of treatment response to lack of drug activity, when in fact the drug was rendered ineffective because of nonadherence. This may lead to unnecessary testing, changes in dosage and regimen, hospitalization, and, importantly, missing an opportunity to derive maximal benefit of an active drug. Clearly, the implications of nonadherence are costly in economic and medical terms, and the onus is on the healthcare team to ensure that patients understand the serious implications of their behavior and rectify them. The healthcare team must emphasize to patients that oral oncolytic therapy is not “just any ordinary pill,” but a vital treatment that can significantly impact treatment outcomes and mortality.

Influence of Patient Perceptions and Barriers

In general, long-term adherence to treatment, including oral oncolytic therapy, is determined largely by the patient’s perception of the risks of not following treatment, perception of treatment benefit, and major barriers to treatment, including economic barriers and the side effects of treatment.3 Built to allow a more rational and targeted avenue for adherence intervention, the Health Belief Model includes concepts of perceived susceptibility, severity, benefits, barriers, and cues to action.10

To mediate a change in adherence behavior, it is important to assess the patient’s perceived threat of MM, and change it through targeted education and communication strategies. Perceived threat is derived from perceived susceptibility, which is defined as patients’ beliefs about their risk for disease progression, symptom worsening, and survival with and without medication, as well as perceived severity, which is patients’ perception of the extent of their disease severity.11 Some patients may be nonadherent because they underestimate their disease severity, and mistakenly assume that their disease is not serious enough and that they have no risk of progressing or having worse disease complications. Healthcare professionals must educate patients about the disease threat and severity based on patients’ baseline level of understanding.

Perceived benefits refer to patients’ understanding of the short- and long-term benefits of their prescribed oral oncolytics for MM control. Notably, some patients may equate asymptomatic disease to being cured, and discontinue their medication with the misguided belief that there is no treatment benefit. In a survey of 10,000 patients, 14% reported being nonadherent because they believed that their treatment would have little or no effect on their disease.12 Another prevalent patient misconception is that oral medications are not as effective as intravenous therapies, which may drive the nonadherent behavior of some patients. It is important to convey to the patient that oral oncolytic therapy is just as effective as intravenous therapy. Importantly, the message that treatment adherence is critical for achieving deep responses must be communicated to patients. Striking results from a study by Marin and colleagues showed that patients who were adherent to their chronic myelogenous leukemia therapy (>90%) had a significantly higher likelihood of achieving a major molecular response (93.7% vs 13.9%; P <.001) or complete molecular response (43.8% vs 0%; P = .002) compared with patients whose adherence rate to imatinib therapy was ≤90%.13 Moreover, the study authors found that some patients may have harbored the belief that occasionally missing a dose was not detrimental. Only patients who were adherent ≥90% of the time achieved molecular responses to imatinib therapy, whereas those who achieved even 80% did not, underscoring the importance of being fully adherent.

Perceived barriers are individual patient barriers that strongly affect medication adherence.11 Key patient barriers to medication adherence to oral oncolytic therapies are listed in the Table.14 In many cases, the patient’s beliefs and behaviors represent barriers to adherence. In addition, treatment-related factors, such as intolerance of treatment side effects and drug–drug interactions, are major patient barriers to medication adherence; however, both of these can be managed with proactive and timely intervention coupled with education. Education may alleviate patients’ fears and concerns regarding side effects, and must include information about early recognition signs, proactive management of side effects with supportive agents, and the importance of promptly reporting symptoms to their healthcare provider.2,15 In addition, all concomitant medications must be reviewed with the patient to prevent exacerbation of or new toxicities.2 Other patient-related barriers may include reluctance to change behaviors, age, sex, cognitive impairment (forgetfulness), comorbid conditions, and polypharmacy.2,16 Patients surveyed have ascribed 24% of nonadherence to forgetfulness, 20% to side effects, and 17% to cost issues.12 These rates may vary depending on various factors, including age, disease type, and complications. In a study of patients with breast cancer receiving hormonal therapy or an oral chemotherapeutic agent, forgetfulness (41%) and intolerance of side effects (36.5%) were the most common reasons for nonadherence.17 Some patients may not assimilate or recall treatment information, with studies showing that 40% to 60% of patients are unable to correctly recall instructions and information approximately 10 to 80 minutes after they were provided. Healthcare professionals need to identify each individual patient’s barriers, and address them effectively to improve medication adherence.


There are also several provider-related barriers that have been found to significantly impact treatment adherence. In particular, poor provider communication skills, poor provider–patient relationship, lack of positive reinforcement from the healthcare provider, and provider–patient discordance on treatment plans have been associated with nonadherence. A recent meta-analysis of the relationship between physician communication and patient treatment adherence found that patients whose physicians communicate poorly are at a 19% higher risk for nonadherence versus those whose physicians communicate well.18 Elements of communication must include effective interviewing skills, provision of useful information, continuous expressions of empathy and concern, and establishment of partnerships and participatory decision-making.

Because nonadherence is a complex issue, a multifactorial approach is needed to enhance adherence, and is encompassed in the mnemonic device, SIMPLE (simplifying regimen, imparting knowledge, modifying patient beliefs, patient communication, leaving the bias, and evaluating adherence).10 Patient education and communication is central to any adherence program, and involves the dissemination of information on the disease, treatment plan, risks and benefits of treatment, potential treatment-related side effects and drug–drug or drug–food interactions, and emphasizing the importance of adherence, to bring about changes in patient beliefs and behaviors.2,15


The benefits of oral oncolytic therapy for the treatment of patients with MM are undisputable; also evident are the high risks for nonadherence to these effective therapies that can, in turn, compromise their activities. It is imperative that several key messages are communicated to the patient to promote adherence and improve outcomes overall. First, patients must be made aware of the serious repercussions of not following the prescribed treatment completely, as well as the benefits of staying on course. Second, concerted efforts must be made to make patients understand that oral oncolytic therapy is not “just any ordinary pill,” but is a critical treatment approach that can adversely affect treatment outcomes and mortality. Finally, it must be conveyed that the benefits of adherence to oral oncolytics are compelling enough to overcome any identified barriers.


  1. CenterWatch. FDA approved drugs for oncology. www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-area/12/oncology. Accessed December 10, 2015.
  2. Cheung WY. Difficult to swallow: issues affecting optimal adherence to oral anticancer agents. Am Soc Clin Oncol Educ Book. 2013;265-270.
  3. Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94:652-661.
  4. World Health Organization. Adherence to long-term therapies: evidence for action. http://apps.who.int/medicinedocs en/d/Js4883e/. Published 2003. Accessed October 15, 2015.
  5. National Community Pharmacists Association. Take as directed: a prescription not followed [news release]. www.ncpanet.org/pdf/adherence/patientadherence-pr1206.pdf. Published December 15, 2006. Accessed December 14, 2015.
  6. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113:5401-5411.
  7. IMS Institute for Healthcare Informatics. Avoidable costs in US health care.
  8. www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMS%20Institute/RUOM-2013/IHII_Responsible_Use_Medicines_2013.pdf. Published 2013. Accessed October 10, 2015.

  9. Benjamin RM. Medication adherence: helping patients take their medicines as directed. Public Health Rep. 2012; 127:2-3.
  10. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer. 2008;99:1763-1768.
  11. Janz NK, Becker MH. The Health Belief Model: a decade later. Health Educ Q. 1984;11:1-47.
  12. Atreja A, Bellam N, Levy SR. Strategies to enhance patient adherence: making it simple. MedGenMed. 2005;7:4.
  13. Frost & Sullivan. Patient nonadherence: tools for combating persistence and compliance issues. www.frost.com/prod/servlet/cpo/115071625.pdf. Published December 2005. Accessed December 4, 2015.
  14. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381-2388.
  15. Oncology Nursing Society. Tools for oral adherence toolkit. www.ons.org/sites/default/files/oral%20adherence%20toolkit.pdf. Updated November 1, 2009. Accessed October 15, 2015.
  16. Jimmy B, Jose J. Patient medication adherence: measures in daily practice. Oman Med J. 2011;26:155-159.
  17. Accordino MK, Hershman DL. Disparities and challenges in adherence to oral antineoplastic agents. Am Soc Clin Oncol Educ Book. 2013;271-276.
  18. daCosta DiBonaventura M, Copher R, Basurto E, et al. Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer. Am Health Drug Benefits. 2014;7:386-396.
  19. Zolnierek KB, Dimatteo MR. Physician communication and patient adherence to treatment: a meta-analysis. Med Care. 2009;47:826-834.
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