With commentary by
Charise Gleason, MSN, NP-C, AOCNP
Advanced Practice Provider Chief
Winship Cancer Institute of Emory University
Nell Hodgson Woodruff School of Nursing
Targeted agents and immunotherapies have revolutionized the management of multiple myeloma, offering better upfront responses and longer remissions.1 Due to these advances, the 5-year survival rate for multiple myeloma has doubled over the past 3 decades, and many patients now achieve a high quality of life with therapy.1
Still, the treatment journey can be a rocky road, as aggressive consolidation therapy may induce adverse events, and maintenance therapy, while more tolerable than ever, may still come with side effects.2,3 In addition to issues with tolerability, treatment regimens for multiple myeloma are often complex and include oral agents taken at home; these factors present a challenge for any patient, but especially those with comorbidities, who may already be taking a variety of other medications, and may benefit from greater oversight than at-home therapy typically provides.4,5 Treatment may also present financial difficulties, and if patients lack social support, have cognitive impairment, or face communication barriers with healthcare providers or pharmacies, it is likely that these patients will struggle to take the right medication at the right time, every time, for years to come.4 In fact, 30% of patients taking oral immunomodulatory agents for multiple myeloma are nonadherent, meaning they aren’t taking their oral therapy at all.6 This suggests that issues with adherence are common—a troubling finding, given the clear association between high adherence and optimal outcomes.5
To achieve better adherence, and therefore better outcomes, nurses and nurse navigators need to identify barriers to adherence before a patient begins treatment, remain vigilant for issues with adherence throughout the treatment journey, and intervene as needed. This article offers a brief review of multiple myeloma therapies, followed by strategies for increasing treatment adherence, including ways of setting patient expectations, discussing quality of life and drug holidays, troubleshooting possible adverse events, and other approaches. Each evidence-based section is accompanied by expert commentary from Charise Gleason, MSN, NP-C, AOCNP, nurse practitioner for the myeloma team and Advanced Practice Provider Chief at the Winship Cancer Institute of Emory University, Atlanta.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: With so many effective therapies available and more on the way, multiple myeloma has become more of a chronic disease for certain patients, so many patients are on maintenance therapy with an oral agent. With oral agents, adherence does become a little more challenging. I don’t think patients always realize how potent these oral medicines are; they think it’s much easier to take a pill, but it’s also easier not to. Because of this, it’s important to have good communication from the start for setting expectations and fostering a good relationship. That way, if the patient has an issue with their medication, they’ll feel comfortable talking about it. Having that open line of communication is essential.
As individual targeted therapies and immunotherapies have advanced, so have ways of using them together to treat multiple myeloma.7 In the frontline setting, most patients now receive at least a triplet regimen, and quadruplets are becoming increasingly recommended.7,8 Although doublet regimens were once a standard of care, they are now typically reserved for frail patients at time of relapse, with a third drug added when performance status improves.8,9 Maintenance treatment typically involves an immunomodulatory drug (IMID) or a proteasome inhibitor (PI), typically given until progression, if toxicity does not occur.9 Drug classes used to treat multiple myeloma, an example agent from each class, and common adverse events are provided in the Table.10-13
Although this is far from an exhaustive list of all possible adverse events, familiarity with the unique safety profile of each agent is invaluable when investigating a suspected adverse event. For example, if a patient taking a triplet of bortezomib, lenalidomide, and dexamethasone complains of severe weakness (asthenia), lenalidomide may be the most likely inciting agent. If, on the other hand, they report “pins and needles” in their feet (peripheral neuropathy), then bortezomib is a more likely culprit. As will be discussed in further detail below, identifying such events and responding to them in a timely manner is an essential part of maintaining adherence.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: If you look at the common adverse events in the Table, or on drug labels, it’s a huge list, but it looks much worse than what we see in practice. When you become familiar with these treatments, it’s not so daunting because you begin to see certain issues more often than others.
With bortezomib (a PI), for example, we think of peripheral neuropathy, some gastrointestinal issues, and thrombocytopenia that’s cyclical. For lenalidomide (an IMID), especially for patients on single-agent maintenance therapy, diarrhea is very common. Muscle cramps are also common with IMIDs. Daratumumab (a monoclonal antibody [mAb]) makes us think of infection and injection site reactions, although reactions have become much less common with the subcutaneous route. Although the daratumumab label may list cytopenia, that’s usually the result of combination therapy. And finally, for dexamethasone (a steroid), we think of insomnia, mood swings, rising blood glucose levels, edema, and immunosuppression. You’re going to see some level of fatigue with most myeloma treatments.
Achieving better adherence among patients with multiple myeloma requires a comprehensive approach that begins before treatment. This strategy can be divided into 4 steps: (1) prepare, (2) monitor, (3) investigate, and (4) intervene. Keep in mind that this is a cyclical process, as shown in the Figure. If a patient has a regimen adjustment, or starts a new phase of treatment, then it is necessary to begin again by preparing the patient for the next leg of their treatment journey.
Preparing a patient for their treatment journey is much like preparing a traveler for a trip to an unfamiliar place. Patients are likely to have the same kinds of questions: What will it be like? How long will it take? Who will be there to help me? By anticipating and answering such questions, nurses and nurse navigators set expectations. This is critical because patients with accurate expectations are more adherent, report fewer adverse events, and maintain a higher quality of life.14
Perhaps the most important question to answer is: Why do I need to take these medications as prescribed? This question is so simple that it may be overlooked, but the answer is impactful: Patients with multiple myeloma who take their medications as prescribed have better outcomes.5 The plain fact that adherence is important may motivate patients to stay on top of their regimen; in addition, understanding why a certain treatment is recommended can help patients feel safer and more comfortable, which can build trust.4,15,16
Trust is a key component of the shared decision-making process, which itself promotes adherence, as shared decision-making has been linked with greater patient autonomy (ie, taking oral medications without supervision), as well as better health and emotional outcomes.17 Ideally, this process should also include caregivers and family, who may help patients in a variety of ways, from emotional to practical support. Nurses and nurse navigators can facilitate these conversations, and help stakeholders predict and overcome obstacles in the road ahead.
Although every patient is different, healthcare providers should be aware of common barriers to adherence and screen patients for these issues before they can occur.4 Barriers can be far-ranging, from practical concerns such as cost or trouble organizing medications, to emotional challenges such as fear and depression, or other issues, such as language barriers, lifestyle factors, or lack of social support.4,15
Nurses and nurse navigators need to be aware of common misconceptions about treatment, as well as common knowledge gaps, as these can lead to poor adherence for different underlying reasons that require unique solutions.4 For example, one patient who isn’t feeling well may think it’s okay to skip a few days of their oral medication without telling their provider. Another patient with cost concerns might skip doses if they are unaware of financial assistance programs. Uncovering these motivations depends on an open, two-way path of communication that should be fostered from the very beginning.
Early conversations with patients and caregivers should also touch on quality of life, as patients may need to weigh the short-term discomfort of adverse events against long-term survival benefit. In this context, it is also important to set expectations about the various time frames and probabilities involved in the treatment journey, including therapy duration and tolerability, as well as likelihood of remission and relapse.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: It’s important to set expectations before starting treatment, especially with patients who are taking an oral regimen. They should know that these oral medications are still potent drugs, and they should be aware of common side effects so they aren’t surprised by them and can report them. Most patients experience some level of fatigue, but other side effects vary from patient to patient, so they should be encouraged to call if they just feel different or worse, because they may be having a less common adverse event.
It’s also helpful to explain that regimen modifications may be needed. We might start at a higher dose with one of these oral agents, but if side effects become an issue, we may modify treatment. We’d rather do it that way and have them let us know what those side effects are, instead of them holding the drug without us knowing.
Once a patient starts treatment, they will need to be monitored to ensure safety and efficacy, and to uphold adherence.4 Frequency of follow-up varies, with patients starting treatment typically requiring more frequent follow-up than those on maintenance therapy.4 Between office appointments, communication can be conducted through virtual visits, e-mails, text messages, and phone calls.4 In each communication, adherence should be checked, with new barriers identified and addressed as needed.4 These communications can also serve as opportunities to reiterate the importance of adherence, and to encourage use of reminder tools, such as pillboxes or calendars, to stay on top of oral medications.4
Many of these interactions will be provider-initiated, meaning it is the doctor’s office reaching out to the patient; however, the opposite direction of communication should be open and encouraged as well, especially when a patient who is starting therapy has concerns about adverse events. Patients should know that new symptoms need to be reported as soon as possible.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: For a patient starting on a new regimen, we like to call and check on them just to see how they’re doing. We encourage them to reach out to us if they have a concern that’s not life-threatening. We’ve got a patient portal so patients can reach out to our team, allowing us to either respond in the patient portal or call them back.
If a patient is struggling to take their pills, or they keep forgetting, we can help them set up a pillbox. We’ve had patients who bring in their pills every month and we fill their pillboxes, although we don’t have to do that a whole lot. There are also reminder alarms available for patients, caregivers, and family members; there’s even an electronic pillbox that caregivers can check to see if their loved one has taken their medicine.
If a patient is struggling to take their cancer treatment, chances are they’re struggling to take their other meds too. For instance, if a patient is on lenalidomide, they may also take aspirin for deep-vein thrombosis prophylaxis. Or they may be taking an antiviral, and you don’t want them to randomly miss their antiviral because they could get shingles. We need to reinforce the importance of these other drugs that come with the cancer treatment. To do this, we maintain an ongoing conversation not only about their cancer treatment, but also the other medications they take because of the regimen they’re on.
When a patient reports a new symptom, they should first be praised for doing so, as this will encourage rapid communication in the future.4 Then, the patient should be reminded that new symptoms can be due to their disease process, treatment, or both.
What happens next can vary widely depending on the patient, the symptom, and the timing of onset. For example, a patient reporting severe vomiting soon after starting a triplet regimen is likely having an adverse event, whereas a patient who complains of recent-onset vomiting after 9 months of maintenance therapy may require more in-depth diagnostics.
Investigating new symptoms is typically a collaborative process, in which nurses and nurse navigators act as chief communicators, bringing together physicians from relevant specialties to create an appropriate diagnostic plan and intervene as needed. Patients should know that this can be a time-intensive process, potentially requiring extensive diagnostics, and/or medication adjustments on a trial-and-error basis.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: It is important to investigate possible adverse events because unmanaged side effects are the most common reason for poor adherence. If a patient contacts us with concerns about their treatment, we first need to decide if we can help without bringing them in, or if we need to assess them. Sometimes we can just handle the issue over the phone. If it’s more serious, patients can come into the infusion center urgent care, the clinic, or the emergency department, depending on the issue.
Workup depends on symptoms, which are typically due to the disease, side effects from the drugs, or infection. Beyond those more common concerns, we do see a lot of other side effects when patients have comorbidities, so it’s not unusual to refer to other specialties such as orthopedics or endocrinology. Patients would like the cancer team to take care of all aspects of their care, but they still need their other providers, especially primary care, to manage other health issues.
If necessary, treatment regimens may be modified, whether due to adverse events or disease progression. Any changes in treatment should serve as reminders to nurses and nurse navigators that adherence may again be at stake. Patients who recently experienced an adverse event may have developed negative emotions surrounding treatment, such as fear of more adverse events, or they may face unique challenges not presented by their previous regimen. Healthcare providers should therefore return to the first step of this four-step process, again preparing patients by setting clear expectations for the road ahead, monitoring closely, and investigating new issues as they arise.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: If you are changing therapy due to disease progression, hopefully it’s not a surprise for the patient, as you’ve already been monitoring for relapse all along. Most patients have biochemical relapse first, so as their numbers start to move, we discuss what might be happening, and the next potential line of therapy.
During these early conversations, you don’t have to go into a lot of detail, but patients should already have something in mind for the next treatment. It is pretty common for patients with myeloma to expect relapse and therapy changes because many of them go to support groups, where they learn from the experiences of others. Patients like to know what’s next, even if they’re on a treatment that’s working for them.
Some patients with multiple myeloma take maintenance medications such as lenalidomide and steroids for years, and these medications may come with side effects, such as mood changes or gastrointestinal disturbances.10,13 With this in mind, it is understandable that some patients, after months or years of therapy, would like to take a break, and may request permission to do so.
When considering this request, first consider the data: In 2018, a phase 3 trial by Facon and colleagues found no difference in median overall survival between patients who took lenalidomide and low-dose dexamethasone continuously versus in a cyclical regimen lasting up to 72 weeks; however, patients on continuous therapy had longer progression-free survival (26 vs 21 months), suggesting that there is a positive impact from taking maintenance therapy full-time.18 Beyond this one trial, data are lacking, so it is challenging to say exactly what effect a drug holiday, or multiple drug holidays, may have on disease course.19
Next, consider expert opinions on the matter: Robert Orlowski, MD, of the MD Anderson Cancer Center, Houston, said in a 2018 interview that the jury is still out on drug holidays. Until more data are available, he recommended that patients on lenalidomide take their medication daily unless adverse events become prohibitive, then a break or dose reduction may be needed.20
Similarly, in a more recent interview from 2021, Peter Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, said the first step to take when a patient asks about a drug holiday is to find out why.21 Is the patient experiencing an adverse event? How severe is it? What efforts have been made to alleviate the issue? If more can be done to control adverse effects, then these steps should be taken. Only then, if an adverse effect cannot be controlled, and is significantly impacting quality of life, should a regimen modification be considered.21 Dr Voorhees also noted that some patients will request a drug holiday even if they aren’t struggling with a specific adverse effect.21 In this scenario, it’s best to discuss the link between adherence and long-term outcome, and to note that duration of first remission is especially important in a treatment landscape that is evolving so fast.21 The longer that remission can be sustained, the more likely it is that better treatments are available when relapse occurs.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: We want to keep patients on the highest dose of treatment that they can tolerate, but patients get tired, and they get treatment fatigue, and there isn’t a drug that we put a patient on that has no side effects. If a patient feels like they’d rather come off treatment altogether, then you need to consider a mini holiday from it.
I don’t typically emphasize drug holidays right from the start. You don’t want to set up the expectation that a patient is not going to have to take their treatment. Instead, I explain that we can make dose modifications if needed and emphasize how important it is to communicate how they are feeling. I don’t want patients to feel like we are rigid or we’re not listening to their concerns, but we have to explain that sprinkling—starting and stopping medications—can lead to resistance. Sometimes we need to re-educate patients about the importance of staying on therapy to control the myeloma. Because at the end of the day, the biggest risk is myeloma coming back, although we don’t want to ignore the importance of quality of life.
A patient’s family members and friends can be invaluable for supporting adherence throughout the treatment journey—whether that means picking up medication from the pharmacy, offering motivation and positivity, keeping track of treatments, or simply being present. Still, it is important to remember that a patient’s loved ones have needs of their own, and may be negatively impacted by the treatment journey on an emotional, physical, social, and spiritual level, possibly altering long-standing relationships and normal family organization.22 Therefore, it is necessary to reinforce a patient’s personal support team with outside help from therapists, social workers, and third-party patient advocacy organizations, all of whom can help navigate the complex, psychosocial consequences of a cancer diagnosis.
Patient advocacy organizations may also be able to provide financial assistance to patients in need, thereby reducing the financial stress that treatment can impose. Leading organizations for multiple myeloma include the International Myeloma Foundation, Patient Access Network Foundation, CancerCare, and the Leukemia & Lymphoma Society.
Commentary by Charise Gleason, MSN, NP-C, AOCNP: Sometimes a patient’s family and friends make recommendations about supplements and other modalities. However, oral drugs for myeloma can have reactions with other medications or supplements, so you don’t want patients taking something without running it by their team. You may need to discuss these supplements one by one—explaining that there are some supplements that are fine while others do nothing but add side effects. It all goes back to communication.
When communicating with a patient’s family, it is important to also listen to the care partner, and we do have circumstances where we have multiple family members involved in a discussion. The key is to keep the focus on the patient while also realizing the impact the diagnosis and treatment has on the caregiver. Try to let the patient answer the questions instead of the family answering for them, but also address the family members’ concerns. When family members or caregivers are also comfortable with the team, they are more open to listening to them, and develop a trust that ultimately benefits the patient.
Targeted agents and immunotherapies have greatly improved outcomes in multiple myeloma, allowing many patients to live for years with a high quality of life. To achieve best outcomes, however, medications need to be taken as prescribed. For nurses and nurse navigators, this paradigm calls for a vigilant approach to adherence, including awareness of barriers to adherence and differences in safety profiles between agents. Healthcare providers need to adequately prepare their patients for their treatment journey, monitor for adherence throughout this process, investigate issues with adverse effects and adherence as they arise, and intervene as necessary, with a cyclical approach whenever the treatment plan changes. Although nurses and nurse navigators can act as champions of adherence, they cannot bear the burden alone, and need to collaborate with other healthcare providers, a patient’s loved ones, social workers, therapists, and patient advocacy organizations, all the while maintaining a strong line of communication with the most important stakeholder of all: the patient.
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