Minimizing Non-adherence and Improving Compliance in Multiple Myeloma

The Managing Myeloma Accredited e-Newsletter Volume 2, Issue 2

Activity Overview  
In multiple myeloma (MM), the emergence of several oral agents and the increased use of maintenance/continuous therapy could result in more treatment non-adherence and therefore reduced efficacy. Patient-related, treatment-related, and clinician-related factors can all contribute to non-adherence and should be understood by health care providers, the goal being to gauge the patient’s risk for inadequate dosing. This CE activity discusses the potential for non-adherence to myeloma therapy and aims to identify ways that clinicians can ameliorate this risk.

Minimizing Non-adherence and Improving Compliance in Multiple Myeloma

Progress in the Therapy of Multiple Myeloma
Multiple myeloma (MM) is a plasma cell neoplasm that is characterized by presence of a monoclonal plasma cell population in the bone marrow that produces a monoclonal immunoglobulin (and/or light chains), along with evidence of end organ damage, which usually includes renal failure, anemia, bone lesions, and immune dysfunction. The new MM definition includes certain features where end organ damage is not necessary to initiate therapy (free light chain ratio ≥100, bone marrow plasmacytosis ≥60% and ≥1 MRI focal lesions ≥5 mm each).1 The outcomes and management of MM in the US has changed dramatically over the last 15 years, with the FDA approval of 10 new drugs (thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, ixazomib, doxorubicin liposomal HCl, panobinostat, elotuzumab, daratumumab), and the survival of an average MM patient has tripled [SEER database 5-year survival]. The majority of MM patients do relapse, requiring subsequent lines of therapy to manage their disease like a chronic condition.2 Even though we recognize the heterogeneity in the clinical presentation and disease biology of newly diagnosed MM patients, the current treatment approaches still follow a “one-size-fits-all” dogma.

The management becomes more challenging for relapsed/refractory MM patients in which the clinician must plan treatments while considering many factors, including disease biology (cytogenetics, FISH, depth and duration of response to previous therapy), disease burden (presence/absence of renal failure, bone fractures, pattern of relapse, etc.), host factors (age, comorbidities, performance status, etc.) and potential financial or logistic limitations (cost of therapy, insurance, etc.). In addition, there are several new novel drug classes and immunotherapies making their way through clinical development. It is still important to channel the relapsed/refractory MM patients towards appropriate clinical trials where possible. There are several FDA-approved therapies that are oral medications [See Table 1 below] and the present review will highlight the significance of drug adherence along with side effects unique to each of these options.

TABLE 1  FDA-approved oral modern therapies for multiple myeloma

Oral Drug

FDA-Approved Indication

Dosing Schedule

Most Common Side Effects

Thalidomide

Newly diagnosed

200 mg daily po plus dexamethasone

Thromboembolism, peripheral neuropathy, asthenia, edema, myalgia/arthralgia, bradycardia, constipation, anemia, thrombocytopenia

Lenalidomide

Newly diagnosed and relapsed

25 mg daily po on Days 1-21 every 28 days (dose modifications for renal impairment, etc.)

Diarrhea, fatigue, anemia, constipation, neutropenia, peripheral edema, insomnia, muscle cramp/spasms, back pain, nausea, asthenia, pyrexia, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor

Pomalidomide

Relapsed/refractory ≥2 prior therapies including
Len/Bor and disease progression ≥60 days of completion of the last therapy

4 mg per day taken orally on days 1-21 every 28 days until disease progression

Fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia

Panobinostat

Relapsed/refractory ≥2 prior therapies including
Len/Bor

20 mg po every other day for 3 doses per week (on Days 1, 3, 5, 8, 10, and 12) of Weeks 1 and 2 of each 21-day cycle for 8 cycles (may continue another 8 cycles if clinical benefit)

Thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia, diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting

Ixazomib

Relapsed MM ≥1 prior therapy

4 mg po Days 1, 8, and 15 every 28-day cycle in combination with Len/Dex

Diarrhea, constipation,
thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain

Len=lenalidomide; Bor=bortezomib; Dex=dexamethasone


Non-Adherence to Oral Medications in Hematologic Malignancies
Non-adherence to oral medications is a problem relevant to management of most chronic medical conditions, and is most commonly observed with hypertension, diabetes, asthma, and even infections.3 In hematologic malignancies, non-adherence with oral medications has been more relevant to chronic myeloid leukemia (CML), and perhaps to acute lymphoblastic leukemia (ALL). The ADAGIO study,4 a prospective study in CML patients taking imatinib mesylate, highlighted the prevalence of non-adherence and its associated suboptimal responses. Other studies have shown that non-adherence does impact depth of response; it may also impact the achievement of molecular response in CML patients who have already achieved complete cytogenetic response.5 Several retrospective and commercial database analyses show both higher medical costs and health care utilization for non-adherent patients.6 This observation is consistently seen even for second- and third-generation tyrosine kinase inhibitors (TKIs).7 Non-adherence has been recognized as a major reason for treatment failure in CML, and NCCN guidelines do include assessment of adherence when there appears to be loss of response to TKI therapy.8

There are several factors that may contribute to non-adherence to oral medications, perhaps best categorized as patient-specific, therapy-specific, and physician-specific factors. Low adherence is observed more in younger patients who may feel better with therapy and may become less compliant over time. Some patients may not have a good understanding of the risks and benefits of treatment, whereas others may make a conscious decision based on health or religious beliefs. Side effects from the treatment, along with polypharmacy, may play a role in non-adherence, as well. In the current health care environment, high co-pays, or lack of drug coverage by insurance may influence decisions to continue certain drugs. On the physician end, poor communication and inadequate patient education may contribute to non-adherence.   

Relevance of Non-adherence to MM Therapy
Multiple myeloma therapy is entering an exciting era; there are several oral agents that are FDA-approved for treatment at various stages of the disease (newly diagnosed, relapsed, relapsed/refractory, etc.). Clinical trials are now underway to develop all-oral induction regimens for newly diagnosed patients. Several randomized phase III clinical trials have shown that continuous therapy appears to be beneficial for survival outcomes in both transplant-eligible9,10 and transplant-ineligible11,12 patients. [See Table 2 below] Therefore, a vast majority of MM patients are now receiving maintenance therapy beyond having achieved best response. The same concept appears to be applicable to the relapsed setting, as well; all the phase III trials continue therapy until disease relapse or progression.13-15

TABLE 2  Phase III clinical trials have shown that continuous therapy appears to be beneficial for survival outcomes in both transplanteligible9,10 and transplantineligible11,12 patients

Trial

Patient Population

Treatment Arms

PFS (P-value)

OS (P-value)

McCarthy, et al. N Engl J Med. 20139

Transplant eligible, newly diagnosed

Len vs. placebo

3-year 66% vs. 39% (<0.001)

3-year 88% vs. 80% (0.03)

Attal, et al. N Engl J Med 201310

Transplant eligible, newly diagnosed

Len vs. placebo

Median PFS 41 months vs. 21 months (<0.001)

3-year 80% vs. 84% (0.29)

Palumbo, et al. N Engl J Med. 201311

Transplant ineligible, newly diagnosed

MP vs. MPL vs. MPL-Len maintenance

Median PFS 31 months vs. 14 months vs. 13 months (<0.001)

Not reached

Benboubker, et al. N Engl J Med. 201412

Transplant ineligible, newly diagnosed

MPT vs. Len/Dex vs. Len/Dex-Len maintenance

Median PFS 21.2 months vs. 20.7 months vs. 25.5 months (<0.001)

Not reached

Stewart, et al. N Engl J Med. 201513

Relapsed, 1-3 prior lines

Len/Dex +/- Carfilzomib

Median PFS 17.6 months vs. 26.3 months (<0.0001)

Not reached

Lonial, et al. N Engl J Med. 201514

Relapsed, 1-3 prior lines

Len/Dex +/- Elotuzumab

Median PFS 14.9 months vs. 19.4 months (<0.001)

Not reached

Moreau, et al. ASH 201515

Relapsed, 1-3 prior lines

Len/Dex +/- Ixazomib

Median PFS 14.7 months vs. 20.6 months (0.012)

Not reached

PFS=progression-free survival: OS=overall survival; Len=lenalidomide; Bor=bortezomib; Dex=dexamethasone; M=melphalan; P=prednisone; L=lenalidomide; T=thalidomide


Non-adherence has not been an issue with MM patients, primarily because there were not many oral treatment options available and the available options had significant side effects with long-term use. The current cadre of FDA-approved oral agents in MM, although better tolerated than cytotoxic chemotherapies, does have safety profiles that may pose challenges for therapy-specific non-adherence. Physicians may be biased towards a treat-to-best-response approach, which may impact their treatment discussions with and education of MM patients. Unlike the CML paradigm (single genetic abnormality being targeted by a biologic), MM is a very heterogeneous disease, and adherence to therapy has not been well-studied in this patient population. Nevertheless, it will be very important to address this issue prospectively, given the improvement in survival for MM patients with continuous therapy. Educating patient about the side effects and helping them identify lifestyle modifications to mitigate those side effects will be very important to achieving improved outcomes. Similarly, early recognition of side effects by the treating physicians will lead to appropriate dose-reduction and/or pharmacologic interventions to reduce side effects (such as peripheral neuropathy management) that may facilitate the patient remaining on therapy longer, and potentially reaping the benefits of improved outcomes. Helping patients maintain tabs on their treatment schedule (providing monthly treatment calendars, pill boxes, etc.) may help improve adherence, as well as ongoing re-enforcement about the benefits of adherence.

Conclusions
There are several issues that remain unanswered about the use of oral agents in MM. We do not know the association of adherence with an optimal dose delivery (percentage of planned dose of oral treatment) or schedule (percentage of planned days of oral treatment) to outcomes with each of the available therapies. There is an ongoing debate about the optimal duration of maintenance for newly diagnosed MM patients, although perhaps the IFM/DFCI 2009 phase III trial may help answer the question (limiting lenalidomide maintenance to 2 years versus continuous therapy).16-18 There are no head-to-head comparisons on which oral agents (PI vs. IMiD) may be best suited for particular MM subsets. However, the available data overwhelmingly supports the continuous therapy approach for both newly diagnosed and relapsed/refractory MM patients. Therefore, adherence to therapy becomes a very relevant clinical concern that needs to be proactively addressed by treating physicians. Taking the lessons learned from TKI therapy in CML, treating physicians may be able to avoid the treatment failures and manage the therapy-related side effects associated with non-adherence more efficiently.




REFERENCES

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