CASE STUDY
Wesley is a 68-year-old male who had just retired as a French teacher when he was diagnosed with IgG kappa multiple myeloma, standard risk by cytogenetics, in 2014. He was initially treated with lenalidomide, bortezomib, and dexamethasone (RVd) and achieved a very good partial remission. He then underwent an autologous stem cell transplant. At 3 months following transplant, he was treated with maintenance lenalidomide at 10 mg po days 1 to 28 (NCCN, 2021). He achieved a complete remission after 8 months of therapy. In the beginning, Wesley tolerated lenalidomide maintenance well. He had no appreciable cytopenias. The nurse navigator worked with Wesley to secure copay assistance through a patient assistance foundation.
Unfortunately, after 24 months of lenalidomide maintenance, Wesley developed diarrhea. He learned to take cholestyramine powder once every morning for prevention of lenalidomide-induced diarrhea. With the help of a food diary, he learned to minimize certain fruits and vegetables in his diet that had been exacerbating the diarrhea ( Faiman et al., 2017 ). Occasionally, he needed to take loperamide up to 8 mg per day to abort the diarrhea when he had more than three stools per day over his baseline. After 5 years of maintenance, he wanted to take a break from treatment. He discussed his concerns with his main oncology team, which included an oncologist, advanced practitioner (AP), and nurse. Based on the deep remission and nearly 5 years on lenalidomide maintenance, he decided to take a planned treatment holiday. The diarrhea improved after 5 months, and as he continued to have no evidence of paraproteins in his serum or urine, he opted to stay off lenalidomide.
Diagnosis of Relapsed MM
Wesley had been walking 2 to 3 miles a day and remained active. It was his lifelong goal to spend 1 month traveling through France with his wife. He was skeptical about his ability to travel after his diagnosis, but over the past 5 years, his disease was stable, and he was finally off all therapy. Therefore, he made plans to travel to Europe. Recently, he noted an increase in thoracic spinal pain when walking only 15 minutes. He reported this pain to his oncology team and further testing was ordered. The results of his lab work revealed normal complete blood count, comprehensive metabolic panel, and beta-2 microglobulin. No new skeletal lesions were noted on PET scan. His monoclonal (M) spike was not detected since autologous stem cell transplant, but his most recent M spike trend over 4 months was 0.2 g/dL to 0.4 g/dL and now 0.8 g/dL. Table 1 shows International Myeloma Working Group criteria for relapse and recommended testing. No other lab or radiologic abnormalities were present, which qualifies for biochemical disease progression.
Table 1
Results of Lab Testing and Criteria for Relapse
Note. Hgb = hemoglobin; SCr = serum creatinine; FLC = free light chain; Ca2+ = calcium; MRD = minimal residual disease; FDG = fluorodeoxyglucose. Information from Kumar et al. (2016) ; NCCN (2022) .
| Clinical relapse requires ≥ 1 of the following criteria: Increase in the size of existing plasmacytomas or bone lesions Hypercalcemia (> 11 mg/dL) Hgb ≥ 2 g/dL not related to therapy or other non-myeloma-related conditions SCr ≥ 2 mg/dL from the start of the therapy and attributable to myeloma Hyperviscosity related to serum protein Increase of 25% from the lowest confirmed response value in n ≥ 1 of the following criteria: Serum M-protein ≥ 0.5 g/dL Urine M-protein ≥ 200 mg/24 hours If no serum or urine M-protein can be measured, the difference between monoclonal and polyclonal FLC levels must increase by > 10 mg/dL | Follow-up and surveillance tests CBC with differential Electrolytes; metabolic panel SCr and corrected serum Ca 2+ M-proteins and immunoglobulins Serum FLC as clinically indicated Bone marrow aspiration and biopsy Assess MRD Imaging as clinically indicated Consider using the same imaging modality during initial workup Whole body low-dose CT Whole body MRI Whole body FDG PET/CT |
Based on these results, his oncology team determined that Wesley should resume antimyeloma, plasma cell–directed treatment. He had been off lenalidomide for 2 years at this point, and therefore was not considered refractory to lenalidomide. Wesley asked if he could just resume lenalidomide as his diarrhea resolved, as it was “working” when he stopped the drug, but his oncology team suggested that a combination therapy including different drugs was likely to be more effective than just resuming lenalidomide at this relapse. The AP sat with Wesley and his wife, and reviewed numerous treatment options at first relapse ( Table 2 ).
Table 2
Suggested Treatment Options in Patients With MM: One to Three Relapses
Note. Information from Nijhof et al. (2017) ; NCCN (2022) ; Kumar et al. (2017) ; Jackson et al. (2019) ; Palumbo et al. (2010) ; Moreno et al. (2019) ; Laubach et al. (2015) .
| Class | Agent | Mechanism of action |
| Immunomodulatory agents (IMiDs) | Thalidomide Lenalidomide Pomalidomide | Both direct and indirect immunomodulatory effects through activation of T cells and NK cells Blocks adhesion molecules between the myeloma cells and the bone marrow stroma |
| Proteasome inhibitors (PIs) | Bortezomib Carfilzomib Ixazomib | Inhibition of the proteasome results in the cell's inability to undergo protein degradation leading to apoptosis |
| Monoclonal antibodies (mABs) | Daratumumab (human anti-CD38) Isatuximab (chimeric anti-CD38 Elotuzumab (humanized anti-SLAMF7) | Daratumumab and isatuximab bind to CD38 leading to apoptosis via antibody-dependent cellular toxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis Elotuzumab binds to SLAMF7 on the surface of the myeloma cells and NK cells. Upon binding to the myeloma cell, it targets it for recognition by the NK cells leading to apoptosis |
| Selective inhibitors of nuclear export (SINE) | Selinexor | Binds to and inhibits nuclear export protein, which leads to cell cycle arrest and apoptosis of cancer cells |
| BH3 mimetics | Venetoclax only for t(11;14) | BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1 |
| Chemotherapy | Cyclophosphamide Melphalan | Alkylating chemotherapy agent used in combination with other myeloma therapies |
Although multiple myeloma (MM) remains an incurable disease, the development of novel therapies since the early 2000s has improved the overall survival for myeloma patients. Over the past 10 years, survival rates of MM have significantly improved and are in the range of approximately 6 years. It is estimated that more than 80% of patients who are eligible for autologous transplant live longer than 4 years ( Attal et al., 2017 ; Durie et al., 2017 ).
Almost all patients treated for MM will relapse, and the duration of response decreases with each relapse. Harousseau and Attal (2017) report that since triple therapy combinations, including one immunomodulatory drug (IMiD), one proteasome inhibitor (PI), and dexamethasone, have been used in combination with maintenance therapy, the depth of response and increased numbers of complete responses have greatly improved overall survival and progression-free survival rates.
In this case study, Wesley relapsed 7 years after his initial treatment and was not on maintenance therapy at the time of slow, biochemical relapse. Therefore, Wesley has numerous treatment options and several factors which should be considered. The acronym TRAP (Timing of the relapse, Response to prior therapy, Aggressiveness of the relapse, and Performance status) is helpful in determining treatment strategies ( Rajkumar, 2018 ). Currently, combination drug therapy with three to four therapies is preferred for relapsed MM ( Moreau et al., 2021 ). Figure 1 depicts a decision algorithm based on consensus recommendations from the International Myeloma Working Group (IMWG).
Goals of therapy should be evaluated for all patients with multiple myeloma. There are numerous factors to consider at the time of relapse. High-risk features of relapse should be considered, such as high-risk cytogenetic findings, aggressiveness of CRAB criteria (Calcium elevation, Renal dysfunction, Anemia, and Bone disease), comorbidity, and the patient's preferences ( Nijhof et al., 2017 ). Ultimately, a shared decision model is the optimal approach when considering future treatment options. Shared decision-making occurs when both the patient and the health-care provider collaborate to develop a treatment plan that works best for the patient. The discussion includes data-driven treatment, the provider's experience in treatment of the disease, as well as the values and preferences that are important to the patient ( Faiman & Tariman, 2019 ; Steffensen et al., 2018 ).
Not all people living with MM value the same treatment attributes equally. Fifer and colleagues (2020) conducted an online survey of 124 people with MM in Australia. The survey also included 44 caregivers, 28 hematologists, and 34 nurses involved in the care of patients with MM. The survey used discrete choice experiments to quantify preferences for treatment. Overall survival, remission period, and annual out-of-pocket cost had the most variation. Caregivers were less cost sensitive than the MM patients and were more concerned with quality of life. Physicians and nurses were more concerned with survival and were more cost-conscious than the patients.
The Agency for Healthcare Research and Quality (AHRQ) recommend a “SHARE” approach to ensure clinicians are employing the concept of shared decision-making in the care of patients. Briefly, the five steps are (AHRQ, 2014):
Seek your patient's participation
Help your patient explore and compare treatment options
Asses your patient's values and preferences
Reach a decision with your patient
Evaluate your patient's decision.
HEALTHY BEHAVIOR AND PROMOTION OF WELLNESS
Advanced practitioners are in a pivotal position to encourage patients towards adopting healthy lifestyles to maximize wellness. Incorporating this discussion when caring for the myeloma patient is key. Glenn (2020) provides a strategy for motivational interviewing to include open-ended questions, reflective listening, and affirming, supportive, and summarizing statements to engage patients in behavior change. Glenn also suggests using the 5As template to guide clinical interventions ( Table 3 ; Goldstein et al., 2004 ).
Table 3
5 As Model to Promote Healthy Behaviors
Note. Information from Gilchrist et al. (2020) .
| Assess the patient's physical activity during the past 7 days. Advise the patient to engage in moderate-intensity physical activity for 150 to 300 minutes or vigorous-intensity physical activity for 75 to 150 minutes, if possible. This advice should be simple. The patient's personal and medical situation needs to be taken into account, such as potential risk for injury, bleeding, etc. Agree on whether the patient is ready for the recommended physical activity; if the patient is not ready, then this is not the time to pursue this further. If the patient is, then proceed to the next step. Assist the patient in developing specific and feasible goals for physical activity with the recommendation of a physician or physical therapist. Ask about logistical, financial, and psychosocial barriers to the activity, and explore strategies to mitigate them. Arrange for the patient to receive physical therapy, occupational therapy, or other support as needed. Discuss a plan to follow up with the patient to support their progression. |
Applying the 5As model to promote healthy behavior and wellness guides the advanced practitioner to ask about addictive behaviors such as alcohol, drugs and tobacco, dietary habits, physical activity, and sun exposure. The importance of assessing physical activity is validated in a recent study conducted by Gilchrist and colleagues (2020) . In this prospective study, higher levels of sedentary time were associated with a significant increase of cancer mortality compared with people who had an active lifestyle.
PATIENT SATISFACTION AND QUALITY OF LIFE
Chari and colleagues (2019) conducted a pilot observational study to determine factors associated with patient-reported satisfaction in patients with relapsed/refractory multiple myeloma (RRMM). An Eastern Cooperative Oncology Group (ECOG) performance status of > 2 (ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours) was associated with lower global satisfaction and perceived effectiveness of treatment ( NCI, 2020 ). Performance status was a main predictor of patient-perceived global satisfaction, as well as patient-perceived treatment effectiveness. Additionally, an all-oral treatment regimen not only predicted shorter time burden but also how patients perceived treatment convenience.
PSYCHOLOGICAL IMPACT OF DIAGNOSIS AND RELAPSE
Individuals diagnosed with MM will endure disease- and treatment-related complications throughout the trajectory of their disease. It is common for patients to receive continued treatment with little time away from treatment. Patients may respond to therapy for a period of time, and then be confronted with disease progression or relapse. Unfortunately, the patient is forced to continually adapt to the many challenges posed by this illness and its treatment regimens ( Cormican & Dowling, 2018 ). Faced with long-term side effects for patients, the evolving challenge in myeloma management is weighing disease progression with quality of life ( Kiely et al., 2017 ).
It is estimated that approximately 25% of patients with MM are diagnosed with psychological distress and symptoms associated with depression. The psychosocial dimensions of health-related quality of life (HRQOL) are a prognostic indicator for patients experiencing psychological issues. For this reason, it is important to assess the psychosocial status of the MM patient ( Maatouk et al., 2018 ). There is a paucity in research to describe the emotional experiences of the MM patient at the time of first and subsequent relapse in disease.
A qualitative study by Hulin and colleagues (2017) found that MM patients at first relapse described it as the most profound period of time in terms of negative emotions. Hopelessness, devastation, and resignation were often associated with the time of first relapse. Other common descriptors used during this period were scared, depressed, worried, confused, sad, and frustrated. The negative emotions of disease progression in the first relapse for MM patients were described as more devastating than the initial MM diagnosis. It is interesting that the majority of patients in the Hulin study (2017) reported that the emotions associated with subsequent relapses improved compared with the emotions during the first relapse, since patients learned what to expect.
CASE STUDY TREATMENT AND OUTCOME
As mentioned in the case study, Wesley and his wife wanted to spend 1 month traveling throughout France. They finally booked the trip 3 months out. Several options were considered, including combinations containing monoclonal antibodies such as isatuximab, daratumumab, and elotuzumab. In collaboration with his health-care team, Wesley opted for ixazomib 4 mg po days 1, 8, and 15 every 28 days; lenalidomide 25 mg po days 1 to 21 every 28 days; and dexamethasone 20 mg po weekly due to his slow, biochemical relapse and desire for an all-oral regimen to allow for travel. He decided that if this three-drug regimen did not control his MM, then he would postpone their trip and participate in a clinical trial with a monoclonal antibody, proteasome inhibitor, and corticosteroid.
After 2 months, Wesley's M-protein had decreased by 90%, achieving a very good partial response. He was feeling more hopeful about his future and was now able to travel and fulfill his lifelong dream of traveling around France for an extended period.
CONCLUSION
Although advancements in MM treatments have resulted in improved survival rates, MM remains incurable. There is an unmet need to address the emotional needs of myeloma patients and improve the overall patient experience during the relapsed phase of disease. It is not uncommon for the relapsed MM patient to feel hopelessness and devastation. In this case, Wesley was able to work with his clinical team and discuss what was important to him. Once he responded to therapy, his physical, psychological, and emotional status improved, and he was well enough to fulfill his goal of traveling to France.
Footnotes
Dr. Faiman has served as a consultant for Bristol-Myers Squibb, GSK, Janssen, Karyopharm, Legend Biotech, Oncopeptides, Sanofi, and Takeda. Dr. Noonan and Ms. Rome have no conflicts of interest to disclose.
References
Attal, M., Lauwers-Cances, V., Hulin, C., Leleu, X., Caillot, D., Escoffre, M.,…Munshi, N. (2017). Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. New England Journal of Medicine, 376(14), 1311–1320. 10.1056/nejmoa1611750
Chari, A., Romanus, D., DasMahapatra, P., Hoole, M., Lowe, M., Curran, C.,…Bell, J. A. (2019). Patient-reported factors in treatment satisfaction in patients with relapsed/refractory multiple myeloma (RRMM). Oncologist, 24(11), 1479–1487. 10.1634/theoncologist.2018-0724
Cormican, O., & Dowling, M. (2018). Living with relapsed myeloma: Symptoms and self-care strategies. Journal of Clinical Nursing, 27(7–8), 1713–1721. 10.1111/jocn.14232
Durie, B. G. M., Hoering, A., Abidi, M. H., Rajkumar, S. V., Epstein, J., Kahanic, S. P.,…Dispenzieri, A. (2017). Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet, 389(10068), 519–527. 10.1016/s01406736(16)31594-x
Faiman, B., Doss, D., Colson, K., Mangan, P., King, T., & Tariman, J. (2017). Renal, GI, and peripheral nerves: Evidence-based recommendations for the management of symptoms and care for patients with multiple myeloma. Clinical Journal of Oncology Nursing, 21(5), 19–36. 10.1188/17.cjon.s5.19-36
Faiman, B., & Tariman, J. (2019). Shared decision making: Improving patient outcomes by understanding the benefits of and barriers to effective communication. Clinical Journal of Oncology Nursing, 23(5), 540–542. 10.1188/19.cjon.540-542
Fifer, S. J., Ho, K.-A., Lybrand, S., Axford, L. J., & Roach, S. (2020). Alignment of preferences in the treatment of multiple myeloma – a discrete choice experiment of patient, carer, physician, and nurse preferences. BMC Cancer, 20(1), 546. 10.1186/s12885-020-07018-6
Gilchrist, S. C., Howard, V. J., Akinyemiju, T., Judd, S. E., Cushman, M., Hooker, S. P., & Diaz, K. M. (2020). Association of sedentary behavior with cancer mortality in middle-aged and older US adults. JAMA Oncology, 6(8), 1210–1217. 10.1001/jamaoncol.2020.2045
Glenn, D. (2020). Behavioral risk factors: A guide for oncology nurses counseling patients. Clinical Journal of Oncology Nursing, 24(5, Suppl 2), 9–18. 10.1188/20.CJON.S2.9-18
Goldstein, M. G., Whitlock, E. P., & DePue, J. (2004). Multiple behavioral risk factor interventions in primary care. American Journal of Preventive Medicine, 27(2 suppl), 61–79. 10.1016/j.amepre.2004.04.023
Harousseau, J. L., & Attal, M. (2017). How I treat first relapse of myeloma. Blood, 130(8), 963–973. 10.1182/blood-2017-03-726703
Hulin, C., Hansen, T., Heron, L., Pughe, R., Streetly, M., Plate, A.,…Ramasamy, K. (2017). Living with the burden of relapse in multiple myeloma from the patient and physician perspective. Leukemia Research, 59, 75–84. 10.1016/j.leukres.2017.05.019
Jackson, G. H., Davies, F. E., Pawlyn, C., Cairns, D. A., Striha, A., Collett, C.,…Russell, N. H. (2019). Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial. Lancet Haematology, 6(12), e616–e629. 10.1016/s2352-3026(19)30167-x
Kiely, F., Cran, A., Finnerty, D., & O'Brien, T. (2017). Self-reported quality of life and symptom burden in ambulatory patients with multiple myeloma on disease-modifying treatment. American Journal of Hospice and Palliative Medicine, 34(7), 671–676. 10.1177/1049909116646337
Kumar, S., Kaufman, J. L., Gasparetto, C., Mikhael, J., Vij, R., Pegourie, B.,…Verdugo, M. (2017). Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood, 130(22), 2401–2409. 10.1182/blood-2017-06-788786
Kumar, S., Paiva, B., Anderson, K. C., Durie, B., Landgren, O., Moreau, P.,…Zamagni, E. (2016). International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncology, 17(8), e328–e346. 10.1016/s1470-2045(16)30206-6
Laubach, J. P., Moreau, P., San-Miguel, J. F., & Richardson, P. G. (2015). Panobinostat for the treatment of multiple myeloma. Clinical Cancer Research, 21(21), 4767–4773. 10.1158/1078-0432.ccr-15-0530
Maatouk, I., He, S., Becker, N., Hummel, M., Hemmer, S., Hillengass, M.,…Hillengass, J. (2018). Association of resilience with health-related quality of life and depression in multiple myeloma and its precursors: Results of a German cross-sectional study. BMJ Open, 8(7), e021376. 10.1136/bmjopen-2017-021376
Moreau, P., Kumar, S. K., San Miguel, J., Davies, F., Zamagni, E., Bahlis, N.,…Cavo, M. (2021). Treatment of relapsed and refractory multiple myeloma: Recommendations from the International Myeloma Working Group. Lancet Oncology, 22(3), e105–e118. 10.1016/s1470-2045(20)30756-7
Moreau, P., Masszi, T., Grzasko, N., Bahlis, N. J., Hansson, M., Pour, L.,…Laubach, J. P. (2016). Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine, 374(17), 1621–1634. 10.1056/nejmoa1516282
Moreno, L., Perez, C., Zabaleta, A., Manrique, I., Alignani, D., Ajona, D.,…Paiva, B. (2019). The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clinical Cancer Research, 25(10), 3176–3187. 10.1158/1078-0432.ccr-18-1597
National Cancer Institute. (2020). SEER Training Modules, ECOG Performance Status. U. S. National Institutes of Health, National Cancer Institute. https://training.seer.cancer.gov/
National Comprehensive Cancer Network. (2022). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.4.2022. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
National Comprehensive Cancer Network. (2020). NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. V.2.2020. http:www.nccn.org/professionals/physician_gls/pdf?fatigue.pdf
Nijhof, I. S., van de Donk, N. W. C. J., Zweegman, S., & Lokhorst, H. M. (2017). Current and new therapeutic strategies for relapsed and refractory multiple myeloma: An update. Drugs, 78(1), 19–37. 10.1007/s40265-017-0841-y
Palumbo, A., Larocca, A., Genuardi, M., Kotwica, K., Gay, F., Rossi, D.,…Richardson, P. (2010). Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial. Haematologica, 95(7), 1144–1149. 10.3324/haematol.2009.017913
Rajkumar, S. V. (2018). Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management. American Journal of Hematology, 93(8), 1091–1110. 10.1002/ajh.25117
Steffensen, K. D., Vinter, M., Crüger, D., Dankl, K., Coulter, A., Stuart, B., & Berry, L. L. (2018). Lessons in integrating shared decision-making into cancer care. Journal of Oncology Practice, 14(4), 229–235. 10.1200/jop.18.00019