Effective supportive care measures are crucial to the successful treatment of patients with multiple myeloma (MM). From the time of initial diagnosis, it is essential to monitor and manage myeloma-related symptoms (ie, hypercalcemia, renal insufficiency, anemia, and bone lesions), which are caused by the increased number of plasma cells and abnormal monoclonal proteins. In addition, as new agents continue to be incorporated into front-line MM regimens, it is equally important to focus on the amelioration of toxicities associated with these drugs to prevent unnecessary treatment delays and discontinuation, as well as promote improved quality of life and survival. In this article, Charise Gleason, MSN, ANP-BC, AOCNP, responds to questions regarding key aspects of nursing care for newly diagnosed MM patients, with an emphasis on the assessment and management of diseaseand therapy-associated complications.
How do you assess bone involvement in newly diagnosed patients with MM? Is a skeletal survey enough, or are additional imaging studies necessary?
The standard of care for assessing myeloma-associated bone disease in newly diagnosed patients remains skeletal survey with a clean set of radiographs.1 These x-rays allow for identification of lytic lesions in bones throughout the body. However, the issue of whether to do more extensive and expensive imaging does arise in some cases. At our center, if a skeletal survey is negative, we advocate magnetic resonance imaging (MRI) to look for evidence of lytic lesions. This is recommended by the International Myeloma Working Group for patients with smoldering multiple myeloma,1,2 since the presence of occult bone lesions on MRI have been associated with an increased risk of progression to MM.2,3
Because MRI is more sensitive than conventional radiography, it can detect patterns of abnormal, diffuse bone marrow, as well as focal lesions prior to osteolysis, thereby providing useful prognostic information.4-6
We also consider MRI in patients with minimally abnormal skeletal surveys who report back pain or other neurologic symptoms. In situations such as these, we are now ordering upfront MRIs with greater frequency, as they allow us to more carefully examine the spine to ensure we are not missing a potentially dangerous, neurologically relevant lesion. We are also able to assess soft tissue and its possible contribution to a patient’s pain. Furthermore, an MRI of the whole spine provides a baseline prior to any supportive spinal interventions, such as kyphoplasty or vertebroplasty.7,8
The use of fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) scan in newly diagnosed MM is also gaining support.5 At our center, we are still trying to determine the exact utility of FDG-PET/CT scanning in our work-up of myeloma patients. These techniques detect bone marrow involvement with high sensitivity and specificity and distinguish intramedullary and extra - medullary lesions quite well, and can reveal inflammatory and infectious complications.5 It has been reported that FDG-PET at the time of initial diagnosis results in higher staging of MM, and consequently, the use of more aggressive front-line therapy.9 We tend to use FDG-PET in 2 types of patients: (1) those with minimal marrow disease but a significant amount of diffuse, lytic bone disease and (2) those with true nonsecretory disease (ie, patients whose disease cannot be measured by urine protein, serum protein, or free light chains). In these patients, instead of performing serial bone marrow biopsies, FDG-PET is a useful modality.
What supportive care strategies do you use to manage hypercalcemia and optimize bone health in newly diagnosed patients with MM? Bisphosphonates are essential for managing hypercalcemia and supporting bone health in patients with MM, as outlined in the 2007 clinical guidelines for bisphosphonate developed by the American Society of Clinical Oncology (ASCO).10 Hypercalcemia occurs in approximately 13% of cases of newly diagnosed MM (Table 1).11 At our center, we define this condition as a serum calcium level >10.3 mg/dL. Patients with hypercalcemia may be relatively asymptomatic for a period of time, but rising calcium levels eventually lead to symptoms such as fatigue, nausea and vomiting, anorexia, constipation, and confusion. It is vital that renal function in these patients is monitored carefully, as hypercalcemia can cause renal impairment. Patients must also remain adequately hydrated, and bisphosphonate therapy, which will reduce calcium levels, should be started as soon as possible. It is also important to remember that treatments for myeloma and those directed at its related symptoms go hand-in-hand. Therefore, the initiation of an effective front-line antimyeloma therapy will also help to control hypercalcemia.
According to ASCO guidelines, intravenous (IV) bisphosphonate therapy to support bone health should continue for 2 years, at which time clinicians should seriously consider discontinuing this treatment in patients with responsive or stable disease.10 At our center, we follow ASCO recommendations, with some flexibility. For example, in newly diagnosed patients, we obtain a bone density scan after 1 year of bisphosphonate therapy. If patients appear to have a low risk of osteopenia and fracture, we may reduce the frequency of bisphosphonate dosing from once monthly to once every 3 months. Results of a new trial, Medical Research Council IX,12 may ultimately extend the length of bisphosphonate treatment, as investigators in this study reported that zoledronic acid offered a survival benefit in MM that appeared to be independent of the prevention of skeletal-related events.
The use of IV bisphosphonates, such as pamidronate and zoledronic acid, carries a rare but real risk of osteonecrosis of the jaw (ONJ),10 a condition in which bones of the maxillofacial skeleton, in particular the tooth-bearing areas, become necrotic and exposed to the oral cavity. The risk of this adverse event in patients with MM was reported as 8.5% in a study published in 2009 by Vahtsevanos and colleagues.13 Investigators in this study also noted that ONJ risk was lower when the bisphosphonate used was pamidronate rather than zoledronic acid.
Any clinician who has treated a patient with ONJ is well aware of the seriousness of this condition. To prevent ONJ, we ask our patients to have a dental visit and undergo any necessary dental work prior to the start of bisphosphonate therapy. We also strongly recommend that they be followed up by their dentist every 4 months. At each visit, we ask patients if they are having any dental problems and remind them that below-the-gum procedures, such as tooth extractions, should be avoided during bisphosphonate therapy. If invasive dental procedures cannot be delayed, we advise patients to be treated by one of the oral surgeons at our center, as our team works closely with these dental professionals to prevent ONJ.
Bone pain, a debilitating symptom of MM, is present at the time of diagnosis in approximately 58% of patients: mild (29%), moderate (20%), and severe (9%).11 Therefore, adequate pain management is an essential component of supportive care for patients with MM, and we recommend the use of opioid analgesics when necessary. Nonsteroidal antiinflammatory drugs (NSAIDs) need to be avoided in MM patients, who are always at risk of renal compromise. Orthopedic procedures, such as kyphoplasty and vertebroplasty, may also afford pain relief and enhance function,7,8 as may low-dose radiation therapy.14
How do you manage renal insufficiency in newly diagnosed MM patients?
Renal insufficiency is present in a high percentage of patients with newly diagnosed MM. The most common etiologies of myeloma-related renal impairment are the precipitation of monoclonal light chains in renal tubules and hypercalcemia. However, dehydration, amyloid light chain amyloidosis, and hyperuricemia may also contribute to this condition.11 Reduced renal function in myeloma patients may also be caused by preexisting diabetes or other diseases, which become more prevalent with advancing age. Evidence suggests that approximately 50% of all newly diagnosed patients have an elevated serum creatinine and about 19% have a serum creatinine >2 mg/dL (Table 1).11 Approximately ≤10% of MM patients present with renal failure that requires dialysis.11,15,16
At our center, we obtain a laboratory baseline for renal function (ie, serum creatinine, creatinine clearance) and continue monitoring levels at every visit. Keeping the patient hydrated is essential—this point cannot be stressed enough. It is also important to be judicious in the use of medications that may cause or worsen renal impairment. These include NSAIDs and IV bisphosphonates (especially zoledronic acid, which is not recommended in cases of severe renal dysfunction). 17,18 Lenalidomide, an agent commonly used in the front-line treatment of MM, requires dose reduction in patients with moderate-to-severe renal impairment to minimize the risk of treatment-related toxicities.19
How do you manage myelosuppression in the front-line setting?
Anemia (hemoglobin ≤12 g/dL) is detected in approximately 75% of patients with MM at the time of diagnosis (Table 1).11 If a patient’s bone marrow is packed with clonal plasma cells, the marrow will not produce its normal cell lines. As a result, myeloma patients tend to be anemic, and in some cases, thrombocytopenic and leukopenic. At our center, we often use transfusion to support newly diagnosed patients. A recommendation from the International Myeloma Foundation Nurse Leadership Board is to initiate red blood cell transfusion when anemia is symptomatic or when hemoglobin is <8 g/dL (Table 2).20 Once patients have started antimyeloma therapy and their disease begins to respond, anemia and other cytopenias tend to improve. At our center, we do not use a lot of growth-factor support, although we sometimes administer filgrastim when a patient exhibits marked neutropenia. We also encourage hydration and mild exercise to sustain blood counts. It is important to educate patients about infection control, and initiate prophylactic antibiotics (eg, pneumocystis pneumonia prophylaxis) and antiviral prophylaxis.
The management of anemia and other cytopenias associated with MM can be especially challenging, since myelosuppression is also a known side effect of several agents used to treat the disease. For example, bortezomib and lenalidomide may cause anemia, neutropenia, and thrombocytopenia; thalidomide use is also associated with neutropenia.20 In addition, the high-dose chemotherapeutic regimens that are used to treat transplant-eligible patients are extremely myelo - suppressive. Clinicians need to determine whether myelosuppression is disease- or treatment-related, because supportive care interventions will vary depending on the cause. If one of our patients has significant cytopenias that are overwhelmingly disease-related, then we typically give full doses of agents along with subsequent maximum supportive care. In contrast, if a patient has severe cytopenias resulting from a specific agent or regimen, we dose-adjust or hold treatment, as necessary.
How does effective symptom management impact the clinical course of myeloma?
CRAB features, and the end-organ involvement they signal, can negatively affect patient quality of life and interfere with myeloma treatment. It stands to reason that effective management of these features will help to stabilize the pa - tient and optimize the benefits of novel therapies. One of the clearest examples is the poor prognosis for survival when renal failure in MM is not reversed.21 CRAB features can also exacerbate medical comorbidities in older MM patients, who typically have a poorer survival than younger patients.22 It is also important to remember that hypercalcemia, renal insufficiency, anemia, and bone lesions, in conjunction with comorbid conditions, affect several clinical aspects of the decision- making process in terms of treatment. These include eligibility for transplantation, aggressiveness of therapy, dosing of drugs, the need for orthopedic procedures, and the ability to tolerate ongoing treatment.
- International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.
- Kyle RA, Durie BGM, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24:1121-1127.
- Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood. 2003;102:687a (abstract).
- Kyle RA, Rajkumar SV. Criteria for diagnosis, staging risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9
- Lütje S, de Rooy JWJ, Croockewit S, et al. Role of radiography, MRI and FDG-PET/CT in diagnosing, staging, and therapeutical evaluation of patients with multiple myeloma. Ann Hematol. 2009;88:1161-1168.
- Baur-Melnyk A, Buhmann S, Dürr HR, et al. Role of MRI for the diagnosis and prognosis of multiple myeloma. Eur J Radiol. 2005;55:56-63.
- Tancioni F, Lorenzetti M, Navarria P, et al. Vertebroplasty for pain relief and spinal stabilization in multiple myeloma. Neurol Sci. 2010;31:151-157.
- Huber FX, McArthur N, Tanner M, et al. Kyphoplasty for patients with multiple myeloma is a safe surgical procedure: results from a large patient cohort. Clin Lymphoma Myeloma. 2009;9:375-380.
- Bredella MA, Steinbach L, Caputo G. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol. 2005;184:1199-1204.
- Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphos-phonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472.
- Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33.
- Rajkumar SV. Zoledronic acid in myeloma: MRC Myeloma IX. Lancet. 2010;376:1965-1966.
- Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol. 2009;27:5356-5362.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple myeloma. V1.2011. www.nccn.org/professional/physician_gls/PDF/myeloma.pdf. Accessed February 15, 2011.
- Hutchinson CA, Cockwell P, Reid S, et al. Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol. 2007;18:886-895.
- Bladé J, Fernandéz-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med. 1998;158:1889-1893.
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- Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008.
- Revlimid® [package insert]. Summit, NJ: Celgene Corporation. October 2010.
- Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Leadership Board. Clin J Oncol Nurs. 2008;12(3 Suppl):13-20.
- Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study. Eur J Hematol. 2000;65:175-181.
- Greipp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420. CONSIDERATIONS