June 2008, Supplement to Volume 12, Number 3
Myelosuppression Associated With Novel Therapies in Patients With Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board
Teresa Miceli, RN, BSN, Kathleen Colson, RN, BSN, BS, Maria Gavino, RN, BSN, Kathy Lilleby, RN, and the IMF Nurse Leadership Board
Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib, which have increased response rates and survival times. However, the agents can cause myelosuppression, which, if not managed effectively, can be life threatening and interfere with optimal therapy and quality of life. The International Myeloma Foundation’s Nurse Leadership Board developed a consensus statement that includes toxicity grading, strategies for monitoring and managing myelosuppression associated with novel therapies, and educational recommendations for patients and their caregivers. Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with appropriate interventions and education.
At a Glance
· The immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib can cause myelosuppression.
· Because anemia, neutropenia, and thrombocytopenia are expected side effects, patients should be monitored closely and educated about side-effect signs and symptoms.
· Anemia, neutropenia, and thrombocytopenia can be managed with a combination of therapies for side effects and appropriate dose reductions of novel therapies.
Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide (Revlimid®, Celgene Corporation) and thalidomide (Thalomid®, Celgene Corporation) and the proteasome inhibitor bortezomib (Velcade®, Millennium Pharmaceuticals, Inc.). The novel therapies have contributed to better response rates and survival times compared with conventional chemotherapy. However, the agents can cause side effects that, although predictable and manageable, have the potential to be life threatening and to interfere with adherence to optimal therapy and patient quality of life (Celgene Corporation, 2007a, 2007b; Fortner, Houts, & Schwarzberg, 2006; Fortner, Tauer, Zhu, Ma, & Schwartzberg, 2004; Ghobrial et al., 2007; Manochakian, Miller, & Chanan-Khan, 2007; Millennium Pharmaceuticals, Inc., 2006; Rajkumar et al., 2005; Richardson & Anderson, 2006; Richardson, Hideshima, Mitsiades, & Anderson, 2007). As with other treatments for multiple myeloma, the novel agents are associated with side effects in the myelosuppression category: anemia, neutropenia, and thrombocytopenia (Celgene Corporation, 2007a, 2007b; Millennium Pharmaceuticals, Inc.). The International Myeloma Foundation’s Nurse Leadership Board, in recognition of the need for specific recommendations on managing key side effects of novel antimyeloma agents, developed a consensus statement for the management of myelosuppression associated with novel therapies to be used by healthcare providers in any type of medical institution (Bertolotti et al. 2007, 2008). The recommendations also are applicable to the management of myelosuppression associated with other therapies for myeloma.
Myelosuppression is a common and expected side effect of novel therapies for multiple myeloma. As a result of myelosuppression, patients may experience anemia, neutropenia, and thrombocytopenia. Depending on their severity, the side effects can have a negative impact on patients’ medical treatment and quality of life by interrupting or reducing therapy and causing life-threatening complications. Neutropenia can result in life-threatening infections (Marrs, 2006). In addition to such physiologic effects, myelosuppression may limit patients’ ability to interact or work outside the home, resulting in depression, anger, financial burden, and a sense of social isolation (Fortner et al., 2004, 2006). Fatigue, the most common side effect of anemia and the most common complaint among patients with cancer, has a significant impact on patients’ quality of life, ability to work, and physical and emotional well-being (Boyer, 2000; Foubert, 2006).
Novel Therapies and Myelosuppression
Anemia (hemoglobin 12 g/dl) is present in 73% of patients at initial diagnosis of multiple myeloma. It can be seen in 97% at some time during the course of the disease. Leukopenia (white blood cell count 4 x 109/L) is seen in 20% of patients at time of diagnosis. Thrombocytopenia (platelet count < 100 x 109/L) is seen in 5% of patients at time of diagnosis (Kyle et al., 2003). Myelosuppression is a common and expected side effect associated with novel therapies for treatment of multiple myeloma. Table 1 summarizes the risks of grade 3 and 4 anemia, neutropenia, and thrombocytopenia that have been reported in patients with myeloma treated with the novel therapies lenalidomide, thalidomide, and bortezomib.
The National Cancer Institute ([NCI], 2007) defined myelosuppression as “a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.” Anemia was defined as abnormally low levels of red blood cells as measured by blood hemoglobin or hematocrit levels. As a result of an imbalance of production versus destruction or loss of red blood cells, the blood has decreased capacity for carrying hemoglobin and oxygen (Foubert, 2006). Neutrophils are the infection-fighting component of the total white blood cell count. Neutropenia is the reduction of circulating neutrophils in the bloodstream, leading to increased risk of infection (Held-Warmkessel, 1998; Marrs, 2006; West & Mitchell, 2004). Thrombocytopenia may result from a lack of production of megakaryocytes or an increase in use of platelets, leading to an abnormally low level of platelets (thrombocytes) in the circulating blood (Fukuyama & Itano, 1999). The severity of anemia, neutropenia, and thrombocytopenia can be quantified with the NCI Common Terminology Criteria for Adverse Events (CTCAE). The NCI CTCAE are used for identifying treatment-related adverse events to facilitate the evaluation of new cancer therapies, treatment modalities, and supportive measures. The grades 1 through 5 (defined using unique clinical descriptions in the NCI CTCAE) refer to the severity of an adverse event; grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life threatening or disabling, and grade 5 is death related to the adverse event. Table 2 defines the NCI CTCAE version 3.0 hematologic toxicity grades 1–4 (NCI, 2006). The grades, along with nursing assessments, should be used to assist in monitoring hematologic toxicities related to novel therapies and to determine which medical and nursing management strategies are needed.
Management of Myelosuppression
General guidelines: Standardized precautions and interventions related to low blood counts vary among institutions.
Anemia: Management of anemia should take into account that some patients tolerate a greater degree of anemia than other patients. Assessment of anemia is more than a one-dimensional evaluation. In addition to the numeric value found in a complete blood count (CBC), symptoms that affect patients’ quality of life also should be assessed (e.g., fatigue). A nursing interview that includes questions regarding performance status, shortness of breath, and chest pain on exertion will aid in determining the need for transfusions. Tools, such as the Brief Fatigue Inventory (Cleeland & Wang, 1999), can assist nurses in assessing patients’ perceptions of fatigue. A patient’s hemoglobin levels and symptoms of anemia leading to a decision to transfuse must be balanced with the risks related to transfusions (i.e., transfusion-acquired infections, transfusion reactions, and transfusion-related lung injury) (Foubert, 2006). Table 3 lists generally accepted medical practices to manage anemia.
Transfusions are to be given at the discretion of a patient’s healthcare provider. Blood products should be leukocyte-reduced to decrease the risk of febrile reactions, human leukocyte antigen alloimmunization, and cytomegalovirus infection (American Association of Blood Banks, America’s Blood Centers, & American Red Cross, 2006). Transfusion policies and availability of blood products vary among institutions. General transfusion guidelines are available from the American Association of Blood Banks, America’s Blood Centers, and American Red Cross and from Cable et al. (2002).
Neutropenia: Neutropenic patients are at greater risk of infection. Not all patients who are neutropenic become febrile. Handwashing by patients and all caregivers is the single most important factor for preventing infection (West & Mitchell, 2004). Nursing assessment and education of patients play a vital role in reducing the risk of febrile episodes, as does prompt intervention in the event of a febrile episode. In the absence of neutrophils, fever may be the only sign of an active infection. Multiple organ systems can be affected by infection, including respiratory, urinary, and gastrointestinal (Held-Warmkessel, 2000; Marrs, 2006). Assess patients for fever and associated symptoms such as chills, myalgias, malaise, nausea, hypotension, and hypoxia (Nunez & Liebman, 1999; West & Mitchell). Observe the oral mucosa and skin for any breaks in tissue and signs of infection. If a patient has a central venous access device, assess the exit site for erythema or exudate. A complete nursing assessment of all systems may reveal the source of a potential or actual infection (Held-Warmkessel, 2000). An accurate patient history also can provide information indicating whether a patient is at high risk of infection when neutropenic. Previous exposures to bacteria, viruses, and fungal contaminants through travel, pets, and childhood infections can reactivate when patients are neutropenic. When a patient is at risk for neutropenia or becomes neutropenic, initiate institutional precautionary standards. Notify the patient’s healthcare provider for medical intervention for neutropenia and neutropenic fever. Table 4 lists generally accepted medical management practices. If a neutropenic patient is found to be febrile, that is considered an emergency situation because the patient can progress quickly to septic shock (Burney, 2000; Turgeon-Lanes & Randolph, 2000). Administer prescribed antibiotics after blood cultures have been obtained and within one hour of presentation. IV hydration and antipyretics also should be administered in a timely manner if prescribed (Burney; Held-Warmkessel, 1998; Nunez & Liebman).
Thrombocytopenia: When platelet counts drop below normal (150–400 x 109/L) to levels less than 100 x 109/L, patients are classified as thrombocytopenic and are at greater risk of bleeding (Fukuyama & Itano, 1999). Life-threatening hemorrhage may occur when platelet levels decrease below 50 x 109/L (grade 3 or 4). In addition to reviewing CBCs, nursing assessment should include a thorough patient history that covers any mucosal or gastrointestinal bleeding, increased bruising, or difficulty stopping bleeding. Physical examination should include evaluation of the mucous membranes and sclerae for signs of bleeding. Observe the skin for petechiae, multiple and large areas of bruising, and oozing from the exit site of a central venous catheter. A neurologic assessment also should be incorporated to monitor for symptoms of intracranial bleeding (Fukuyama & Itano; Held-Warmkessel, 1998, 2000). Generally accepted practices to manage thrombocytopenia include the following.
· Initiate institutional precautionary standards for thrombocytopenia.
· Minimize invasive procedures.
· Transfuse platelets prior to any necessary invasive procedures.
· Transfuse if signs of bleeding are present.
Recommendations for Monitoring Complete Blood Counts
All patients receiving novel therapies should have their CBCs monitored closely. Monitoring of serum creatinine levels also is important because decreased renal function may result in more severe anemia (Pandit & Vesole, 2003). If prolonged myelosuppression persists after dose modification or delay, further evaluation is recommended to rule out other possible causes, such as a reaction to another medication or progressive disease. The novel therapies bortezomib, lenalidomide, and thalidomide have specific recommendations for blood count monitoring, as follows.
· Thalidomide: Prescribing information recommends that blood count and differential be monitored on an ongoing basis, particularly in patients who may be prone to neutropenia (Celgene Corporation, 2007b).
· Lenalidomide: CBCs should be checked every two weeks for the first 12 weeks, then at least monthly thereafter (Celgene Corporation, 2007a).
· Bortezomib: Prescribing information recommends that blood counts be monitored prior to each dose of bortezomib (Millennium Pharmaceuticals, Inc., 2006).
Specific recommendations for monitoring and managing myelosuppression associated with thalidomide, lenalidomide, and bortezomib are presented in Table 5.
Recommendations for Patient and Caregiver Education
Healthcare providers should educate patients and their caregivers on the basic concepts of myelosuppression (see Figure 1). Education should occur prior to patients becoming myelosuppressed and should be reinforced frequently (West & Mitchell, 2004).
Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with careful monitoring of patients’ blood counts, dose adjustments when indicated, prophylactic treatment, and concomitant therapies as necessary. Nursing assessment, intervention, and education of patients and caregivers play a vital role in promoting patient adherence and maintenance of prescribed therapy, thereby enhancing patient outcomes.
The authors gratefully acknowledge Brian G.M. Durie, MD, and Robert A. Kyle, MD, for critical review of the manuscript and Lynne Lederman, PhD, medical writer for the International Myeloma Foundation, for assistance in preparation of the manuscript.
American Association of Blood Banks, America’s Blood Centers, & American Red Cross. (2006). Circular of information for the use of human blood and blood components. Retrieved September 10, 2007, from http://www.aabb.org/Documents/About_Blood/Circulars_of_Information/coiwnv0702.pdf
Amgen Inc. (2007a). Aranesp® (darbepoeitin alfa) [Package insert]. Thousand Oaks, CA: Author.
Amgen Inc. (2007b). Epogen® (epoeitin alfa) [Package insert]. Thousand Oaks, CA: Author.
Bertolotti, P., Bilotti, E., Colson, K., Curran, K., Doss, D., Faiman, B., et al. (2007). Nursing guidelines for enhanced patient care. Haematologica, 92(Suppl. 2), 211.
Bertolotti, P., Bilotti, E., Colson, K., Curran, K., Doss, D., Faiman, B., et al. (2008). Management of side effects of novel therapies for multiple myeloma: Consensus statements developed by the International Myeloma Foundation’s Nurse Leadership Board. Clinical Journal of Oncology Nursing, 12(3, Suppl.), 9–12.
Boyer, C.G. (2000). Chemotherapy-related anemia and fatigue in home care patients: A home care nurse’s guide to recognition, assessment, and intervention. Home Healthcare Nurse, 18(4, Suppl.), 3–15.
Burney, K.Y. (2000). Tips for timely management of febrile neutropenia. Oncology Nursing Forum, 27(4), 617–618.
Cable, R., Carlson, B., Chambers, L., Kolins, J., Murphy, S., Tilzer, L., et al. (2002). Practice guidelines for blood transfusion: A compilation from recent peer-reviewed literature. Retrieved September 10, 2007, from http://www.redcross.org/services/biomed/profess/pgbtscreen.pdf
Celgene Corporation. (2007a). Revlimid® (lenalidomide) [Package insert]. Summit, NJ: Author.
Celgene Corporation. (2007b). Thalomid® (thalidomide) [Package insert]. Summit, NJ: Author.
Centers for Disease Control and Prevention. (1996). Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report, 45(RR11), 1–25.
Cleeland, C.S., & Wang, X.S. (1999). Measuring and understanding fatigue. Oncology, 13(11A), 91–97.
Fortner, B.V., Houts, A.C., & Schwartzberg, L.S. (2006). A prospective investigation of chemotherapy-induced neutropenia and quality of life. Journal of Supportive Oncology, 4(9), 472–478.
Fortner, B.V., Tauer, K., Zhu, L., Ma, L., & Schwartzberg, L.S. (2004). The impact of medical visits for chemotherapy-induced anemia and neutropenia on the patient and caregiver: A national survey. Community Oncology, 1(4), 211–217.
Foubert, J. (2006). Cancer-related anaemia and fatigue: Assessment and treatment. Nursing Standard, 20(36), 50–57.
Fukuyama, S.N., & Itano, J. (1999). Thrombocytopenia secondary to myelosuppression. American Journal of Nursing, April(Suppl.), 5–12.
Ghobrial, J., Ghobrial, I.M., Mitsiades, C., Leleu, X., Hatjiharissi, E., Moreau, A.S., et al. (2007). Novel therapeutic avenues in myeloma: Changing the treatment paradigm. Oncology, 21(7), 785–792.
Held-Warmkessel, J. (1998). Chemotherapy complications. Nursing, 28(4), 41–46.
Held-Warmkessel, J. (2000). Assessment of febrile neutropenic patients. Clinical Journal of Oncology Nursing, 4(4), 182–184.
Khorana, A.A., Francis, C.W., Culakova, E., Fisher, R.I., Kuderer, N.M., & Lyman, G.H. (2006). Thromboembolism in hospitalized neutropenic cancer patients. Journal of Clinical Oncology, 24(3), 484–490. [CrossRef]
Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., et al. (2003). Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceedings, 78(1), 21–33.
Lonial, S., Richardson, P.G., San Miguel, J., Sonneveld, P., Schuster, M., Blade, J., et al. (2007). Hematologic profiles with bortezomib in relapsed MM [Abstract PO-622]. Haematologica, 92(Suppl. 2), 159–160. Retrieved April 10, 2008, from http://www.haematologica.it/content/vol92/6_supplement_2/index.dtl
Lonial, S., Waller, E.K., Richardson, P.G., Jagannath, S., Orlowski, R.Z., Giver, C.R., et al. (2005). Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood, 106, 3777–3784. [CrossRef]
Manochakian, R., Miller, K., & Chanan-Khan, A.A. (2007). Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma. Oncologist, 12(8), 978–990. [CrossRef]
Marrs, J.A. (2006). Care of patients with neutropenia. Clinical Journal of Oncology Nursing, 10(2), 164–166. [CrossRef]
Millennium Pharmaceuticals, Inc. (2006). Velcade® (bortezomib) [Package insert]. Cambridge, MA: Author.
National Cancer Institute. (2006). Common Terminology Criteria for Adverse Events v.3.0. Retrieved December 28, 2007, from http://ctep.cancer.gov/forms/CTCAEv3.pdf
National Cancer Institute. (2007). Dictionary of cancer terms. Retrieved December 28, 2007, from http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44173
Nunez, A.M., & Liebman, M.C. (1999). Febrile neutropenia. American Journal of Nursing, 99(Suppl.), 9–12, 34–36.
Pandit, S.R., & Vesole, D.H. (2003). Management of renal dysfunction in multiple myeloma. Current Treatment Options in Oncology, 4(3), 239–246. [CrossRef]
Rajkumar, S.V., Hayman, S.R., Lacy, M.Q., Dispenzieri, A., Geyer, S.M., Kabat, B., et al. (2005). Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood, 106(13), 4050–4053. [CrossRef]
Richardson, P.G., & Anderson, K. (2006). Thalidomide and dexamethasone: A new standard of care for initial therapy in multiple myeloma. Journal of Clinical Oncology, 24(3), 334–336. [CrossRef]
Richardson, P.G., Hideshima, T., Mitsiades, C., & Anderson, K.C. (2007). The emerging role of novel therapies for the treatment of relapsed myeloma. Journal of the National Comprehensive Cancer Network, 5(2), 149–162.
Rome, S., Doss, D., Miller, K., Westphal, J., & the IMF Nurse Leadership Board. (2008). Thromboembolic events associated with novel therapies in patients with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board. Clinical Journal of Oncology Nursing, 12(3, Suppl.), 21–27.
Smith, T.J., Khatcheressian, J., Lyman, G.H., Ozer, H., Armitage, J.O., Balducci, L., et al. (2006). 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. Journal of Clinical Oncology, 24(19), 3187–3205. [CrossRef]
Spivak, J.L. (1994). Recombinant human erythropoietin and the anemia of cancer. Blood, 84(4), 997–1004.
Turgeon-Lanes, P., & Randolph, S. (2000). Home care management of febrile neutropenia: Creating a pilot program. Home Health Care Consultant. 7(1), 1A–6A.
West, F., & Mitchell, S.A. (2004). Evidence-based guidelines for the management of neutropenia following outpatient hematopoietic stem cell transplantation. Clinical Journal of Oncology Nursing, 8(6), 601–613. [CrossRef]
Zitella, L., Friese, C., Gobel, B.H., Woolery-Antill, M., O’Leary, C., Houser, J., et al. (2006) . Putting Evidence Into Practice®: Prevention of infection. Retrieved September 10, 2007, from http://www.ons.org/outcomes/volume1/prevention.shtml1
Teresa Miceli, RN, BSN, is an adult bone marrow transplant coordinator at the Mayo Medical Center in Rochester, MN; Kathleen Colson, RN, BSN, BS, is a multiple myeloma clinical research nurse at Dana-Farber Cancer Institute in Boston, MA; Maria Gavino, RN, BSN, is a clinical research nurse at the University of Texas M.D. Anderson Cancer Center in Houston; and Kathy Lilleby, RN, is a clinical research nurse at the Fred Hutchinson Cancer Research Center in Seattle, WA. Miceli has served as a speaker for the Oncology Nursing Society and is a member of the speakers bureau for Medical Education Resources. Colson and Gavino are members of the speakers bureaus for Celgene Corporation and Millennium Pharmaceuticals, Inc. Lilleby is a member of the speakers bureau for Millennium Pharmaceuticals, Inc. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted October 2008. Accepted for publication January 5, 2008.)
Digital Object Identifier:10.1188/08.CJON.S1.13-19
Patient Education Sheet: Managing Myelosuppression From Novel Agents for Multiple Myeloma
Novel therapies used to treat multiple myeloma include thalidomide, lenalidomide, and bortezomib. The drugs can cause myelosuppression, which is a decrease in bone marrow activity, resulting in fewer red blood cells (anemia), white blood cells (neutropenia), and platelets (thrombocytopenia). The risk of side effects varies with each medication. Managing the side effects can reduce your discomfort, prevent serious complications, and allow you to receive the best treatment for your myeloma. Your healthcare provider may change your dose or schedule of medication to help manage your symptoms. Do not stop or adjust medications without discussing it with your healthcare provider.
Anemia is a decrease in red blood cells, or hemoglobin, which carry oxygen in the blood. It may result from myeloma treatment, decreased kidney function, myeloma disease, or other medications.
Symptoms of anemia can include fatigue, low energy level, difficulty with normal daily activities, shortness of breath with activity, and chest pain with activity.
If you experience symptoms of anemia, contact your healthcare provider.
Try not to use too much energy in daily activities.
Your healthcare provider may prescribe a red blood cell supplement such as iron, erythropoietin, or a red blood cell transfusion. If necessary, changes may be made in medications you are taking.
Neutropenia is a decrease in white blood cells, which protect against infection. It may result from myeloma treatment, myeloma disease, or other medications.
The greatest concern with neutropenia is infection. Symptoms can include fever of 100.5°F (38°C) or higher, shaking chills, dizziness, fainting, redness at a wound site, difficulty breathing, cough, or sinus congestion.
If you experience fever or symptoms of infection, contact your healthcare provider immediately.
To reduce your risk of infection, wash your hands carefully and often, avoid crowds, and take antibiotics as prescribed by your healthcare provider.
Your healthcare provider will check your blood counts regularly based on your plan of care and may prescribe antibiotics to prevent infection and growth factors to stimulate white blood cell growth. If necessary, changes may be made to medications you are taking.
Thrombocytopenia is a decrease in platelets that protect against bleeding. It may result from myeloma treatment, myeloma disease, or other medications. It may be associated more frequently with lenalidomide and bortezomib.
Symptoms of thrombocytopenia may include bruising, pink urine, nosebleeds, small red or purple spots on the body (petechiae), and bleeding that does not stop with pressure.
If you experience signs or symptoms of a low platelet count, contact your healthcare provider immediately.
To reduce your risk of bruising or bleeding, avoid taking aspirin, ibuprofen, or naproxen. Avoid activities that can cause bruising or bleeding, such as contact sports, anal sex, and heavy lifting. Participate in gentle exercise only.
Your healthcare provider will monitor blood counts regularly based on your plan of care and may prescribe a platelet transfusion. If necessary, changes may be made in medications you are taking.
Note. For more information, please contact the International Myeloma Foundation (1-800-452-CURE; www.myeloma.org). The foundation offers the Myeloma ManagerTM Personal Care AssistantTM computer program to help patients and healthcare providers keep track of information and treatments. Visit http://manager.myeloma.org to download the free software.
Note. Patient education sheets were developed in June 2008 based on the International Myeloma Foundation Nurse Leadership Board’s consensus guidelines. They may be reproduced for noncommercial use.