Multiple Myeloma (MM) is a B-cell neoplasm originating from the plasma cell. The American Cancer Society estimates that in 2012 there will be 21,700 new cases and 10,710 deaths in the United States due to MM, making it the third most common hematologic malignancy.1 The median age at diagnosis is 69, and it is more prevalent in men versus women and in blacks versus whites.2 Using data generated between 2002 and 2008, the 5-year overall survival rate in myeloma is approximately 41%, a number that is steadily increasing, due primarily to the newer treatment regimens currently being used.2 Although highly treatable, there is still no cure for MM and almost all patients become chemotherapy resistant at some point during treatment.
The former gold standard treatment for MM, melphalan and prednisone, was introduced more than 30 years ago. Since then, newer immunomodulatory agents (IMiDs) and a proteasome inhibitor have been studied in numerous clinical trials and approved by the US Food and Drug Administration (FDA) in an attempt to offer patients newer, more effective treatment options and to overcome the multidrug resistance that is common among MM patients.3 Other agents for treating MM, including new proteasome inhibitors and IMiDs, are currently in clinical trials.
The treatment landscape in MM is changing rapidly. Helping patients manage the side effects of these therapies and supporting their adherence to therapy can potentially increase survival rates and promote a better quality of life.
Velcade (bortezomib) for injection (Millennium, The Takeda Oncology Company) is a proteasome inhibitor indicated for the treatment of patients with MM and for patients with mantle cell lymphoma who have received at least 1 prior therapy.4
The recommended starting dose of bortezomib is 1.3 mg/m2, administered intravenously (IV) over 3 to 5 seconds at a concentration of 1 mg/mL, or subcutaneously (SC) at a concentration of 2.5 mg/mL.4 Additional details about the new SC indication will be discussed in a later section of this article. Consult the full prescribing information at www.velcade.com for detailed dosage and administration guidelines.
The most commonly reported side effects (incidence ≥30%) in clinical trials include asthenic conditions (fatigue, malaise, weakness), diarrhea, nausea, constipation, peripheral neuropathy (PN), vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia.4 We discuss selected side effects in this article, as well as some of the newer data regarding administration and the implications for nursing practice.
PN can be either disease or treatment related, and bortezomib-induced peripheral neuropathy (BIPN) is a frequent cause of either dose reduction or changes in the treatment plan.5 In the pivotal trial of previously untreated MM patients using bortezomib in combination with melphalan and prednisone, 47% developed some degree of sensory PN (13% grade 3, 1% grade 4).4 However, severe sensory and motor PNs have also been reported. Sensory nerves affected by neuropathy include small fibers, which manifest as altered pain, temperature, and sensation, and large fibers that can result in loss of position sense (proprioception), and ability to feel vibrations, touch, or pressure.6 The underlying mechanism for development of BIPN is not known, but accumulation of bortezomib in the dorsal root ganglia cells, mitochondrial-mediated dysregulation of Ca2+ homeo stasis, and dysregulation of neuro trophins have been implicated.5
A recent article in the Journal of the Peripheral Nervous System, the official journal of the Peripheral Nerve Society, notes that preexisting neuropathy is not an uncommon finding in oncology patients.7 For patients with newly diagnosed MM, the incidence of preexisting PN at diagnosis has been estimated from less than 1% to a high of 13%.8 Bruna and colleagues evaluated the role of preexisting neuropathy induced by vincristine or bortezomib as a risk factor for development of more severe bortezomib-induced neuropathy in a mouse model. They reported that the presence of a severe neuropathy prior to treatment with bortezomib resulted in a more marked involvement of peripheral nerves.7
Richardson and colleagues assessed PN in two phase 2 studies (256 patients total) with relapsed and/or refractory MM treated with IV bortezomib 1.0 or 1.3 mg/m2.9 Patients were evaluated for PN at baseline, during, and after the study using both the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. They found that at baseline, 81% of 239 patients had PN by questionnaire and 203 of 244 patients (83%) had PN by neurologic exam. Not surprisingly, the incidence of grade ≥3 PN during the study was higher among patients with baseline neuropathy compared with those patients without (14% vs 4%, respectively). The BIPN seen in this trial appeared to be a cumulative, dose-related effect with increased incidence during the first 5 treatment cycles. For 71% of the patients with clinically significant neuropathy, there was resolution or improvement of symptoms after dose modification or completion of therapy.9
Because of the increased incidence of PN in MM patients treated with bortezomib, they should be carefully assessed for preexisting neuropathies prior to beginning therapy and periodically during treatment. Patients who are diagnosed with PN prior to starting bortezomib therapy should receive a careful risk-benefit evaluation. In addition, starting bortezomib SC may be an option for patients with preexisting or at high risk for developing PN.4 When assessing patients, pay particular attention to those patients with conditions such as diabetes or autoimmune disorders (rheumatoid arthritis or lupus), chronic kidney disease, infections, low levels of vitamin B12, poor circulation, heavy alcohol use, exposure to environmental workplace toxins, or hypothyroidism, which can place patients at higher risk for developing neuropathies.10
Patients receiving bortezomib may complain of feeling cold, a burning sensation, and/or tingling/numbness in their extremities, the classic stocking and glove distribution.11 Dose modification guidelines found in the prescribing information should be followed when patients report or are found to have grade 2 neuropathy or grade 1 associated with pain, as listed in Table 1.
Many different grading scales are available to diagnose PN, but no standard method for administration or interpretation of the scales has been developed.12 One example of testing uses Semmes-Weinstein monofilaments. With the patient’s eyes closed, a fine filament is applied to each hand and foot, and the patient is instructed to note when the filament is felt. In the Romberg test, the patient stands still with his/her heels together and eyes closed. If the patient loses his/her balance, the test is positive for loss of proprioception. Another simple test can also be performed using a sharp safety pin or similar object, alternating between the sharp and dull ends, asking the patient to report the sensation.
There is no standard treatment for BIPN, and patients should be assessed individually for appropriate potential therapy. In addition to bortezomib dose reduction or schedule modification, BIPN can be treated with antidepressants, anticonvulsants, amino acids, lidocaine patches, and narcotics, albeit with limited response and potential side effects such as sedation, dry mouth, and constipation.12 Non pharmacologic approaches include massage, physical and occupational therapy, and more recently, acupuncture. A recent case report in the literature describes a 48-year-old African American man with MM who was successfully treated with bortezomib and stem cell transplantation but developed debilitating PN during his third cycle of bortezomib and was resistant to both gabapentin and morphine sulfate treatment. He was successfully treated with 14 acupuncture sessions, was able to return to work, and remained pain free and asymptomatic 1 year later.13
Nurses have a unique opportunity to assess, educate, and follow up with patients regarding PN. Patient education safety checklists should include reviewing items such as ensuring the water heater temperature is adjusted according to their ability to feel hot and cold; use of rubber gloves for dishwashing and heavy-duty pot holders for handling pans; wearing cotton socks and gloves in cold temperatures; and avoiding clutter in their homes, including slippery area rugs and bath mats.14-16 Ongoing assessment for PN should be done on a regular basis and include such items as asking patients about stocking and glove numbness, tingling, burning, sensitivity to touch, pain, and interference with their activities of daily living. Nurses should observe the patient’s gait to note any difficulty related to altered proprioception or numbness in the feet and check his or her ability to button, zipper, or tie. If PN is confirmed, nurses should counsel the patient about his or her ability to drive or operate machinery safely and take action with family members as appropriate.
Thrombocytopenia (platelet count <100 × 109/L) associated with bortezomib therapy is thought to be due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors.17 Platelet budding from megakaryocytes is regulated in part by the activity of nuclear factor κB (NF-κB), and the proteasome inhibition seen with bortezomib prevents activation of NF-κB. Further, the cyclic, transient thrombocytopenia seen with bortezomib administration is predictable when compared with cytotoxic chemotherapies such as alkylating agents. Lonial and colleagues assessed patients from 2 studies using bortezomib: the Study of Uncontrolled Multiple Myeloma Managed With Proteasome Inhibition Therapy (SUMMIT) and Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST). They found that significant predictors of grade 3/4 thrombocytopenia included low baseline platelet count, high baseline M-protein concentration, and the number of previous treatments. Further analysis revealed that the thrombocytopenia seen with bortezomib is transient; lower platelet counts are seen during the first 10 days of treatment, with recovery during the 10-day rest period. Most importantly, overall response rates to bortezomib did not appear to be impacted by the baseline platelet count.17
The pretreatment nursing assessment of MM patients should include a thorough patient history for any previous bleeding from mucosal or other sites (eg, gastrointestinal [GI]), history of bruising, or prolonged bleeding following injury or surgery. A neurologic assessment should also be performed to monitor for symptoms of intracranial bleeding.18 Nurses should discuss with their patients that the thrombocytopenia associated with bortezomib therapy is an expected, cyclical, transient, and manageable side effect of therapy. Reviewing thrombocytopenic precautions is essential, and if your institution or practice does not have a specific teaching sheet on this topic, an excellent version is available free from the National Institutes of Health: Patient Education: Understanding Your Complete Blood Count.19 Some important points to stress when teaching thrombocytopenic precautions include using a soft toothbrush and electric shavers; avoid enemas, rectal thermometers, suppositories, and tampons; blow the nose gently; avoid eating irritating foods such as popcorn or apple peels; avoid using knives or other sharp instruments; and a review of aspirin-containing medications such as pain relievers and certain prescription medications. (The patient guide referenced above contains a list of common aspirin-containing products.)
The manufacturer’s recommended dose-modification guidelines for bortezomib-associated hematologic toxicities are listed in Table 2.
GI Events and Management
The incidence of grade 3/4 selected GI side effects among previously untreated MM patients receiving bortezomib-melphalan-dexamethasone in a prospective randomized trial was 33% to 48%.4 Nausea (48%), diarrhea (46%), constipation (37%), and vomiting (33%) were the most common side effects observed in this group of patients.4 Since the median age of newly diagnosed MM patients is 62 years, they may have preexisting GI conditions that could be exacerbated by the combination of bortezomib-melphalan-prednisone.20 Patients should be educated about the potential GI side effects prior to beginning bortezomib therapy and appropriate interventions reviewed with them (eg, use of antiemetics, laxatives, antidiarrheals, fluid intake, and dietary restrictions).
Herpes Virus Infection (Shingles) and Management
Because patients with MM are more susceptible to infections, it is important to note that in the randomized trials of patients with previously untreated and relapsed MM, the reactivation of herpes simplex virus was more common in patients treated with bortez-omib (13%) than in the control groups (4%-5%).4 Patients who received prophylactic antiviral therapy were less likely to experience reactivation of the herpes virus (3%) than those who did not receive the antiviral treatment (17%).4 It is therefore recommended that MM patients receiving bortezomib should also receive prophylactic antiviral therapy to avoid virus reactivation and/or other more serious complications.4,21
SC Route of Administration Now Approved
On January 23, 2012, the FDA approved bortezomib for SC administration in patients with MM and relapsed mantle cell lymphoma.22 This approval was based on a pivotal study by Moreau and colleagues,23 who conducted a randomized, phase 3, noninferiority study of 222 (221 evaluable) patients in 53 sites across 10 countries in Europe, Asia, and South America. Patients with relapsed MM who had received 1 to 3 previous therapies were randomly assigned to receive up to eight 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 by either SC injection (n = 147) or IV infusion (n = 74). The primary objective was to show noninferiority of SC versus IV bortezomib in terms of overall response rate (complete response + partial response; ORR) after 4 cycles in all patients with measurable disease who received 1 or more doses of drug. Noninferiority was defined as retaining 60% of the IV treatment effect. SC injections of 2.5 mg/mL (3.5 mg bortezomib reconstituted with 1.4 mL normal [0.9%] saline to limit the injection volume) were given on a rotating basis in the thighs or abdomen. Alternating sites between right and left abdomen, upper and lower quadrant, or right and left thigh (proximal and distal) was the protocol recommendation (Figure).
IV injections were given at a concentration of 1 mg/mL (3.5 mg in 3.5 mL normal saline) as a 3-5 second IV push. Patients received a median of 8 cycles, and the ORR after 4 cycles was 42% in both treatment arms (P = .002), thus demonstrating the noninferiority hypothesis in ORR. There were no significant differences in the time to progression (10.4 vs 9.4 months) and 1-year overall survival (72.6 % vs 76.7%) with SC versus IV bortezomib, respectively. Grade 3 or worse adverse events were noted in 84 patients (57%) in the SC group versus 52 (70%) in the IV group, with the most common being thrombocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12% vs 8%), respectively. Most significantly, the incidence of PN of any grade was less common with SC versus IV administration (38% vs 53%; P = .044). Injection site reactions consisted mainly of reversible redness and rarely resulted in reporting of an adverse event. In addition, in the SC group there were fewer dose reductions and discontinuations due to adverse events. The investigators suggested that in addition to reducing bortezomib-related PN, the increased patient convenience and similar efficacy of SC dosing may be a consideration for future studies of bortezomib maintenance therapy.23
Reconstitution of Bortezomib for SC and IV
Use It is important to remember that the reconstitution of bortezomib for SC use is different from that for IV use, and caution should be used when calculating the volume to be administered.
- The reconstituted concentration of bortezomib for SC administration (2.5 mg/mL) is greater than that for IV administration (1 mg/mL)
- For SC dosing, add 1.4 mL 0.9% sodium chloride to make a final concentration of 2.5 mg/mL
- For IV dosing, add 3.5 mL 0.9% sodium chloride to make a final concentration of 1 mg/mL
- The recommended starting dose is 1.3 mg/m2 for both routes of administration4,24
- To calculate the total volume of reconstituted bortezomib to use, determine the patient’s body surface area (BSA) in square meters (m2) and use the following equations:
Through numerous trials and thousands of patient experiences, bortezomib has been shown to be a safe, effective treatment for patients with MM. Since patient adherence to treatment can significantly impact response rates, oncology nurses can have a positive effect on this important aspect of treatment by effectively and appropriately educating patients about managing the expected side effects of bortezomib therapy. As was effectively demonstrated by Moreau and colleagues,23 the use of SC bortezomib is a potential alternative to IV administration, especially for patients at risk of developing side effects and/or those with poor venous access.
- American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012. Accessed May 16, 2012.
- Surveillance, Epidemiology, and End Results (SEER). SEER stat fact sheets: myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html#incidence-mortality. Accessed May 16, 2012.
- Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7-64.
- Velcade (bortezomib) for Injection [package insert]. Cambridge, MA: Millennium: The Takeda Oncology Company; 2012.
- Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599.
- Wolfe GI, Trivedi JR. Painful peripheral neuropathy and its nonsurgical treatment. Muscle Nerve. 2004;30:3-19.
- Bruna J, Alé A, Velasco R, et al. Evaluation of preexisting neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model. J Peripher Nerv Syst. 2011;16:199-212.
- Tariman JD, Love G, McCullagh E, et al; IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):29-36.
- Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120.
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. www.ninds.nih.gov/disorders/peripheralneuropathy. Updated August 10, 2011. Accessed November 14, 2011.
- Richards T. Managing the side effects of lenalidomide and bortezomib. Community Oncol. 2009:56-57. www.communityoncology.net/co/journal/0602.html. Accessed October 28, 2011.
- Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376.
- Bao T, Zhang R, Badros A, et al. Acupuncture treatment for bortezomib-induced peripheral neuropathy: a case report. Pain Res Treat. 2011. www.ncbi.nlm.nih.gov/pmc/articles/PMC3199913/?tool=pubmed. Accessed November 28, 2011.
- Almadrones LA, Arcot R. Patient guide to peripheral neuropathy. Oncol Nurs Forum. 1999;26:1359-1360.
- Sorich J, Taubes B, Wagner A, et al. Oxaliplatin: practical guidelines for administration. Clin J Oncol Nurs. 2004;8:251-256.
- Sweeney CW. Understanding peripheral neuropathy in patients with cancer: background and patient assessment. Clin J Oncol Nurs. 2002;6:163-166.
- Lonial S, Waller EK, Richardson PG, et al; SUMMIT/ CREST Investigators. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106: 3777-3784.
- Miceli T, Colson K, Gavino M, et al. Myelosuppression associated with novel therapies in patients with multiple myeloma: a consensus statement of the IMF Nurse Leadership Board. Clin J Onc Nurs. 2008;12(3 suppl):13-20.
- National Institutes of Health Clinical Center. Patient Education: Understanding Your Complete Blood Count. www.cc.nih.gov/ccc/patient_education/pepubs/cbc97.pdf. Published November 2008. Accessed November 21, 2011.
- Multiple Myeloma Research Foundation. Newly diagnosed patients: what is multiple myeloma. www.themmrf.org/living-with-multiple-myeloma/newlydiagnosed-patients/what-is-multiple-myeloma/. Accessed November 21, 2011.
- Taniguchi D, Takahara O, Takasaki Y, et al. Fatal cytomegalovirus pneumonia and associated herpes virus infection in a relapsed/refractory multiple myeloma patient treated with bortezomib plus dexamethasone. Case Rep Oncol. 2009;2:140-143.
- FDA Approves Subcutaneous Administration of VELCADE® In All Approved Indications. Businesswire; January 23, 2012. www.bioportfolio.com/news/article/926407/Fda-Approves-Subcutaneous-Administration-Of-Velcade-In-All-Approved-Indications.html. Accessed January 25, 2012.
- Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.
- Dear Healthcare Professional letter. Velcade Web site. http://www.velcade.com/Files/PDFs/V-12-0047_SC_Patient_Announcement_Letter_FINAL.pdf. Accessed January 30, 2012.