Managing Adverse Events in the Late-line Setting for Multiple Myeloma

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Introduction

With the implementation of novel targeted therapies and more effective supportive care measures, we are seeing improved outcomes in patients with multiple myeloma (MM).1 The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the first-in-class proteasome inhibitor bortezomib are commonly used to treat patients with MM, in both the front-line and relapsed and/or refractory settings.2 Despite the proven efficacy of these agents,1 nearly all patients eventually experience disease progression. Therapeutic options for these individuals are limited, and prognosis remains poor.3 In a recent study of patients with myeloma who relapsed or were refractory to bortezomib and IMiDs, median overall survival and event-free survival were 8 months and 5 months, respectively.4

The management of relapsed and/or refractory myeloma is challenging for many reasons. When formulating therapeutic strategies, clinicians must consider diseaseand patient-related factors, such as cytogenetic profile, duration of response to initial treatment, age, performance status, and comorbidities.5 Supportive therapy is an especially important aspect of care, due to symptoms caused by the disease itself, which are often more severe in the late-line setting, and because pretreated patients are likely to be experiencing residual toxicities.6 Nurses must carefully monitor for numerous complications, and be prepared to initiate effective management strategies that will allow patients to continue with their prescribed therapies.

At a recent roundtable meeting, I had the opportunity to discuss adverse events (AEs) and myeloma-related symptoms observed in patients with relapsed and/or refractory MM. Although several complications were identified by nurses as having the potential to negatively impact patient outcomes, this article focuses on current challenges and recommended interventions related to hematologic toxicities, peripheral neuropathy (PN), and renal dysfunction.

Myelosuppression

Table
Incidence of Grade 3/4 Hematologic Toxicities with Commonly Used Antimyeloma Therapies.
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Anemia, thrombocytopenia, and neutropenia are common and expected complications in patients with MM. They can be caused by the disease itself or may be a result of antimyeloma therapies, including lenalidomide, thalidomide, and bortezomib (Table).7 In addition to closely monitoring blood counts to assess the severity of myelosuppression, it is also necessary to consider factors such as patient comorbidities, institutional protocols, and current treatments when determining appropriate interventions. For example, grade 1 and 2 anemia may be treated with erythropoietin-stimulating agents (ESAs), but this practice varies from one center to the next.

Nurses also need to be aware of the increased risk for thrombosis in patients who are being treated with IMiDs when ESAs are used at the same time, and must take the necessary precautions.7 Although effective treatment of the myeloma itself often results in a resolution of anemia, hemoglobin levels of 6.5 to <8.0 g/dL typically necessitate transfusion, as well as dose interruptions and/or modifications of agents such as lenalidomide or bortezomib.7 Similarly, dose reductions, temporary discontinuation of therapy, and in some cases, growth factor support, may be necessary for patients who develop neutropenia, depending on severity.7 In the case of thrombocytopenia, careful assessment of platelet counts helps to determine whether treatment should be held or dose attenuated, and when transfusion may be an appropriate course of action. It is important to note that although thrombocytopenia is a common toxicity associated with bortezomib, platelet levels typically decrease during each cycle of treatment, and return toward baseline between cycles.7

Peripheral Neuropathy

Many patients present with PN at the time of diagnosis. This complication is also a common AE associated with the use of agents such as thalidomide and bortezomib.8 Signs and symptoms of PN include temporary numbness, tingling, sensitivity to touch, and muscle weakness. However, this AE may also cause permanent paresthesias and more intense symptoms of pain, as well as muscle wasting and organ dysfunction, which can result in problems related to digestion, blood pressure, and bodily functions.8

It is important to obtain a baseline assessment of PN, and then perform follow-up assessments regularly to determine grade and severity. Nurses must also educate their patients to report symptoms early so that the appropriate steps can be taken to address this toxicity.

Pharmacologic interventions to relieve pain involve a number of options, including the use of pregabalin, gabapentin, and nortriptyline.8 It is often necessary to reduce the dose of specific antimyeloma therapies until symptoms improve; this is essential to prevent permanent neurologic damage. Bortezomib-associated PN tends to be reversible in most patients after dose modification or treatment discontinuation. Thalidomide-associated PN has a greater propensity to be irreversible, and may be related to higher cumulative doses and longer treatment duration.8

The management of this toxicity in the late-line setting for MM remains a significant challenge, as there must be a careful balance between providing effective therapy for the disease and not aggravating preexisting symptoms.

Renal Dysfunction

Approximately 20% to 60% of patients with MM will experience renal insufficiency or kidney failure during the course of their disease.9 As with myelosuppression and PN, renal complications may be related to myeloma or specific therapies.9,10 It is important to ascertain the source of renal impairment to ensure proper supportive care. Close monitoring of creatinine clearance levels is essential, and patients must remain properly hydrated, but not to the point where they experience fluid overload. Treating the myeloma and reducing tumor burden often results in improved renal function. Some agents used in the treatment of relapsed and/or refractory MM, however, must be dose-adjusted for renal insufficiency; others cannot be administered when individuals are receiving dialysis.9 As a patient’s renal function fluctuates during the course of the disease, our management approaches continually need to be adjusted accordingly.

Conclusion and Future Directions It is imperative for nurses to share with each other their knowledge and experience related to effective supportive care strategies and the management of AEs commonly seen in the late-line setting. There is also a need for novel drugs that can provide patients with safe and effective options when they relapse or become resistant to currently used therapies. An investigational agent that is showing promise for such patients is carfilzomib, a next-generation proteasome inhibitor.11,12 This agent has demonstrated clinical activity and good tolerability in patients with relapsed and/or refractory myeloma, including individuals who were heavily pretreated and those with specific comorbidities.13,14

As new treatments continue to be developed and evaluated in clinical trials, we need to stay informed about the efficacy of these agents, as well as their toxicity profiles and the recommendations for minimizing AEs. There should be a diverse methodology for the dissemination of this information to ensure that healthcare professionals and patients are educated at levels appropriate to their needs. As nurses, we must remain vigilant in our efforts to effectively treat the disease, as well as care for the other needs of our patients, to ensure the best quality of life.

References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
  2. Harousseau JL.Ten years of improvement in the management of multiple myeloma: 2000-2010. Clin Lymphoma Myeloma Leuk. 2010; 10:424-442.
  3. Laubach JP, Mahindra A, Mitsiades CS. The use of novel agents in the treatment of relapsed and refractory multiple myeloma. Leukemia. 2009;23:2222-2232.
  4. Kumar S, Crowley J, Klein SK, et al. Treatment patterns and outcome among patients with multiple myeloma relapsing and or refractory to bortezomib and immunomodulatory drugs: a multicenter International Myeloma Working group study. J Clin Oncol (ASCO) Annual Meeting Proceedings. 2010;28(suppl 15):Abstract 8125.
  5. Lonial S. Relapsed multiple myeloma. Hematology Am Soc Hematol Educ Program. 2010;2010:303-309.
  6. Richardson P, Mitsiades C, Schlossman R, et al. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program. 2007;2007:317-323.
  7. 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 Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20.
  8. Tariman JD, Love G, McCullagh E, Sandifer S; 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.
  9. Faiman BM, Mangan P, Spong J, Tariman JD; The International Myeloma Foundation Nurse Leadership Board. Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15 suppl:66-76.
  10. Bladé J, Fernández-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.
  11. Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell. 2005;8:407-419.
  12. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281-3290.
  13. diCapua Siegel DS, Martin T, Wang M, et al. PX-171-003-A1, an open-label, single arm, phase (P) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): long-term follow-up and subgroup analysis. J Clin Oncol. 2011;29:Abstract 8027.
  14. Niesvizky R, Vij R, Martin T, et al. Carfilzomib pharmacokinetics, safety, and activity in patients with relapsed or refractory multiple myeloma and renal dysfunction: final results. Haematologica. 2011;96 (suppl 2): 370-371: Abstract 0890.
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TOP - Supplements published on May 1, 2012
Last modified: July 22, 2021