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Challenges in the Treatment of Relapsed and/or Refractory Myeloma

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Introduction

Multiple myeloma (MM) is often diagnosed after a seemingly harmless activity, such as hopping off a curb, results in an unexpected bone fracture. Regardless of the method by which a patient discovers that he or she has myeloma, it is a very traumatic experience. Fortunately, the management of this debilitating disease has come a long way. Several decades ago, the cutting-edge regimen for MM was melphalan plus prednisone.1 However, this combination was associated with significant toxicities and some rather complex preparation issues related to the use of melphalan. Soon after, thalidomide, lenalidomide, and bortezomib began to arrive on the scene, and we saw improvements in patient outcomes.2 Unfortunately, we are still dealing with a disease that is associated with significant morbidity and mortality, especially in the late-line setting. As a result, the search continues for more effective supportive care strategies and new agents that can improve patient outcomes.

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

One of the adverse events we commonly see in patients who are treated with bortezomib and thalidomide is peripheral neuropathy (PN).3,4 With the exception of skeletal-related events, this complication probably takes the most time and energy when it comes to management strategies in the late-line setting, and dose modifications are often necessary during treatment. Recently, a new mode of administration for bortezomib was approved, and many patients now receive the drug as a subcutaneous injection, which has been shown to reduce the incidence of PN without sacrificing efficacy.5 This method is generally well tolerated, although injection- site reactions do take some time to return to normal. We are also seeing good results with the investigational agent carfilzomib, a next-generation proteasome inhibitor that is structurally and mechanistically distinct from bortezomib.6 In addition to impressive efficacy, very low rates of PN are associated with the use of this agent,7 which is a pleasant surprise with a proteasome inhibitor.

Approximately 50% of patients with MM experience elevated creatinine levels, caused by excess light chains spilling over into the kidneys.8 Renal impairment is associated with higher tumor burden, more aggressive disease, and increased mortality.8 It also affects drug selection and dosing strategies. Over-the-counter nonsteroidal anti-inflammatory drugs can impair kidney function; therefore, it is important to ascertain whether patients are using these medications, so that we can offer them safe alternatives. The intravenous bisphosphonates zoledronic acid and pamidronate must be dosereduced in patients with varying degrees of renal impairment.9 Lenalidomide use in moderate and severe renal impairment requires dose adjustment, as this drug is renally excreted.8 Since bortezomib is hepatically metabolized, dose adjustments are not required in patients with renal dysfunction.8 Recent data on the use of carfilzomib in the late-line setting for MM also points to good tolerability in renally-impaired patients.10

Conclusion

As pharmacists, we need to be aware of the latest developments in MM, not only for our own knowledge, but so that we can pass this information along to our fellow clinicians and to patients. Individuals with myeloma are well informed about their disease and become excited at the prospect of new agents on the horizon. They know that they have years of therapy ahead of them, and demand that quality of life be factored into the equation along with efficacy.

References

  1. Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208:1680-1685.
  2. Richardson PG, Mitsiades C, Schlossman R, et al. New drugs for myeloma. Oncologist. 2007;12:664-689.
  3. 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.
  4. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology. 2004: 62:2291-2293.
  5. 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.
  6. 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.
  7. 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.
  8. Dimopoulos MA, Kastritis E, Rosinol L, et al. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia. 2008; 22:1485–1493.
  9. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. Niesvizky R, Naib T, Christos PJ, et al.
  10. 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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Last modified: July 22, 2021