Although a variety of efficacious primary therapies are available to treat multiple myeloma (MM), the disease is characterized by frequent relapses, with a 5-year survival rate of only 46.6%.1 Thus, determining optimal therapy in patients with progressed disease is critical in extending survival and maintaining quality of life. The case presented here discusses the benefits and risks associated with various treatments following progression and the impact of these factors on the choice of therapy.
Mr. B, a 75-year-old white male, presents with severe neck pain radiating down the left arm. An MRI of the neck and vertebrae reveal vertebral lesions. He has a hemoglobin of 8.5 g/dL, serum creatinine of 0.8 g/dL, calcium of 9.1 mg/dL, and albumin of 4.3 g/dL. Serum protein electrophoresis reveals an immunoglobulin A (IgA) lambda paraprotein of 0.9 g/dL, and quantitative immunoglobulin shows an IgA level of 1496 mg/dL with decreased IgG and IgM levels to below the normal limits of normal. A bone marrow biopsy is reported to be 90% cellular with 40% lambda-restricted plasma cells. Cytogenetics shows a normal male karyotype. Upon fluorescence in situ hybridization testing, he is found to have a 4;14 translocation in 30% of cells. His beta 2 microglobulin is 3.6 mg/L. A skeletal survey shows lytic lesions in the cervical spine and pelvic bones.
According to the International Staging System criteria, Mr. B is diagnosed as having stage II MM based on his beta 2 microglobulin and albumin.2
The National Comprehensive Cancer Network (NCCN) recommends several two- and three-drug combinations for primary treatment of nontransplantation candidates with MM.2 Of these options, 15 mg lenalidomide 21/28 days plus 20 mg dexamethasone weekly is chosen as first-line therapy for Mr. B. on the basis of trials demonstrating superior rates of progression-free survival (PFS).
Since numerous studies have demonstrated that bisphosphonates are effective in reducing the pain and skeletal-related events seen in patients with MM, Mr. B was started on zoledronic acid at 4 mg monthly. Recently, zoledronic acid was also shown to significantly improve PFS and overall survival (OS) in newly diagnosed MM patients compared with clodronic acid, another bisphosphonate (PFS: HR 0.89, P = .02; OS: HR 0.86, P = .01), further supporting the use of this agent in the treatment of Mr. B.3
The Case Continues
Mr. B. achieves partial remission and remains on lenalidomide and dexamethasone for 22 months, at which point he experiences a new onset of left hip pain. Imaging studies show a new lytic lesion in the left hip. At this time, serum protein electrophoresis also shows a 25% increase in M protein over nadir values.
Treatment Following Progression
Of the many preferred regimens recommended by the NCCN for the treatment of relapsed MM, one half contain bortezomib.2 Since Mr. B’s disease has progressed on lenalidomide and dexamethasone, it is decided to change his therapy to bortezomib 1.5 mg/m2 weekly, 4 wk/5wk plus dexamethasone, 20 mg weekly, with continuation of zoledronic acid. Unfortunately, after three cycles, he develops painful neuropathy affecting his fingers.
Due to his drug-related neuropathy, the bortezomib in Mr. B’s regimen is replaced with carfilzomib 20/27 mg/m2, a proteasome inhibitor that is associated with minimal or no neuropathy, and he continues on dexamethasone and zoledronic acid.4 The combination of carfilzomib and dexamethasone has proven highly active in patients with relapsed/refractory MM in early studies and is now being explored in the ENDEAVOR phase III trial, with results from the preplanned interim analysis recently reported at ASCO.5-7
During the first cycle, Mr. B complains of mild dyspnea in the evening after administration of carfilzomib. An echocardiogram shows normal ejection fraction, and serum brain natriuretic peptide and troponin levels are normal. Over a period of time his neuropathy improves, with attainment of a very good partial response on therapy.
In this patient, the development of drug-related adverse effects was an important determinant of treatment following relapse. Peripheral neuropathy is a common adverse effect associated with the use of bortezomib, occurring in 46% of previously untreated patients receiving bortezomib, melphalan, and prednisone in clinical trials, compared with only 1% in those receiving melphalan and prednisone. Of the bortezomib-related neuropathy cases, 12% were grade 3 toxicity and 1% >grade 4.8 High rates of neuropathy are also seen in previously treated patients receiving bortezomib. In a trial of bortezomib versus dexamethasone in relapsed MM, peripheral neuropathy occurred in 35% of those receiving bortezomib, compared with 4% in those receiving dexamethasone, with grade 3 neuropathy seen in 7% of the bortezomib group.8
In contrast, in the recent ASPIRE trial comparing carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed disease, including those previously treated with bortezomib, the rates of peripheral neuropathy associated with the two regimens were virtually identical (17.1% and 17.0%, respectively), indicating that carfilzomib does not cause neuropathy.4 As seen in Mr. B, the replacement of bortezomib with carfilzomib resulted in an improvement in neuropathy.
Although dyspnea has been noted in up to 30% to 35% of patients receiving carfilzomib, the majority of these cases have been grade 1 or 2, with grade 3 or 4 seen in approximately 5% of patients.9 However, rates of dyspnea were much lower in the ASPIRE trial, with only 19% of patients in the carfilzomib, lenalidomide, and dexamethasone arm and 15% in the lenalidomide and dexamethasone arm experiencing this adverse effect.4
The etiology of dyspnea is not completely clear, but it may be the result of a variety of pathophysiologic mechanisms, including pulmonary artery hypertension and cytokine release phenomenon. It may also be caused by excessive fluid administration, and in rare cases, may be related to an unidentified cardiotoxicity of the drug. However, in the majority of cases, workup fails to reveal any decline in myocardial contractivity. Cardiopulmonary adverse effects may possibly be minimized by a reduction in hydration and the use of steroids, such as 20 mg of dexamethasone, which would have additional therapeutic benefits as well.
The availability of carfilzomib offers an important new option for patients who have relapsed, particularly those who have been previously treated with bortezomib-containing regimens. In addition to its favorable adverse effect profile, carfilzomib has proven highly effective in treating patients with relapsed/refractory disease. As seen in the interim analysis of the ENDEAVOR trial comparing carfilzomib + dexamethasone versus bortezomib + dexamethasone, the median PFS with the carfilzomib combination was significantly greater (18.7 months) than that with the bortezomib combination (9.4 months) (HR = 0.53, P <.0001).7 The encouraging results seen with the combination of carfilzomib and dexamethasone have also been observed with the combination of carfilzomib, lenalidomide, and dexamethasone. In the ASPIRE trial comparing this regimen versus lenalidomide and dexamethasone, the addition of carfilzomib to lenalidomide and dexamethasone significantly increased PFS from 17.6 months to 26.3 months (P <.0001) and 24-month OS rates from 65.0% to 73.3% (P = .04).4
Carfilzomib represents an important advance in the treatment of patients with relapsed/refractory MM. As demonstrated in clinical trials, the addition of carfilzomib to other therapies, such as dexamethasone or dexamethasone plus an immunomodulatory agent, has resulted in impressive increases in efficacy without the neuropathy associated with bortezomib. Cardiopulmonary toxicity, an adverse effect seen with carfilzomib, is rare and can be minimized by careful hydration and the use of steroids.
NCI. SEER Stat Fact Sheets: Myeloma. Accessed 6/18/15 at: http://1.usa.gov/1TSrp2V
NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 4.2015 Accessed 6/18/15 at: http://bit.ly/1L1bhch.
Morgan GJ, Davies FE, Gregory WM, et al. Long-term follow-up of MRC myeloma IX trial: survival outcomes with bisphosphonates and thalidomide treatment. Clin Cancer Res. 2013;19;6030-6038. Abstract
Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. Abstract
Papadopoulos KP, Siegel DS, Vesole DH, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015;33:732-739. Abstract
ClinicalTrials.gov. Phase 3 study with Carfilzomib and Dexamethasone Versus Velcade and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR). Accessed 6/18/15 at: http://1.usa.gov/1TSrt2v.
Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. J Clin Oncol. 2015;33(suppl): Abstr 8509. Absract
Bortezomib [Package Insert]. Millennium Pharmaceuticals, Inc.; Cambridge, MA. 2014. Accessed 6/26/15 at: http://1.usa.gov/1HleHo0.
Carfilzomib [Package Insert]. Onyx Pharmaceuticals, Inc.; Thousand Oaks, CA. January 2015. Accessed 6/26/15 at: http://1.usa.gov/1TSs98a.