This case illustrates an elderly relapsed/refractory multiple myeloma (MM) patient who was refractory to both lenalidomide and bortezomib. The immunomodulatory agent, pomalidomide, and the proteasome inhibitor, carfilzomib, are two newer agents approved for use in this treatment setting.1,2 In addition, the histone deacetylase inhibitor panobinostat was recently approved for use in combination with bortezomib and dexamethasone in MM patients in this treatment setting.3 The objective of this case is to emphasize the importance of treatment choice in this setting of patients who have a poor outcome: a median overall survival of 3 months with no treatment.4
A 72-year-old male presented at diagnosis with anemia (Hb 8.3 g/dL), mild renal failure (creatinine 1.2 mg/dL), serum total proteins 11.5 g/dL, monoclonal component 48% (5520 mg/dL), immunoglobulin G (IgG) 7130 mg/dL, bone marrow plasma cells 80%, fluorescence in situ hybridization (FISH) negative, no lytic lesions, International Staging System (ISS) stage II, and Karnofsky performance status 90%. According to a geriatric assessment scoring system from the International Myeloma Working Group (IMWG), he was classified as a fit patient based on his age, an Activity of Daily Living (ADL) score of 5, an Instrumental Activity of Daily Living (IADL) score of 8, and a Charlson Comorbidity Index (CCI) of 1 due to mild diabetes.5 Patients may be classified as fit (score = 0), intermediate fitness (score = 1), or frail (score ≥2).
The patient was prescribed lenalidomide plus dexamethasone (Rd) until progression or intolerance. After achieving a stringent complete response, the patient progressed after 2 years of Rd treatment with fatigue, a doubling of monoclonal component in 2 months (from 9.2% to 26.6%), osteopenia, and bone marrow plasma cells 40%. The patient appeared to be refractory to Rd and was then prescribed bortezomib plus dexamethasone (Vd). After six cycles of Vd, the patient again progressed. He presented with mild anemia (Hb 11.5 g/dL), monoclonal component 43.2%, new lytic lesions at skull and jaw, bone marrow plasma cells 22%, FISH negative, ISS stage II, and Karnofsky performance status 80%.
The patient was diagnosed with MM refractory to both lenalidomide and bortezomib. He was in good clinical condition according to the Karnofsky scale and did not suffer from relevant comorbidities.
With limited options, the patient was prescribed pomalidomide plus dexamethasone. He was considered eligible for pomalidomide treatment, and recent studies suggest positive results with this regimen in relapsed/refractory MM.6 Other treatment options for this patient would have been a carfilzomib-based regimen or panobinostat in combination with bortezomib and dexamethasone.7,8
After the second cycle with pomalidomide plus dexamethasone, the patient achieved a partial response (more than 50% reduction of monoclonal component), and after the sixth cycle he achieved a very good partial response (more than 90% reduction of monoclonal component). The regimen has been well tolerated, with grade 1 fatigue and rash and grade 2 vasculitis and erysipelas occurring during treatment. The patient is still receiving pomalidomide plus low-dose dexamethasone.
MM patients who are refractory to both lenalidomide and bortezomib have a poor outcome: a median overall survival of 3 months with no treatment.4 The recent MM-003 randomized phase III trial in this setting showed a median progression-free survival (PFS) of 4.0 months with pomalidomide plus low-dose dexamethasone versus 1.9 months with high-dose dexamethasone (P <.0001).6 Another option for patients refractory to both bortezomib and an immunomodulatory agent is carfilzomib-based treatment. In the phase III ASPIRE trial in relapsed MM patients who received prior bortezomib and/or lenalidomide, median PFS was significantly improved with the three-drug combination of carfilzomib, lenalidomide, and dexamethasone (26.3 months versus 17.6 months in the control group, P = .0001).7 Panobinostat in combination with bortezomib and dexamethasone is also an option for patients with relapsed or refractory MM. In the phase III PANORAMA1 trial in patients with relapsed or refractory MM, median PFS was significantly improved with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone (11.99 months versus 8.08 months, P <.0001).8
This case showed an elderly, refractory MM patient who benefited from pomalidomide plus dexamethasone after early progression during lenalidomide and bortezomib therapy. In this patient setting, either pomalidomide-based regimens or carfilzomib-based regimens are valid treatment options.6,7 Panobinostat plus bortezomib and dexamethasone is another alternative.8 Pomalidomide, carfilzomib, and panobinostat have shown no significant differences in efficacy in older patients with MM (65 years of age or older) compared with younger patients with MM in clinical trials.1-3 However, pneumonia was more common with pomalidomide in older versus younger patients, and there were increased rates of adverse effects and discontinuation with panobinostat in older patients versus younger patients.1,3
In relapsed/refractory MM, criteria including patient fitness and response to prior therapy should influence choice of treatment. Pomalidomide plus dexamethasone represents a highly effective combination with a good safety profile for patients with relapsed/refractory MM, including elderly patients.
Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2014.
Carfilzomib [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.
Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
Kumar SK, Lee JH, Lahuerta JJ, et al; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-157. Abstract
Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma: an International Myeloma Working Group report. Blood. 2015;125:2068-2074. Abstract
San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066. Abstract
Stewart AK, Rajkumar SV, Dimopoulos MA, et al; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. Abstract
San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206. Abstract