For transplantation-ineligible patients with high-risk, relapsed multiple myeloma, treatment with a regimen that includes an immunomodulatory agent and/or proteasome inhibitor is recommended. In those patients with dual-refractory myeloma, treatment with the next-generation immunomodulatory agent may be an efficacious and well-tolerated treatment option. The following case illustrates the treatment of transplantation-ineligible patients with dual-refractory high-risk disease. In addition, this case highlights the importance of recognizing the criteria for CRAB-negative myeloma.
Mr. B is a 65-year-old black male patient with a 5-year history of kappa light chain monoclonal gammopathy of undetermined significance. He presents with reproducible right-sided rib and low back pain. Concern for disease progression prompted further evaluation. Light chain nephelometry revealed a significant increase of the kappa light chain to 2500 mg/L, serum and urine protein electrophoresis does not reveal a monoclonal spike, serum calcium is normal, and hemoglobin and creatinine are consistent with his known chronic renal insufficiency. The bone marrow is hypercellular with 65% plasma cells and CD-138 selected fluorescent in-situ hybridization shows high-risk features of chromosome 17p deletion.1 His beta2-microglobulin is 4.2 mg/L and his albumin is 3.2 g/dL, values consistent with International Staging System stage 2 disease.2 The skeletal survey is negative for lytic lesions, but MRI of the lumbar spine reveals myelomatous changes in the marrow of L2.
Mr. B is diagnosed with CRAB-negative multiple myeloma. With chronic renal insufficiency, the patient is ineligible for transplantation, and treatment with a regimen that includes an immunomodulatory agent and/or proteasome inhibitor in combination with dexamethasone is recommended.
In patients with CRAB-negative myeloma, such as this patient, a regimen inclusive of lenalidomide and dexamethasone is associated with improvements in progression-free survival and overall survival.3 Mr. B receives lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle and dexamethasone 40 mg weekly for nine cycles followed by lenalidomide 10 mg daily on days 1 to 21 of a 28-day cycle. He tolerates treatment well with the exception of developing a maculopapular rash and mild cytopenias. Despite achieving a very good partial response for nearly 4 years while on lenalidomide, Mr. B’s kappa light chain eventually increases. Treatment is switched to bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 of a 21-day cycle and dexamethasone 20 mg, because this regimen is associated with a median progression-free survival of 8.7 months and overall survival of 22 months in lenalidomide-refractory patients.4 The patient achieves a partial response for five cycles, but then progresses. Since his disease is refractory to lenalidomide and bortezomib, he is switched to pomalidomide 2 mg by mouth days 1 to 21 of a 28-day cycle and dexamethasone 40 mg by mouth weekly.5 He tolerates this regimen well and develops no dose-limiting cytopenias, fatigue, infections or gastrointestinal symptoms. After 6 months, he has a partial response, and dexamethasone is discontinued while pomalidomide is continued as maintenance therapy.
CRAB symptoms (hypercalcemia, renal insufficiency, anemia and bone lesions) characterize the presentation of symptomatic multiple myeloma; however, some patients present without CRAB criteria and are at high risk for early disease progression.6 The most recent International Myeloma Working Group guidelines updated the criteria for patients with CRAB-negative myeloma or those patients with >60% clonal bone marrow plasma cells, and/or an involved:uninvolved serum free light chain ratio >100, and/or >1 focal lesion (>5 mm) on MRI based in part on a recent clinical trial showing that compared with observation alone, early intervention for these patients delayed time to progression to symptomatic disease and provided an overall survival benefit.3,6
Pomalidomide is an effective option for patients heavily pretreated with lenalidomide and bortezomib.7 In patients with relapsed refractory myeloma previously treated with more than two therapies including lenalidomide and bortezomib, treatment with pomalidomide and dexamethasone (4 mg daily days 1–21 of a 28-day cycle and dexamethasone 40 mg weekly) was associated with a 33% overall response rate, 4.2 month median progression-free survival, and 16.5 month median overall survival.8 In this study, treatment outcomes were not significantly affected by refractoriness to either lenalidomide or both lenalidomide and bortezomib.8 In this refractory population, the median progression-free survival was 3.8 months, and the median overall survival was 16 and 13.4 months for patients refractory to lenalidomide, and lenalidomide and bortezomib, respectively.8 Since the pharmacokinetic profile of pomalidomide is not significantly affected by renal function and efficacy has been shown to be similar at 2 and 4 mg doses for pomalidomide, we recommended initiating pomalidomide at 2 mg, days 1 to 21 of a 28-day cycle in our patient.5,9 Further, it is our standard practice to initiate dexamethasone at 20 mg weekly in those patients older than the age of 70.
New diagnostic criteria identify a subset of patients with CRAB-negative myeloma who are at high risk for early disease progression and who may benefit from early treatment intervention. In those patients with myeloma refractory to either lenalidomide alone or lenalidomide and bortezomib, treatment with pomalidomide and dexamethasone may be an efficacious and well-tolerated treatment option.
Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007;109:3489-3495. Abstract
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-20. Abstract
Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. New Engl J Med. 2013;369:438-447. Abstract
Pantani L, Zamagni E, Zannetti BA, et al. Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. Ann Hematol. 2014;93:123-128. Abstract
Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118: 2970-2975. Abstract
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548. Abstract
Siegel D, Richardson PG, Dimopoulos MA, et al. Efficacy and safety of pomalidomide plus low-dose dexamethasone in advanced multiple myeloma: results of randomized phase 2 and 3 trials (MM-002/MM-003). Abstract 3185. Presented at: 55th ASH Annual Meeting and Exposition, December 7-10, 2013; New Orleans, LA. Accessed 2/23/15 at: http://bit.ly/1JDtjSb.
Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123:1826-1832. Abstract
Matous J, Siegel DS, Duong HK, et al. MM-008: pharmacokinetics and tolerability of pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and renal impairment. J Clin Oncol. 2013;31(suppl): abstr 8585. Abstract