Until recently, patients with refractory/relapsed multiple myeloma (MM) have had few treatment options. The availability of new therapies in two classes, immunomodulatory agents and proteasome inhibitors, has greatly expanded available treatments. In combination regimens with drugs from other classes, these new treatments have increased response and overall survival. The case presented here describes the therapeutic choices for treating a newly diagnosed, and subsequently relapsed, patient with MM, and discusses the rationale for treatment decisions regarding this patient.
Mr. M, a 67-year-old black male, presents with complaints of back pain. Initial X-ray studies identify a compression fracture of the T10 vertebral body. Laboratory work done at the time of diagnosis shows that he is also somewhat anemic, with a hemoglobin of 9.6 g/dL, and has a mildly elevated creatinine of 1.4 g/dL, serum calcium of 8.9 mg/dL, and albumin of 3.1 g/dL. With additional testing, he is found to have a monoclonal immunoglobulin G kappa paraprotein measuring 2.7 g/dL, and an immunoglobulin G level of 4360 mg/dL with decreased levels of immunoglobulin M and immunoglobulin A. The patient undergoes a bone marrow biopsy, which shows a hypercellular marrow with 60% kappa restricted plasma cells; cytogenetics show a normal male karyotype; and fluorescence in situ hybridization testing reveals hyperdiploidy. He has a beta2 microglobulin of 5.9 mg/L. A skeletal survey identifies widespread axial and appendicular lesions.
Based on these findings, Mr. M is diagnosed as having stage 3 MM according to the International Staging System.1
Mr. M is placed on a 3-drug regimen of bortezomib, lenalidomide, and dexamethasone, one of several primary therapeutic options for transplant-eligible patients.1 In addition, he is given zoledronic acid, a bisphosphonate used to prevent/alleviate skeletal-related events in patients with MM. After four cycles, he experiences a very good partial response to the bortezomib, lenalidomide, and dexamethasone regimen. He then undergoes a transplantation, and 3 months posttransplantation is in complete remission. At this point, he is placed on lenalidomide maintenance therapy and continued on zoledronic acid to complete 2 years of bisphosphonate therapy.
The Case Continues
However, 18 months after the start of maintenance therapy, he is observed to have a slowly rising paraprotein. At this point, his lenalidomide dose is increased to 25 mg on a 21/28-day schedule, and dexamethasone is added to the regimen. Unfortunately, after 2 months on this regimen, his paraprotein increases further.
Imaging studies performed at this time show new lytic lesions in the long bones of the upper extremities, and repeat bone marrow biopsies show 20% plasma cells with a normal male karyotype.
Mr. M is started on therapy with bortezomib and dexamethasone, to which he achieves a partial response. Although he experiences grade 1 neuropathy, he continues on bortezomib and dexamethasone for the next 10 months.
Switch in Therapy
At this point, he again has a rise in his paraprotein and, as a result, it is decided to switch his therapy.
The new proteasome inhibitor, carfilzomib, has been approved to treat patients such as Mr. M who have received at least two other treatments, including bortezomib and either lenalidomide or thalidomide, and whose disease has progressed on their last therapy or within 60 days of their last therapy.2 In light of encouraging clinical trial results with carfilzomib in combination with other agents, Mr. M is started on treatment with carfilzomib (20 mg/m2 on days 1, 2, 8, 9, 15, and 16), pomalidomide (4 mg/day), and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16).3,4 At the second week of therapy, the dose of carfilzomib is increased to 27 mg/m2. Prehydration with 250 cc of saline is administered with each dose of carfilzomib. Mr. M tolerates treatment well and his neuropathy is stable. The treatment plan at this point is to continue carfilzomib, pomalidomide, and dexamethasone until disease progression.
This case illustrates the choices that must be made between a number of primary therapies for a newly diagnosed MM patient and how these choices have an impact on further treatment when the patient relapses. A variety of 2- and 3-drug combinations are currently available as primary treatment for transplantation-eligible MM patients.1 In the case discussed here, Mr. M was placed on the combination of bortezomib, lenalidomide, and dexamethasone, a regimen that includes a proteasome inhibitor and an immunomodulatory agent, two drug classes that are active in MM. A recent phase II study in 140 previously untreated MM patients compared three- and four-drug combinations of bortezomib, lenalidomide, dexamethasone, and cyclophosphamide, all followed by bortezomib maintenance. The combination of bortezomib, lenalidomide, and dexamethasone resulted in a ≥very good response rate of 51% and a 1-year progression-free survival (PFS) of 83%, whereas bortezomib, cyclophosphamide, and dexamethasone, another possible option in Mr. M’s case, yielded rates of 53% and 100%, respectively. No meaningful advantage was noted with the 4-drug combination, compared with the three-drug regimens.5
The determination of therapy following relapse is based on the clinical efficacy and particular adverse effects associated with each option. The new proteasome inhibitor, carfilzomib, offers increased treatment options for patients such as Mr. M, who have relapsed following treatment with bortezomib and lenalidomide.
One of these options is the combination of carfilzomib, lenalidomide, and dexamethasone. In the recent ASPIRE trial in 792 patients with relapsed MM, patients receiving this combination had a significantly longer PFS of 26.3 months, compared with PFS of 17.6 months in patients receiving lenalidomide and dexamethasone alone (P = .0001). The 24-month overall survival rate was also significantly longer in patients receiving the carfilzomib-containing regimen than in those receiving only lenalidomide and dexamethasone (73.3% versus 65.0%, respectively; P = .04).3 However, the three-drug combination of carfilzomib, lenalidomide, and dexamethasone was not chosen in this case because the patient had already progressed on lenalidomide and dexamethasone.
Regimens containing carfilzomib and the newly approved immunomodulatory agent, pomalidomide, are particularly useful in patients such as Mr. M, who have relapsed on both bortezomib and lenalidomide. In a phase I/II trial in relapsed/refractory patients, the combination of carfilzomib, pomalidomide, and dexamethasone as used in Mr. M’s case resulted in an overall response rate of 50% and a very good or better response rate of 13%.4
The two-drug combination of pomalidomide and dexamethasone has also proven useful in relapsed patients. In a meta-analysis of six randomized, controlled trials in 641 patients with relapsed/refractory MM, this combination resulted in an overall response rate of 31% in all patients, 32% in patients >65 years old, and 27% in high-risk patients.6 Other reports of this combination in relapsed/refractory patients cite a PFS of 15.7 weeks.7 However, recent data suggest that three-drug salvage regimens increase depth of response and PFS compared with two-drug regimens.
Finally, a new histone deacetylase inhibitor, panobinostat, has recently been approved in combination with bortezomib and dexamethasone for the treatment of multiple myeloma.8 In a trial comparing panobinostat, bortezomib, and dexamethasone versus bortezomib and dexamethasone, the patients receiving the panobinostat-containing regimen had a PFS of approximately 10.6 months and a response rate of 59%, compared with 5.8 months and 41%, respectively, in those receiving bortezomib and dexamethasone alone.8 The combination of panobinostat and carfilzomib has also shown encouraging results in a preliminary phase I/II trial, with a 50% overall response rate and a median PFS of 14.3 months.9
As demonstrated in these trials, carfilzomib in combination with other agents may produce responses even in patients who are refractory to bortezomib. However, in order to achieve optimal results with this agent it’s important to use the drug correctly. Although carfilzomib was originally recommended for use only as a single agent, postmarketing experience has shown that patients who have failed multiple drugs are unlikely to respond to carfilzomib alone and that combination therapy with carfilzomib, dexamethasone, and a third drug is best to maximize response in highly refractory patients.10 To obtain the best response, the initial dose 20 mg carfilzomib can be increased to 27 mg with the second week of therapy. Assuming the patient is tolerating therapy, it often is not necessary to wait for the second cycle to escalate the dose. In addition to giving a sufficient dose of carfilzomib, care must be taken to include an adequate dose of dexamethasone. Finally, in order to avoid the shortness of breath and edema that can be associated with carfilzomib, fluid hydration can be limited to 250 cc of saline per dose of carfilzomib in the first cycle, with no hydration mandated in subsequent cycles.
Three-drug regimens containing novel agents have greatly expanded treatment options for both newly diagnosed and refractory MM patients. Used at correct dosages, the combination of carfilzomib and dexamethasone with either cyclophosphamide or lenalidomide has proven effective in increasing progression-free and overall survival even in patients who are refractory to bortezomib and lenalidomide.
NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 4.2015. Accessed 6/9/15 at: http://bit.ly/1L1bhch.
Carfilzomib [package insert]. Onyx Pharmaceuticals, Inc., Thousand Oaks, CA. January 2015.
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
Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74.
Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382. Abstract
Shen Z, Liu G. Pooled analysis of the reports of pomalidomide after failure of lenalidomide and (or) bortezomib for multiple myeloma. Hematol Oncol. 2015 Feb 3. [Epub ahead of print] Abstract
Hanaizi Z, Flores B, Hemmings R, et al. The European Medicines Agency review of pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Oncologist. 2015;20:329-334. Abstract
FDA News Release. FDA approves Farydak for treatment of multiple myeloma. Accessed 6/9/15 at: http://1.usa.gov/1LPvilt.
Kaufman JL, et al. Phase I study of the combination of carfilzomib and panobinostat for patients with relapsed and refractory myeloma: a Multiple Myeloma Research Consortium (MMRC) clinical trial. ASH Annual Meeting, December 6-9, 2014, San Francisco, CA
NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2015 Accessed 6/9/15 at: http://binged.it/1Tb0mQ2.