Can Cyclophosphamide Plus Pomalidomide and Dexamethasone Overcome Lenalidomide Resistance in Patients with Relapsed/Refractory Myeloma?

Adding cyclophosphamide to the treatment combination of pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (MM) resulted in a superior overall response rate (ORR) and progression-free survival (PFS), compared with pomalidomide and dexamethasone alone, according to a phase I/II study published in Blood.

For MM patients who are refractory to lenalidomide and who have received more than two prior therapies, combination treatment with pomalidomide and low-dose dexamethasone is a standard treatment option. In this two-part study, Rachid C. Baz, MD, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues sought to identify the recommended doses of pomalidomide, dexamethasone, and cyclophosphamide (phase I; Arm A), and then compare the efficacy of the pomalidomide and dexamethasone combination with or without cyclophosphamide (phase II).

Patients were eligible to participate in the study if they:

  • Received at least two prior lines of therapies, including an immunomodulatory drug
  • Were refractory to lenalidomide (defined as disease progression during active therapy or within 60 days of discontinuation)
  • Had measurable disease
  • Had an Eastern Cooperative Oncology Group performance status of 0-2
  • Had a serum creatinine <3 mg/dL

Patients in the phase I study were also required to have an absolute neutrophil count ≥1,000/mm3 and a platelet count ≥50,000/mm3, while patients in the phase II study who had >50 percent bone marrow plasmacytosis were eligible if platelet counts were >30,000/mm3.

Exclusion criteria included hypersensitivity to thalidomide or lenalidomide, presence of HIV or active hepatitis B or C, previous treatment with pomalidomide (more than 1 cycle), and active malignancy that required therapy within the next year.

Eighty patients were enrolled at three U.S. academic institutions between December 2011 and March 2014. Overall, patients had advanced MM and had received a median of four prior therapies (range = 2-12).

The phase I study included 10 patients (Arm A) who received:

  • Pomalidomide 4 mg orally on days 1 through 21 of a 28-day cycle
  • Cyclophosphamide orally on days 1, 8, and 15 (dose escalation of 300 mg to 500 mg to identify the recommended dose)
  • Dexamethasone 40 mg on days 1 through 4, and 15 through 18 of a 28-day cycle for the first 4 cycles, followed by 40 mg on days 1, 8, 15, and 22

Based on the results of the phase I trial, phase II of the trial randomized 70 patients 1:1 to receive:

  • Pomalidomide 4 mg orally on days 1 through 21 and low-dose dexamethasone 40 mg weekly (Arm B; n=36) of a 28-day cycle
  • Pomalidomide 4 mg orally on days 1 through 21, cyclophosphamide 400 mg orally on days 1, 8, and 15, and low-dose dexamethasone 40 mg weekly (Arm C; n=34) of a 28-day cycle

Patients in Arm B whose disease progressed were allowed to cross over and receive weekly oral cyclophosphamide (Arm D).

The ORR (the study’s primary endpoint, defined as partial response or better) for Arms B and C were 38.9 percent (95% CI 23-54.8) and 64.7 percent (95% CI 48.6-8.8), respectively (p=0.035). In addition, 22 percent (n=8) of patients in Arm B and 15 percent (n=5) of patients in Arm C achieved a minimal response (MR).

By June 2015, most patients from the phase II study experienced progressive disease (Arm B: 33/36; Arm C: 29/34), with patients in the cyclophosphamide group achieving longer median PFS: 9.5 months (95% CI 4.6-14) versus 4.4 months (95% CI 2.3-5.7; p=0.106). The median OS was 16.8 months (95% CI 9.3 to not reached) in Arm B and was not reached in Arm C (p=0.168). See TABLE 1 for best responses to treatment in each patient cohort.

As of June 2015, 51 patients had died (36 in Arm B and 15 in Arm C).

Of the 33 patients in Arm B who experienced disease progression, 17 crossed over to Arm D during the study period. Among these 17 patients, one achieved partial response, four achieved MR, and eight had stable disease (the remaining four patients had continued progressive disease). The ORR was 6 percent and the clinical benefit rate (the proportion of patients who crossed over and achieved complete response, partial response, and stable disease compared with pomalidomide-dexamethasone alone) was 29 percent. The median PFS from the start of Arm D was 4.4 months (95% CI 0.9-8) and, as of the data cutoff, all patients experienced disease progression.

To identify patients who would respond better to the triplet regimen, Dr. Baz and researchers also conducted a multivariable analysis of patient factors associated with better treatment response (TABLE 2), including the presence of high-risk cytogenetics and a higher number of prior therapies.

Adverse events (AEs) were predominantly hematologic in nature, the authors noted, with a higher rate of grade ≥3 AEs reported in Arm C than Arm B. Grade ≥3 AEs included anemia (11% in Arm B vs. 24% in Arm C; p=0.21), neutropenia (31% vs. 52%; p=0.14), and thrombocytopenia (6% vs. 15%; p=0.25). “Differences in the rates of meaningful AEs could not be demonstrated,” Dr. Baz and colleagues wrote. “However, one can anticipate that cyclophosphamide would result in additional hematologic toxicities.”

“For patients who are contemplating a pomalidomide-based regimen, a triplet regimen (such as pomalidomide, cyclophosphamide, and dexamethasone) would be preferred over the doublet regimen (pomalidomide and dexamethasone), followed by the sequential addition of cyclophosphamide to patients who are pomalidomide-refractory,” Dr. Baz told ASH Clinical News.

The phase II design of the study may have limited the power to detect a statistically significant difference in efficacy outcomes and toxicity measures, the authors noted. “Nevertheless, we were able to demonstrate a statistically significant improvement in overall response rate and progression-free survival.”

The pomalidomide, dexamethasone, and cyclophosphamide regimen studied in Arm C also represents an all-oral regimen that is more convenient for patients, Dr. Baz added. “It may be less costly than regimens that combine pomalidomide with proteasome inhibitors or monoclonal antibodies. Accordingly, pomalidomide, cyclophosphamide, and dexamethasone is a reasonable option for many patients with lenalidomide-refractory [MM],” Dr. Baz concluded.


Reference

Baz RC, Martin TG, Lin HY, et al. Randomized multicenter phase II study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 March 1. [Epub ahead of print]

Table 1. IMWG Best Response on Treatment in Each Study Cohort
Response Arm A(n=10) Arm B(n=36) Arm C(n=34) Arm D(n=17)
Complete/stringent CR 1(10%) 1(3%) 1(3%)
Very good PR 1(10%) 4(11%) 3(9%)
PR 3(30%) 9(25%) 18(53%) 1(6%)
Minimal response 2(20%) 8(22%) 5(15%) 4(23%)
Stable disease 2(20%) 7(19%) 1(3%) 8(47%)
Progressive disease 1(10%) 5(14%) 3(9%) 4(23%)
Not evaluable 2(6%) 3(9%)
IMWG = International Myeloma Working Group; CR = complete response; PR = partial response

Table 2. Patient Factors Associated with Treatment Response
ORR PFS OS
Unadjusted OR (95% CI) Adjusted OR (95% CI) Unadjusted HR (95% CI) Adjusted HR (95% CI) Unadjusted HR (95% CI) Adjusted HR (95% CI)
Age(in 10 year increments) 1.16(0.64-2.11) 1.22(0.62-2.40) 0.80(0.59-1.10) 0.72(0.50-1.04) 0.83(0.56-1.24) 0.88(0.51-1.49)
Number of prior therapies(≥5 vs. <5) 1.23(0.47-3.21) 1.77(0.56-5.60) 0.79(0.47-1.33) 0.54(0.29-0.99) 0.94(0.48-1.85) 0.66(0.32-1.38)
B2-microglobuin(mg/L) 1.03(0.84-1.25) 0.99(0.80-1.23) 1.09(0.99-1.20) 1.15(1.03-1.28) 1.30(1.15-1.47) 1.38(1.21-1.58)
High-risk cytogenetics 0.36(0.11-1.22) 0.33(0.09-1.22) 1.73(0.92-3.27) 1.77(0.88-3.55) 2.12(1.00-4.48) 2.21(0.98-4.98)
Study arm(Arm C vs. Arm B) 2.88(1.09-7.61) 2.98(0.99-8.99) 0.66(0.40-1.10) 0.54(0.29-1.00) 0.63(0.32-1.22) 0.54(0.25-1.17)
ORR = overall response rate; PFS = progression-free survival; OS = overall survival; OR = odds ratio; HR = hazard ratio

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