Written in Blood
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:
• Had a serum creatinine <3 mg/dL
Patie nts 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 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:
• Pomalidomide 4 mg orally on days 1 through 21 33/36; Arm C: 29/34), with patients in the cyclophosphamide group achieving longer median PFS:
of a 28-day cycle
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
• Received at least two prior lines of therapies,
• Cyclophosphamide orally on days 1, 8, and 15
including an immunomodulatory drug
(dose escalation of 300 mg to 500 mg to identify months (95% CI 9.3 to not reached) in Arm B and
was not reached in Arm C (p=0.168). See TABLE 3 for
the recommended dose)
• Were refractory to lenalidomide (defined as
best responses to treatment in each patient cohort.
disease progression during active therapy or
• Dexamethasone 40 mg on days 1 through 4,
As of June 2015, 51 patients had died (36 in Arm
within 60 days of discontinuation)
and 15 through 18 of a 28-day cycle for the
B and 15 in Arm C).
first 4 cycles, followed by 40 mg on days 1, 8,
Of the 33 patients in Arm B who experienced
• Had measurable disease
15, and 22
disease progression, 17 crossed over to Arm D
during the study period. Among these 17 patients,
• Had an Eastern Cooperative Oncology Group
Based on the results of the phase I trial, phase II of
one achieved partial response, four achieved MR,
performance status of 0-2
the trial randomized 70 patients 1:1 to receive:
and eight had stable disease (the remaining four
patients had continued progressive
disease). The ORR was 6 perTABLE 3. IMWG Best Response on Treatment in Each Study Cohort
cent and the clinical benefit rate
Response
Arm A (n=10)
Arm B (n=36)
Arm C (n=34)
Arm D (n=17)
(the proportion of patients who
Complete/stringent CR
1 (10%)
1 (3%)
1 (3%)
crossed over and achieved complete response, partial response,
Very good PR
1 (10%)
4 (11%)
3 (9%)
and stable disease compared with
PR
3 (30%)
9 (25%)
18 (53%)
1 (6%)
pomalidomide-dexamethasone
Minimal response
2 (20%)
8 (22%)
5 (15%)
4 (23%)
alone) was 29 percent. The median
Stable disease
2 (20%)
7 (19%)
1 (3%)
8 (47%)
PFS from the start of Arm D was
4.4 months (95% CI 0.9-8) and,
Progressive disease
1 (10%)
5 (14%)
3 (9%)
4 (23%)
as of the data cutoff, all patients
Not evaluable
2 (6%)
3 (9%)
experienced disease progression.
IMWG = International Myeloma Working Group; CR = complete response; PR = partial response
To identify patients who would
respond better to the triplet regiTABLE 4. Patient Factors Associated with Treatment Response
men, Dr. Baz and researchers also
ORR
PFS
OS
conducted a multivariable analysis
Unadjusted OR
Adjusted OR
Unadjusted HR
Adjusted HR
Unadjusted HR
Adjusted HR
of patient factors associated with
(95% CI)
(95% CI)
(95% CI)
(95% CI)
(95% CI)
(95% CI)
better treatment response (TABLE
4), including the presence of highAge
1.16
1.22
0.80
0.72
0.83
0.88
(in 10 year
(0.64-2.11)
(0.62-2.40)
(0.59-1.10)
(0.50-1.04)
(0.56-1.24)
(0.51-1.49)
risk cytogenetics and a higher
increments)
number of prior therapies.
Number of prior
1.23
1.77
0.79
0.54
0.94
0.66
Adverse events (AEs) were pretherapies
(0.47-3.21)
(0.56-5.60)
(0.47-1.33)
(0.29-0.99)
(0.48-1.85)
(0.32-1.38)
dominantly hematologic in nature,
(≥5 vs. <5)
the authors noted, with a higher
B2-microglobuin
1.03
0.99
1.09
1.15
1.30
1.38
rate of grade ≥3 AEs reported in
(mg/L)
(0.84-1.25)
(0.80-1.23)
(0.99-1.20)
(1.03-1.28)
(1.15-1.47)
(1.21-1.58)
Arm C than Arm B. Grade ≥3 AEs
included anemia (11% in Arm B
High-risk
0.36
0.33
1.73
1.77
2.12
2.21
cytogenetics
(0.11-1.22)
(0.09-1.22)
(0.92-3.27)
(0.88-3.55)
(1.00-4.48)
(0.98-4.98)
vs. 24% in Arm C; p=0.21), neutropenia (31% vs. 52%; p=0.14), and
Study arm
2.88
2.98
0.66
0.54
0.63
0.54
(Arm C vs. Arm B)
(1.09-7.61)
(0.99-8.99)
(0.40-1.10)
(0.29-1.00)
(0.32-1.22)
(0.25-1.17)
thrombocytopenia (6% vs. 15%;
p=0.25). “Differences in the rates of
ORR = overall response rate; PFS = progression-free survival; OS = overall survival; OR = odds ratio; HR = hazard ratio
32
ASH Clinical News
April 2016