A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma

Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 08/2012; 27(1). DOI: 10.1038/leu.2012.236
Source: PubMed
ABSTRACT
Patients with asymptomatic (smoldering) multiple myeloma (AMM) have a high risk of transformation to active multiple myeloma (MM). Bisphosphonates such as zoledronic acid (ZLD) reduce skeletal events in MM and the immunomodulatory agent thalidomide (Thal) has proven effectiveness in active MM. We hypothesized that treatment with Thal and ZLD would prolong the time to progression (TTP) to MM over ZLD alone. Eligible patients had asymptomatic MM and all patients received ZLD 4 mg intravenous monthly; the treatment arm also received Thal 200 mg per day. The TTP was superior for Thal/ZLD (n=35) patients compared with ZLD alone (n=33); median TTP of 2.4 years (95% confidence interval (CI): 1.4-3.6) versus 1.2 years (95% CI: 0.7-2.5) (hazard ratio (HR), 2.05; 95% CI: 1.1-3.8; P-value: 0.02). At 1 year, 86% of Thal/ZLD patients were progression free compared with 55% on ZLD alone (P=0.0048). The overall response rate after year 1 was 37% for Thal/ZLD with a median duration of response of 3.3 years (95% CI: 1.1-NA); there were no confirmed responses to ZLD alone (P=0.0004). The addition of Thal to standard ZLD produces anti-tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for further studies in patients with AMM to delay chemotherapy.Leukemia advance online publication, 2 October 2012; doi:10.1038/leu.2012.236.

Full-text

Available from: Shaji K Kumar, Jul 07, 2014
ORIGINAL ARTICLE
A phase III randomized trial of thalidomide plus zoledronic
acid versus zoledronic acid alone in patients with asymptomatic
multiple myeloma
TE Witzig
1
, KM Laumann
2
, MQ Lacy
1
, SR Hayman
1
, A Dispenzieri
1
, S Kumar
1
, CB Reeder
3
, V Roy
4
,JALust
1
, MA Ger tz
1
, PR Greipp
1
,
H Hassoun
5
, SJ Mandrekar
2
and SV Rajkumar
1
Patients with asymptomatic (smoldering) multiple myeloma (AMM) have a high risk of transformation to active multiple myeloma
(MM). Bisphosphonates such as zoledronic acid (ZLD) reduce skeletal events in MM and the immunomodulatory agent thalidomide
(Thal) has proven effectiveness in active MM. We hypothesized that treatment with Thal and ZLD would prolong the time to
progression (TTP) to MM over ZLD alone. Eligible patients had asymptomatic MM and all patients received ZLD 4 mg intravenous
monthly; the treatment arm also received Thal 200 mg per day. The TTP was superior for Thal/ZLD (n ¼ 35) patients compared with
ZLD alone (n ¼ 33); median TTP of 2.4 years (95% confidence interval (CI): 1.4–3.6) versus 1.2 years (95% CI: 0.7–2.5) (hazard ratio
(HR), 2.05; 95% CI: 1.1–3.8; P-value: 0.02). At 1 year, 86% of Thal/ZLD patients were progression free compared with 55% on ZLD
alone (P ¼ 0.0048). The overall response rate after year 1 was 37% for Thal/ZLD with a median duration of response of 3.3 years
(95% CI: 1.1-NA); there were no confirmed responses to ZLD alone (P ¼ 0.0004). The addition of Thal to standard ZLD produces anti-
tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for
further studies in patients with AMM to delay chemotherapy.
Leukemia (2013) 27, 220–225; doi:10.1038/leu.2012.236
Keywords: smoldering multiple myeloma; thalidomide; zoledronic acid
INTRODUCTION
Patients with active multiple myeloma (MM) typically have a
preceding phase of disease characterized by a detectable
monoclonal protein (M-protein) and clonal plasma cells in the
marrow, but no symptoms or organ damage.
1
This is referred to as
either monoclonal gammopathy of undetermined significance
(MGUS) or asymptomatic (smoldering) MM (AMM) depending on
laboratory features. MGUS patients have a detectable serum
M-protein (usually o3 g/dl), o10% monoclonal marrow plasma
cells, normal hemoglobin, and no lytic bone lesions. MGUS is
common with an incidence of 3% in patients over the age of 50
years.
2
MGUS rarely resolves spontaneously and there is a risk of
progression from MGUS to MM or another B-cell malignancy of
approximately 1% per year.
3
These patients also have an increased
risk of skeletal fractures compared with the normal population.
4
Patients with AMM are distinguished from those with MGUS in
that they have higher amounts of M-protein and/or X10%
marrow plasma cells. These latter features translate into a 10% risk
per year of transformation to active MM.
5
In both MGUS and AMM,
patients do not have hypercalcemia, renal dysfunction due to the
M-protein, or symptomatic lytic bone lesions (calcium, renal,
anemia, bone (CRAB) criteria) and the marrow plasma cells are
usually in a low proliferative state.
6,7
A recent consensus
conference created guidelines for the management of these
patients.
8
The treatment of active MM has improved with the develop-
ment of bortezomib and the immunomodulatory agents thalido-
mide (Thal) and lenalidomide. Bisphosphonates can prevent the
bone complications and now have an important role in MM
therapy.
9–11
However, the disease remains incurable for most
patients. The presence of an easily identifiable precursor state
such as MGUS or AMM offers an opportunity to intervene with the
goal of preventing the transformation to active MM. In the past,
the chemotherapy agents used to treat MM were more toxic and
not suited for early intervention because of the risk
of myelodysplasia, marrow failure and acute leukemia. The
development of new agents and a better understanding of
the biology of the disease offer new opportunities to intervene at
the pre-active myeloma state.
We hypothesized that treatment with the immunomodulatory
Thal and a bisphosphonate would prolong the time to progression
(TTP) over a control arm of zoledronic acid (ZLD) alone. This is the
first report of this phase III trial of Thal/ZLD versus ZLD for patients
with untreated AMM.
PATIENTS AND METHODS
This was a randomized phase III trial conducted at the Mayo Clinic and
Memorial Sloan Kettering for patients with new, untreated AMM (http://
ClinicalTrials.gov as NCT00432458). All patients signed informed consent
1
Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN, USA;
2
Division of Biomedical Statistics and Informatics,
Department of Health Sciences Research, Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN, USA;
3
Division of Hematology Oncology, Department of
Medicine, Mayo Clinic, Scottsdale, AZ, USA;
4
Division of Hematology Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA and
5
Hematology/Oncology, Memorial
Sloan Kettering Cancer Center, New York, NY, USA. Correspondence: Dr TE Witzig, Hematology/Stabile 628, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
E-mail: witzig@mayo.edu
Received 3 July 2012; accepted 31 July 2012; accepted article preview online 20 August 2012; advance online publication, 2 October 2012
Leukemia (2013) 27, 220225
&
2013 Macmillan Publishers Limited All rights reserved 0887-6924/13
www.nature.com/leu
Page 1
approved by the site’s Institutional Review Boards. The study was
conducted in accordance with the Declaration of Helsinki and was
monitored by an independent data monitoring committee, which met
every 6 months to review safety data, monitor protocol progress and
review the planned interim analysis.
Patient selection
Eligible patients were X18 years of age and had AMM with measureable
disease as defined by a serum M-protein X1 g/dl by protein electrophor-
esis or 4200 mg of M-protein in the urine over 24 h. The on-study bone
marrow was required to contain X10% plasma cells. Other requirements
were: absolute neutrophil count X1500/ml, platelets X100 000/ml,
creatinine p2 mg/dl, and Eastern Cooperative Oncology Group (ECOG)
performance status of 0,1 or 2. Patients could not be taking any other
bisphosphonates, have Xgrade 2 neuropathy, symptomatic bone lesions
from myeloma, amyloidosis or another active malignancy. Patients with
small lytic lesions on plain skeletal survey radiographs that were suspicious
for myeloma but completely asymptomatic were eligible.
Therapy
We used a dynamic allocation procedure to balance the marginal
distributions of the stratification factors—presence of lytic bone lesions
on skeletal survey, high versus normal b2 microglobulin (4uln versus
puln), and high versus low bone marrow labeling index (41% versus
o1%). All patients were administered intravenous ZLD 4 mg (flat dose) in
100 ml normal saline over 15 min every 28 days. Patients randomized to
Thal/ZLD also received Thal 200 mg/day; there was no placebo. Patients
who progressed on ZLD alone went off study without crossover. A cycle
was 28 days. Thal was supplied by Celgene Pharmaceuticals (Summitt, NJ,
USA) and ZLD by Novartis (East Hanover, NJ, USA). The protocol was later
amended to change the ZLD dosing to every 3 months for year 1 and
yearly thereafter due to data from other studies regarding osteonecrosis of
the jaw and one case in our study. There were no corticosteroids allowed
in either arm. The patients were seen monthly and tested with a complete
blood count, serum creatinine. Serum (and urine where indicated)
M-proteins were assessed every three months and marrow exam and
skeletal survey were evaluated every 6 months. Adverse events (AEs) were
graded per NCI CTC v2.0 (National Cancer Institute Common Toxicity
Criteria version 2.0), with dose modifications based on AEs.
Study design
The primary goal of the study was the comparison of the TTP distributions
between the two treatment regimens using an intention-to-treat principle.
Secondary goals were to compare the confirmed overall response rate
assessed within the first 12 months of treatment, progression-free survival
(PFS) at 1 year, duration of response between the 2 groups, and the AE
profile of the two regimens. Standard myeloma response criteria were
used.
12
Responses were categorized as complete response, partial
response or very good partial response. A confirmed response is defined
to be a complete response, partial response or very good partial response
on two consecutive evaluations X2 weeks apart; confirmed response was
evaluated using the first 12 months of treatment. Duration of response was
the time from documentation of a response to disease progression.
Progression was defined as an increase in the serum or urine M-protein to
425% above the lowest response level, which must also be an absolute
increase of at least 0.5 g/dl for serum and 200 mg per 24 h for urine. The
appearance of new lytic bone lesions or plasmacytomas were also to be
considered progression. Time to progression was defined as time from
randomization to documentation of progression. Patients who died
without progression were censored at the time of death. Progression-
free survival was the time from randomization to the earlier of progression
or death from any cause, whichever happened first. Overall survival was
defined as time from randomization to death from any cause. Time to
treatment failure was defined as the time from the date of randomization
to the date at which the patient is removed from treatment due to
progression, unacceptable toxicity, refusal or death. The TTP and PFS were
also evaluated defining progressive disease as the development of CRAB
criteria as recommended by recent consensus panels.
13,14
The statistical design aimed to enroll 120 eligible patients (60 per arm)
over 4 years, with a minimum follow-up of 12 months, to have at least 90%
power at a two-sided type I error rate of 0.05 to detect an increase in the
median TTP from 12 months to 24 months (corresponding to a hazard ratio
(HR) of 2.0 comparing ZLD with Thal/ZLD), and 80% power to detect an
increase in median TTP from 12 to 21 months (corresponding to a HR of
1.81 comparing ZLD with Thal/ZLD). The final analysis would take place
after a total of 90 progressions or 50 progressions in the control arm (ZLD)
had been observed. A single interim analysis was planned to occur after
one-half of the required number of events for the primary analysis has
occurred (that is, after 45 total progressions or 25 progressions in the ZLD
arm was observed). The Lan–DeMets method
15
for computing discrete
sequential boundaries with an alpha spending function corresponding to
the O’Brien-Fleming stopping boundaries was used to account for
sequential testing and to maintain the overall preset type I error rate.
Fisher’s exact tests and Wilcoxon rank-sum tests were used to compare
the baseline characteristics and adverse event patterns (regardless of
relationship to study treatment) between the arms. w
2
tests were used to
compare the confirmed overall response rate and the PFS rate at 1 year
between the arms. The distribution of TTP, PFS, time to treatment failure
and overall survival were estimated using the Kaplan–Meier method, and
differences in treatment arms evaluated using the stratified log-rank test,
as well as a univariate Cox proportional hazards model adjusting for the
stratification factors. All randomized patients were included in the efficacy
analyses according to the intention-to-treat principle. P-values p0.05 were
considered statistically significant.
RESULTS
Patient characteristics
The study was activated July 2003 and accrued 68 patients; 35 to
Thal/ZLD and 33 to ZLD alone (Figure 1). The patients were, in
general, stage I myeloma with no lytic bone lesions, high B2M, low
plasma cell proliferative rate, and good performance status
(Table 1). All patients received study treatment.
Safety
All patients were evaluable for AEs, regardless of attribution
(Table 2). The rate of grade 1–2 neuropathy as expected was
significantly higher with Thal/ZLD compared with ZLD alone, 80
versus 18%, Po0.001; the grade 2 neuropathy rate was 34%. Thirty
patients have reported grade 3 þ AEs (17 Thal/ZLD; 13 ZLD,
Fisher’s exact P ¼ 0.47). There was one case of grade 3
osteonecrosis of the jaw on the ZLD-alone arm. Eight patients
have reported grade 4 adverse events (five Thal/ZLD; three ZLD,
Fisher’s exact P ¼ 0.71). Overall, only one grade 4 event was felt to
be at least possibly related to study treatment—grade 4
Figure 1. CONSORT (consolidated standards of reporting trials)
diagram of patient accrual and randomization for this trial.
Thalidomide and zoledronic acid for asymptomatic myeloma
TE Witzig et al
221
& 2013 Macmillan Publishers Limited Leukemia (2013) 220 225
Page 2
neutropenia in Thal/ZLD. The other grade 4 AEs on Thal/ZLD are as
follows: one infection without neutropenia, one ischemia/infarc-
tion, one thrombosis, and one headache. All grade 4 events on
ZLD were deemed unlikely or not related to study treatment—one
pulmonary event in cycles 8 and 13, one ischemia—cerebral and
one fatigue. There were no grade 5 AEs.
Although AEs were manageable, 18% (11/68) of patients dis-
continued therapy due to AEs (Table 3). Of these 11 patients, 10
were on Thal/ZLD. An additional 17 (27%) refused further therapy
for various reasons including simple refusal, insurance issues and
re-location.
Response and outcome assessment
The overall response rate was 37% (13/35) with Thal/ZLD and 0%
(0/33) with ZLD alone (Po0.001). Within the 13 responders, there
were 12 partial response and 1 very good partial response. The
median duration of response for the 13 responders was 3.3 years
(95% confidence interval (CI): 1.1-NR). Thal/ZLD was also superior
to ZLD alone in preventing progression within 12 months of study
entry. Eighty-six percent (30/35) of patients on Thal/ZLD remained
progression-free and alive at 1 year compared with 55% (18/33)
on ZLD alone (P ¼ 0.0048). The patients treated with Thal/ZLD also
had a significantly longer TTP than those on ZLD alone (Figure 2a).
The median TTP was 2.4 years (95% CI: 1.4–3.6) for Thal/ZLD
compared with 1.2 years (95% CI: 0.7–2.5) for ZLD alone (HR
2.05;95% CI: 1.1–3.8, P ¼ 0.02). The median PFS for Thal/ZLD was
also 2.4 years (95% CI: 1.4–3.5) compared with 1.2 years (95% CI:
0.7–2.5) for ZLD alone (HR 1.98; 95% CI: 1.1–3.6, P ¼ 0.03). The
Kaplan–Meier estimate for the median time to treatment failure in
Thal/ZLD is 16.5 months (95% CI: 9.5–27.6) and in ZLD alone is 11.1
months (95% CI: 8.4–16.7; P ¼ 0.03). There was no difference in
overall survival (Figure 2b) between the arms.
We also evaluated TTP defining progressive disease as the
development of CRAB criteria. Patients receiving Thal/ZLD had a
median time to fulfillment of CRAB criteria of 4.3 years compared
with 3.3 years for the ZLD group (P ¼ 0.24). When PFS was
evaluated with regard to CRAB criteria (Table 4; Figure 3), Thal/ZLD
again had a longer median PFS of 4.1 years compared with 3.3
years for ZLD alone (P ¼ 0.18).
The median follow-up of the study patients is 5.9 years (range,
1.5–8.0) and six patients still receiving treatment—five on Thal/
ZLD and one on ZLD alone (Table 3). Eighteen (27%) patients have
Table 1. Baseline characteristics (by arm)
Thal/ZLD
(N ¼ 35)
ZLD
(N ¼ 33)
Total
(N ¼ 68)
P-value
a
Age 0.61
b
Median 63.0 63.0 63.0
Range (47.0–
84.0)
(47.0–
80.0)
(47.0–
84.0)
Gender 0.80
c
Female 13 (37%) 14 (42%) 27 (40%)
Male 22 (63%) 19 (58%) 41 (60%)
Durie–Salmon
stage at initial
diagnosis
0.68
c
Ia 26 (81%) 23 (82%) 49 (82%)
IIa 5 (16%) 3 (11%) 8 (13%)
IIIa 1 (3%) 2 (77%) 3 (5%)
ECOG
performance
score
1.00
c
0 33 (94%) 32 (97%) 65 (96%)
1 2 (6%) 1 (3%) 3 (4%)
Mayo AMM risk
classification
d
0.92
c
0 Factors 1 (3%) 2 (6%) 3 (4%)
1 Factors 12 (34%) 10 (20%) 22 (32%)
2 Factors 22 (63%) 21 (64%) 43 (63%)
Stratification
factors: beta 2
microglobulin
0.76
c
High (XULN) 29 (83%) 26 (79%) 55 (81%)
Lytic bone lesions 1.00
c
Yes 2 (6%) 2 (6%) 4 (6%)
Bone marrow
labeling index
1.00
c
High (4 1.0) 3 (8%) 3 (9%) 6 (9%)
Low (p 1.0) 31 (89%) 30 (91%) 61 (90%)
Not available 1 (3%) 0 (0%) 1 (1%)
Descriptive
factors: anemia
0.33
c
Yes (o lower
normal limit)
14 (40%) 18 (54.5%) 32 (47%)
Peripheral blood
circulating
plasma cells
0.90
c
Yes 13 (38%) 14 (44%) 27 (41%)
No 20 (59%) 18 (56%) 38 (58%)
Not applicable 1 (3%) 0 (0%) 1 (1%)
Missing 1 1 2
Abbreviations: AMM, Asymptomatic multiple myeloma; Thal, thalidomide;
ULN, upper limit of normal; ZLD, zoledronic acid.
a
P-values are calculated
excluding the missing observations.
b
Wilcoxon rank-sum test.
c
Fisher’s
exact test.
d
Risk fac tors were % marrow plasma cells 410%, abnormal FLC
ratio o0.125 or 48; or serum M protein size, more than 30 g/l.
26
Table 2. Major adverse events regardless of attribution in 68 patients
with AMM
Adverse Event Thal/ZLD ZLD P value
a
Neuropathy
Grade 1–2 28 (80%) 6 (18%) o0.001
Grade 3–4 0 (0%) 0 (0%) Not
applicable
Fatigue
Grade 1–2 26 (74%) 17 (52%)
Grade 3–4 1 (3%) 3 (9%)
Constipation
Grade 1–2 22 (63%) 6 (18%)
Grade 3–4 0 (0%) 0 (0%)
Thromboembolism (grade 3–4)
Grade 3 0 (0%) 1 (3%)
Grade 4 1 (3%) 0 (0%)
Any grade 2 þ 32 (91%) 16 (48%) 0.0001
Any grade 3 þ 17 (49%) 13 (39%) 0.47
Any grade 4 þ 5 (14%) 3 (9%) 0.71
Any hematologic grade 3 þ 6 (17%) 2 (6%) 0.26
Any hematologic grade 4 þ 1 (3%) 0 1.0
Any non-hematologic
grade 3 þ
15 (43%) 12 (36%) 0.63
Any non-hematologic
grade 4 þ
4 (11%) 3 (9%) 1.0
Abbreviations: AMM, asymptomatic multiple myeloma; Thal, thalidomide;
ZLD, zoledronic acid.
a
Fisher’s exact test.
Thalidomide and zoledronic acid for asymptomatic myeloma
TE Witzig et al
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Page 3
died—nine in each arm and three of these deaths were due to
other causes and without progression to MM. Seventeen (25%)
patients remain asymptomatic and without need for myeloma
therapy.
Based on the study design, a single interim analysis (IA) was to
be performed when 45 total progressions were observed.
However, due to slow accrual, the independent data monitoring
committee requested an IA in July 2008, after only 41 total
progressions were observed. The observed P-value for TTP
comparison was 0.06. On the basis of a conditional power
analysis, the likelihood of stopping the trial early for superiority in
favor of arm Thal/ZLD was less than 2% if the IA were to happen
after 45 progressions. Moreover the observed hazard rate did not
exceed the futility boundary. Thus, there was not enough
evidence to terminate accrual to the study based on the interim
efficacy or futility analyses. Rather, the study was closed at the
recommendation of the independent data monitoring committee
prior to reaching the targeted accrual of 120 patients because of
slow accrual.
DISCUSSION
Patients with AMM have a substantial risk of progression to active
MM. As opposed to patients with MGUS, this group of patients has
a high enough risk of transformation to warrant clinical trials that
aim to prevent or delay the need for chemotherapy and
transplant. This randomized phase III trial demonstrates that
patients who received Thal with ZLD had a higher overall response
rate, a longer TTP, and were more likely to be progression free at
one year than patients receiving ZLD alone. This trial was designed
and initiated before the availability of lenalidomide and is
important because it provides proof of concept that patients at
high-risk for transformation to MM can respond to non-cytotoxic,
non-steroidal agents and delay the time to requiring treatment for
active MM. It also confirms that the bisphosphonate ZLD alone is
unable to produce a measureable tumor response in these
patients. As this trial did not have a placebo arm, it remains
possible that ZLD alone, despite not producing tumor responses,
was able to delay the time to CRAB criteria or chemotherapy
compared with patients not receiving bisphosphonates.
Although this is the first trial of an immunomodulatory with a
potent bisphosphonate in AMM to show myeloma benefit, there
have been other trials in this patient population comparing single-
agent bisphosphonate with observation. Martin et al.
16
performed
a single arm study in 12 patients with AMM providing 12 courses
of intravenous pamidronate. One patient achieved a minor
response but there were no other responses. In a phase III trial,
Musto et al.,
17
randomized 163 patients with asymptomatic MM to
receive monthly ZLD for one year or observation. Bone events
were less likely in the ZLD group (55% versus 78%, P ¼ 0.04) but
there was no difference in risk of transformation to active MM.
More recently, D’Arena et al.
18
randomized 177 patients with
AMM to monthly pamidronate for one year or observation. There
was no difference in the TTP between the two arms (46 and 48
months, respectively). Similar to the trial of Musto et al.
17
with ZLD,
pamidronate did reduce the risk of skeletal events—73% (40/55)
of patients in the control group developed a bone event
compared with only 39% (22/56) in the pamidronate treated
group.
In our study, we used a more potent bisphosphonate, ZLD, and
continued dosing beyond one year; however, we also did not see
any actual antitumor responses with ZLD alone. We did observe
MM treatment responses with the combination of Thal/ZLD and
this also translated to a longer time to development of CRAB
criteria in the treatment arm than ZLD alone. As we tested the
combination of Thal/ZLD, we are unable to determine the specific
benefit provided by ZLD over what could have been achieved
with Thal alone. However, there is some evidence that
Table 3. Current status of patients
Thal/ZLD
(N ¼ 35)
ZLD
(N ¼ 33)
Total
(N ¼ 68)
Follow-up (years)
Median 5.5 6.0 5.9
Range (3.1–8.0) (1.5–7.9) (1.5–8.0)
Survival status
Alive 26 (74.3%) 24 (72.7%) 50 (73.5%)
Dead 9 (25.7%) 9 (27.3%) 18 (26.5%)
Progression status
No progression 9 (25.7%) 8 (24.2%) 17 (25.0%)
Progression 26 (74.3%) 25 (75.8%) 51 (75.0%)
Ended treatment 30 (85.7%) 32 (97.0%) 62 (91.2%)
Reason ending treatment
Refused further
treatment
9 (30.0%) 8 (25.0%) 17 (27.4%)
Adverse event 10 (33.3%) 1 (3.1%) 11 (17.7%)
Disease progression 8 (26.7%) 23 (71.9%) 31 (50.0%)
Died on study 1 (3.3%) 0 (0.0%) 1 (1.6%)
Other 2 (6.6%) 0 (0.0%) 2 (3.2%)
Last cycle
Median 17.0 12.0 14.0
Range (1.0–102.0) (1.0–55.0) (1.0–102.0)
Abbreviations: Thal, thalidomide; ZLD, zoledronic acid.
0
20
40
60
80
100
a
b
012345
6
%Progression Free
Time (years)
Thal/ZLD; N=35; median 2.4 years
ZLD; N=33; median 1.2 years
Stratified log-rank p-value 0.02
0
20
40
60
80
100
0
123456
% Alive
Time (years)
Thal/ZLD; N=35; median NA
ZLD; N=33; median NA
Stratified log-rank p-value 0.97
Figure 2. Kaplan–Meier TTP (a) and overall survival (b) by arm.
Thalidomide and zoledronic acid for asymptomatic myeloma
TE Witzig et al
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bisphosphonates can also impact treatment of MM when
combined with chemotherapy for active MM, even in patients
without bone disease. Morgan et al.
11,19
evaluated ZLD and
clodronic acid along with chemotherapy for patients with active,
new untreated MM. In that study, patients in the ZLD group had a
lower incidence of skeletal events compared with those patients
treated with clodronic acid (27% versus 35%, respectively; HR of
0.74). Even more importantly, patients receiving ZLD with
chemotherapy had superior disease free survival (HR of 0.88)
and a reduced risk of death (0.84) compared with the clodronic
acid/chemotherapy group. Studies in other cancers such as breast
cancer have also shown that ZLD can reduce the risk of relapse.
20
The study drugs used in this trial were well tolerated.
Osteonecrosis of the jaw is a known complication of bispho-
sphonates.
21
When we became aware of this potential
complication from others and the one case in our study, we
reduced the frequency of ZLD. Osteonecrosis of the jaw is an
infrequent complication when used in current schedules and with
preventive dentistry.
11
The Thal arm was less well tolerated and
one-third of the patients ended treatment early due to AEs; an
additional 30% refused further treatment. Although 80%, of
patients in the Thal arm developed neuropathy, most were grade 1,
and there were no grade 3–4 neuropathies. We did allow dose
reductions to improve tolerability and the four patients currently
on trial are receiving Thal 100 mg per day (n ¼ 3) and one on
50 mg every other day. This rather high dropout rate on the Thal/
ZLD arm despite dosing flexibility points out an important issue
for future trials in AMM. When patients are asymptomatic, they
cannot feel better on treatment. Asymptomatic patients are
obviously more aware of treatment side effects and less tolerant
of them when the alternative is observation alone. In future,
studies for asymptomatic MM the regimens chosen must be very
well-tolerated or if they have some toxicity should be delivered
over a shorter period of time.
The risk of progression of AMM to active MM has been
described and can be readily identified based on the percentage
of marrow plasma cells, the level of serum M-protein, the
proliferative rate of the myeloma cells, the serum immunoglobulin
free light chain, and the number of circulating tumor cells.
22–26
Preventive strategies are most needed for patients at the highest
risk of progression. This study demonstrates that the risk of
progression to active MM can be significantly reduced with a
combination of Thal and ZLD. However, the sample size was too
small to demonstrate overall survival differences. Therefore, while
our trial provides compelling rationale for preventive trials in
AMM, we acknowledge that it does not at this time necessarily
change clinical practice. Moreover, this trial was designed prior to
the availability of lenalidomide, which is a more attractive agent
than Thal for preventive trials given its more favorable non-
hematologic safety profile. There are preliminary data that
lenalidomide plus dexamethasone can delay progression and
improve survival in AMM.
27
An ongoing randomized trial by the
ECOG is also testing the role of lenalidomide as preventive therapy
in this setting.
CONFLICT OF INTEREST
The study drugs thalidomide and Zometa (zoledronic acid) were provided by
Celgene Pharmaceuticals and Novartis Oncology, respectively. Dr Witzig, Rajkumar,
Lacy, Dispenzieri, Hassoun all have received research funding from Celgene for
clinical trials. Dr Witzig has received research funding from Novartis for other clinical
trials. Dr Gertz has received honoraria for lectures from Celgene. The remaining
authors declare no conflicts of interest.
ACKNOWLEDGEMENTS
This study was supported by R01CA100080 from the National Cancer Institute; the
Predolin Foundation; registered at http://ClinicalTrials.gov as NCT00432458.
Table 4. Protocol versus CRAB progression criteria for TTP and PFS
Thal/ZLD (N ¼ 35) ZLD (N ¼ 33) Stratified log-rank P-value
TTP protocol criteria 2.4 years (95% CI: 1.4–3.6) 1.2 years (95% CI: 0.7–2.5) 0.02
Number of events 26 25
Hazard ratio (ZLD versus Thal/ZLD) 2.05 (95% CI: 1.1–4.3) 0.02
TTP CRAB criteria 4.3 years (95% CI: 2.4–NA) 3.31 years (95% CI: 1.4–5.1) 0.24
Number of events 19 22
Hazard ratio (ZLD versus Thal/ZLD) 1.47 (95% CI: 0.7–2.8) 0.25
PFS protocol criteria 2.4 years (95% CI: 1.4–3.5) 1.2 years (95% CI: 0.7–2.5) 0.02
Number of events 28 26
Hazard ratio (ZLD versus Thal/ZLD) 2.3 (95% CI: 1.2–4.5) 0.03
PFS CRAB criteria 4.1 years (95% CI: 2.1–5.9) 3.3 years (95% CI: 1.4–4.9) 0.18
Number of events 18 22
Hazard ratio (ZLD versus Thal/ZLD) 1.5 (95% CI: 0.8–2.7) 0.19
Abbreviations: CI, confidence interval; CRAB, calcium, renal, anemia, and bone events; NA, not applicable; PFS, progression free survival; Thal/ZLD, thalidomide,
zoledronic ac id; TTP, time to progression; ZLD, zoledronic acid.
0
20
40
60
80
100
0
12345
6
% Progression Free
Time (years)
Thal/ZLD Protocol Criteria
ZLD Protocol Criteria
Thal/ZLD CRAB Criteria
ZLD CRAB Criteria
Figure 3. Kaplan–Meier TTP curves with disease progression defined
using standard International Myeloma Working Group (Protocol)
Criteria and development of CRAB.
Thalidomide and zoledronic acid for asymptomatic myeloma
TE Witzig et al
224
Leukemia (2013) 220 225 & 2013 Macmillan Publishers Limited
Page 5
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  • Source
    • "ZA has recently been tested as an additive therapeutic for earlystage breast cancer [13]. ZA also benefited patients with newly diagnosed multiple myeloma [14]. These findings clearly demonstrate the beneficial therapeutic effects of ZA on cancer patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment.To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR.In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth.Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.
    Full-text · Article · Aug 2015 · Oncotarget
  • Source
    • "Investigators have since begun to carry out clinical trials to evaluate novel drugs and new combinations of existing treatments in SMM. From the year 2003 onwards, two phase randomized, controlled trials (RCTs) have been completed [19], [20] and one phase III RCT with 370 SMM patients is ongoing. Immuno-modulatory agents (IMiDs) were used in each of these three more recent RCTs. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose Whether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM. Methods MEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events. Results Overall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59). Conclusions Early treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn’t significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence.
    Full-text · Article · Oct 2014 · PLoS ONE
  • Source
    • "Nitrogen-containing bisphosphonates, such as zoledronic acid, have a predominant role in the supportive therapy of MM patients [110] with benefit in survival [111–113]. Nitrogen-containing bisphosphonates inhibit bone resorbing osteoclasts, delay tumor growth rate as a consequence of MDSC depletion, and increased recruitment of T cells in murine models of solid tumors [99, 114]. However, no data are currently available about MDSC amount in MM patients treated with bisphosphonates. "
    [Show abstract] [Hide abstract] ABSTRACT: Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.
    Full-text · Article · Jun 2014 · BioMed Research International
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