Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma.
ABSTRACT The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.
- SourceAvailable from: James Richard Berenson
Article: Carfilzomib in multiple myeloma.[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Advances in drug therapy for multiple myeloma (MM) during the previous decade have improved survival outcomes; however, the disease remains incurable as patients eventually relapse or become refractory to all available therapies. Therefore, there is a clear need for more effective and well-tolerated treatments. Areas covered: We review preclinical and clinical data regarding the use of carfilzomib , a proteasome inhibitor that is structurally and mechanistically distinct from bortezomib, for the treatment of MM patients. Carfilzomib pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are summarized, based on Phase I/II trial data. Expert opinion: Carfilzomib represents a significant advance in the management of relapsed and/or refractory MM patients, including those intolerant or resistant to bortezomib. High response rates have been demonstrated with carfilzomib as a single agent or in combination with alkylating agents, immunomodulators and corticosteroids, even among patients who have failed multiple prior therapies. Carfilzomib also has significant potential in the frontline setting, with encouraging response and survival rates observed for combination regimens. Further evaluation of carfilzomib-containing regimens is ongoing in Phase III trials and investigator-sponsored studies, which include combinations with novel investigational agents. These findings will shape the future role of carfilzomib for MM patients across multiple settings.Expert Opinion on Biological Therapy 08/2014; · 3.65 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways.BioMed Research International 01/2014; 2014:456037. · 2.71 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Glucocorticoids (GCs) selectively trigger cell death in the multiple myeloma cell line MM1S which express NR3C1/Glucocorticoid Receptor (GR) protein, but fail to kill MM1R cells which lack GR protein. Given recent demonstrations of altered microRNA profiles in a diverse range of haematological malignancies and drug resistance, we characterized GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate expression of multiple genes involved in cell cycle control, cell organization, cell death and immunological disease in MM1S cells, which remain unaffected in MM1R cells. With respect to microRNAs, mir-150-5p was identified as the most time persistent GC regulated microRNA, out of 5 QPCR validated microRNAs (mir-26b, mir-125a-5p, mir-146-5p, mir-150-5p, and mir-184), which are GC inducible in MM1S but not in MM1R cells. Functional studies further revealed that ectopic transfection of a synthetic mir-150-5p mimics GR dependent gene expression changes involved in cell death and cell proliferation pathways. Remarkably, despite the gene expression changes observed, overexpression of mir-150-5p in absence of GCs did not trigger significant cytotoxicity in MM1S or MM1R cells. This suggests the requirement of additional steps in GC induced cell death, which can not be mimicked by mir-150-5p overexpression alone. Interestingly, a combination of mir-150-5p transfection with low doses GC in MM1S cells was found to sensitize therapy response, whereas opposite effects could be observed with a mir-150-5p specific antagomir. Although mir-150-5p overexpression did not substantially change GR expression levels, it was found that mir-150-5p evokes GR specific effects through indirect mRNA regulation of GR interacting transcription factors and hormone receptors, GR chaperones, as well as various effectors of unfolded protein stress and chemokine signalling. Altogether GC-inducible mir-150-5p adds another level of regulation to GC specific therapeutic responses in multiple myeloma.PLoS ONE 12/2014; 9(12):e113842. · 3.53 Impact Factor
Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd)
versus lenalidomide-low-dose dexamethasone (Rd) for newly
Francesca Gay,1S. Vincent Rajkumar,1* Morton Coleman,2Shaji Kumar,1Tomer Mark,2
Angela Dispenzieri,1Roger Pearse,2Morie A. Gertz,1John Leonard,2Martha Q. Lacy,1
Selina Chen-Kiang,3Vivek Roy,4David S. Jayabalan,2John A. Lust,1Thomas E. Witzig,1
Rafael Fonseca,5Robert A. Kyle,1Philip R. Greipp,1A. Keith Stewart,5and Ruben Niesvizky2
The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clari-
thromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexametha-
sone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospi-
tal-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates
selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was per-
formed according to age, gender, and transplant status. On intention-to-treat analysis, complete response
(45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were
significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P 5 0.071), and
progression-free survival (median 48.3 vs. 27.5 months, P 5 0.044) were higher with BiRd. There was a
trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P 5 0.170). Main grade 3–4 toxicities of
BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P 5 0.012). Infections (16.7% vs.
9.7%, P 5 0.218) and dermatological toxicity (12.5% vs. 4.2%, P 5 0.129) were higher with Rd. Results of
this case-matched analysis suggest that there is significant additive value when clarithromycin is added to
Rd. Randomized phase III trials are needed to confirm these results. Am. J. Hematol. 85:664–669,
C 2010 Wiley-Liss, Inc.
Multiple myeloma (MM) accounts for over 11,000 deaths
each year in the United States [1,2]. For over 40 years, mel-
phalan and prednisone (MP) remained the standard of care
for elderly patients. For more than a decade vincristine, dox-
orubicin, dexamethasone (VAD) was used as pretransplant
induction therapy for patients eligible for stem cell transplan-
tation (SCT) [2–4]. Lenalidomide (CC-5013) is an oral
immunomodulatory structural derivative of thalidomide, that
is more potent in preclinical studies than the parent drug
[5,6]. It has a different toxicity profile, with fewer nonhema-
tologic side-effects compared with thalidomide and a more
predictable and manageable toxicity [7,8]. In newly diag-
nosed patients, the combination of lenalidomide plus high-
dose dexamethasone (RD) was compared with high-dose
dexamethasone in a double-blinded placebo-controlled trial
and was superior to high-dose dexamethasone in terms of
both response rates (complete response [CR] rate: 22.1%
vs. 3.8%) and 1-year progression-free survival (PFS) (77%
vs. 55%, P 5 0.002), but no differences in overall survival
(OS) were reported . Another recent phase III study com-
pared the combination of lenalidomide plus low-dose dexa-
methasone (Rd) with the RD regimen: 2-year OS (87% vs.
75%, P < 0.001) was significantly better with Rd and major
grade 3 or higher toxic-effects, including thrombosis (26%
vs. 12%) and infections (16% vs. 9%), were significantly
higher in the RD group. These differences were confirmed
in both younger and elderly patients .
Clarithromycin is an antibiotic that has shown efficacy in
association with steroids and both thalidomide  and
lenalidomide . It optimizes the pharmacologic effects of
glucocorticoids by increasing the area under the curve and
the maximum concentration levels of some steroids ; it
has an immunomodulatory effect  and may have direct
antineoplastic properties .
Based on initial report of moderate activity of thalidomide
in heavily pretreated MM, a combination of clarithromycin,
thalidomide and low-dose dexamethasone (BLT-D) was
studied. This early study yielded results considerably supe-
rior to those reported both for thalidomide alone and subse-
1Division of Hematology, Department of Internal Medicine, Mayo Clinic Col-
lege of Medicine, Rochester, Minnesota;2Division of Hematology and Medi-
cal Oncology, Department of Medicine, Center for Lymphoma and Myeloma,
Weill-Cornell Medical College, New York Presbyterian Hospital-Cornell Medi-
cal Center, New York, New York;
Medical College, New York Presbyterian Hospital-Cornell Medical Center,
New York, New York;
College of Medicine, Jacksonville, Florida;5Division of Hematology and On-
cology, Mayo Clinic College of Medicine, Scottsdale, Arizona
3Department of Pathology, Weill-Cornell
4Division of Hematology and Oncology, Mayo Clinic
Contract grant sponsor: National Cancer Institute, National Institutes of
Health, Bethesda, MD; Contract grant numbers: CA62242, CA107476;
Contract grant sponsor: Eastern Cooperative Oncology Group, Boston, MA.
Conflict of Interest: F.G. has received honoraria from Celgene. M.A.G has
received honoraria from Celgene, Millenium, Genzyme and Amgen. S.K.
has a consultant/advisory relationship and has received research support
from Celgene. M.Q.L., A.D., T.E.W, have received research funding/grants
from Celgene. T.M. has received research funding from Celgene and hono-
raria from Celgene and Millenium. J. L. consultancy for Celgene. R.F. con-
sultancy for Celgene, Medtronic, Genzyme, Amgen, Bristol-Myers Squibb,
Otsuka American Pharmaceutical. R.A.K. has received honoraria from Cel-
gene. P.R.G. has received honoraria from Celgene and Amgen. A.K.S. has
a consultant/advisory relationship with Celgene and Millenium and has
received research funding from Millenium. R.N. has received honoraria from
Celgene, Millenium and Onyx, has a consultant/advisory relation with Cel-
gene, Millenium and Onyx and has received research funding from Celgene.
The remaining authors declare no conflict of interest.
*Correspondence to: S. Vincent Rajkumar, Division of Hematology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905.
Received for publication 25 May 2010; Accepted 25 May 2010
Am. J. Hematol. 85:664–669, 2010.
Published online 4 June 2010 in Wiley Online Library (wileyonlinelibrary.
C 2010 Wiley-Liss, Inc.
American Journal of Hematology
quently for thalidomide and high-dose dexamethasone
(without clarithromycin). Among the novel aspects of the
BLT-D regimen were the use of weekly dexamethasone and
clarithromycin. The putative efficacy was buttressed by a
recent report where the same combination of drugs was
used: however the dexamethasone was used in high-dose.
Results were almost comparable with BLT-D .
Because of the putative superiority of lenalidomide over
thalidomide, the combination of clarithromycin (Biaxin), lena-
lidomide and low-dose dexamethasone (BiRd) has been
investigated in a phase II study, showing a partial response
(PR) rate of 90.3%, including 38.9% CR; 2-year event free
survival (EFS) was 97.2% months, and 2-year OS was
90.5%. Major toxic effects were thromboembolic events
(12.5%), corticosteroid related morbidity (in particular myop-
athy in 11.1% of patients) and cytopenia (neutropenia in
19.4% of patients and thrombocytopenia in 22.2% .
No comparative study of Rd vs BiRd has been reported
so far and none are ongoing or planned. The goal of this
retrospective cohort case-matched study was to compare
the efficacy and the toxicity of these two regimens as pri-
mary therapy for newly diagnosed MM patients.
Materials and Methods
Patients and criteria of matching.
diagnosed MM who were treated at the New York Presbyterian Hospi-
tal-Cornell Medical Center, from December 2004 to November 2006,
with BiRd, was analyzed. For comparison of their outcome, an equal
number of pair mates were selected among newly diagnosed patients
seen at the Mayo Clinic who received Rd, from March 2005 to Decem-
ber 2008. Data were obtained by review of medical records and exist-
ing database, after approval from the respective Institutional Review
Boards. Case matching was blinded and was performed with respect to
age (±5 years), sex, and transplant (SCT), (patients who received SCT
were matched with patients who received SCT; patients who did not
receive SCT were matched with patients who did not receive SCT).
Treatment regimen. Patients treated with BiRd were enrolled in a
phase II dose-escalating trial conducted at New York Presbyterian Hos-
pital-Cornell Medical Center: lenalidomide was given orally 25 mg/day
on days 3 to 21 of Cycle 1 and on days 1 to 21 of subsequent cycles;
dexamethasone was given orally 40 mg on days 1, 2, 3, 8, 15, and 22
during Cycle 1 and weekly on days 1, 8, 15, and 22 of each subsequent
cycle; clarithromycin was given orally at a dose of 500 mg twice daily,
beginning on day 2 of Cycle 1. Each cycle was repeated every 4 weeks.
Patients treated with Rd received lenalidomide at a dose of 25 mg/
day, days 1–21 plus low-dose dexamethasone at a dose of 40 mg
orally day 1, 8, 15, 22; each cycle was repeated every 4 weeks. Treat-
ment was continued until progression or relapse.
In both treatment groups patients were allowed to discontinue treat-
ment to pursue SCT, but treatment until progression, relapse or unac-
ceptable toxicity was permitted at the physician’s discretion.
A series of 72 patients with newly
In both treatment groups patients received antithrombotic prophylaxis
Assessment of efficacy and safety.
standard International Myeloma Working Group (IMWG) Uniform
Response Criteria . Briefly, a PR was defined as a 50% or higher
decrease in the serum monoclonal protein (M-protein) levels from base-
line and a greater than 90% reduction in 24-hr urine M-protein excre-
tion (or <200 mg/24 hr) (if M-protein was unmeasurable, a 50% or
higher decrease in the difference between involved and uninvolved free
light chain (FLC) or a 50% or higher reduction in bone marrow plasma
cells); for patients with soft tissue plasmacytomas, a 50% size reduc-
tion was required. A very good PR (VGPR) required a 90% or greater
reduction in serum M-protein and urinary M-protein less than 100 mg/
24 hr or M-protein detectable by immunofixation but not on electropho-
resis. A CR was defined as negative serum and urine immunofixation,
disappearance of any soft tissue plasmacytoma and less than 5%
plasma cells on bone marrow examination. Disease that did not satisfy
the criteria for PR, VGPR, CR or progressive disease (PD) was classi-
fied as stable disease (SD). Disease progression required any of the
following: 25% or greater increase in serum M-protein (absolute ?0.5
g/dL) or urine M-protein (absolute ?200 mg/dL) or, in case of unmea-
surable M-protein, in the difference between involved and uninvolved
FLC (absolute >10 mg/dL) or 25% increase in bone marrow plasma
cell percentage; development of new bone lesions, plasmacytomas; or
disease-related hypercalcemia. All responses needed to be confirmed
at least in two consecutive assessments. Time to progression (TTP)
was calculated from start of therapy until progression, relapse or last
known remission (death for causes other than progression were cen-
sored); PFS was calculated from start of therapy until the date of pro-
gression, relapse, death from any cause, or known remission; time to
next treatment (TTNT) was calculated from the start of therapy until the
date the patient received a new alternative treatment; OS was calcu-
lated from start of therapy until the date of death or the date the patient
was last known to be alive. All adverse events (AEs) were graded
according to the National Cancer Institute-Common Terminology Crite-
ria (version 3.0) .
The response criteria used were
efficacy (response rate, PFS, TTP, TTNT, and OS) and the toxicity pro-
file (rate of grade 3-4 AEs) of these two regimens. Outcome was ana-
lyzed on an intention-to-treat basis. The Chi-square test or two-sided
Fisher exact test were used to compare differences in nominal varia-
bles and the rank sum test was used for continuous variables. Time-to-
event analysis was performed using the Kaplan-Meier method . All
comparisons were determined by the log-rank test and by the Cox pro-
portional hazards model to estimate crude hazard ratios (HRs) and
95% confidence intervals (95% CIs). Analyses were performed using
SAS software, version 9.1. Times of observation were censored on
May 2009 for Rd patients and on March, 2009 for BiRd patients.
The endpoint of this study was to compare the
Patient characteristics are listed on Table I. Baseline
characteristics were similar; the two groups were compara-
ble with respect to the major variables known to affect out-
come. A similar proportion of patients in the two groups
presented with International Staging System (ISS) Stage I
or II at diagnosis (80.3% vs. 74.2%, P 5 0.402).
In both treatment groups, 44.4% of patients received
SCT at some point during the course of the disease; 38.8%
of patients in BiRd group and 34.7% of patients in Rd
group received a SCT upfront, defined as part of first line
Response to therapy
Based on standard IMWG criteria, the response rate was
significantly higher in BiRd patients compared with Rd (Ta-
ble II). In an intention-to-treat analysis, a CR was achieved
in the BiRd group in 45.8% vs. 13.9% in the Rd group, (P
< 0.001), and 73.6% vs. 33.3%, respectively (P < 0.001)
achieved at least a VGPR. Median duration of treatment
was longer in BiRd patients compared with Rd patients
(11.8 vs. 6.0 months). Response rates, for BiRd and Rd
patients who completed 6 months and 1 year of treatment,
TABLE I. Patient characteristics
BiRd (N 5 72) N (%)
Rd (N 5 72)
Age—median, (range) years
Sex—no. of patients (%)
International Staging System
Type of M protein
BiRd: clarithromycin/lenalidomide/low-dose dexamethasone; Rd: lenalidomide/
aPercentage calculated on number of patients whose data were available.
American Journal of Hematology 665
were evaluated. CRs were higher in BiRd group, but the dif-
ference was not statistically significant; VGPR rate was sig-
nificantly higher for BiRd patients both after 6 months of
therapy (56.7% vs. 35.0%, P 5 0.033) and after 1 year
(72.2% vs 44.4%, P 5 0.046).
The median duration of follow-up for survivors from diag-
nosis was 37.3 months in the BiRd group and 15.7 months
in the Rd group. A similar proportion of patients was still
receiving treatment at the time of analysis in the two
groups (20.8% vs. 23.6%, respectively in the BiRd group
and Rd group, P 5 0.689). In the following analysis,
patients who received SCT and patients who switched to
another chemotherapy regimen before progression were
censored at the date of transplant or chemotherapy
TTP was longer in the BiRd group (median 48.3 months)
than in patients receiving Rd (median 27.5 months) (HR
0.51; 95% CI 0.25–1.06; P 5 0.071), (Fig. 1A). Similarly,
PFS was longer in BiRd patients (median values: 48.3
months vs. 27.5 months, HR 0.50; 95% CI 0.25–0.98; P 5
0.044) (Fig. 1B). The previous analyses were repeated
without censoring patients who received SCT or switched to
another chemotherapy regimen: both TTP (Fig. 1C) and
PFS (Fig. 1D) were significantly longer in BiRd group. The
TABLE II. Responses to treatment
Best responses Response rate at 6 monthsResponse rate at 1 year
BiRd N (%)Rd N (%)
BiRd N (%)Rd N (%)
BiRd N (%)Rd N (%)
P-valueN 5 72N 5 72N 5 60N 5 40N 5 36N 5 18
CR or VGPR
BiRd: clarithromycin/lenalidomide/low-dose dexamethasone; Rd: lenalidomide/low-dose.
dexamethasone; CR, complete response; VGPR, very good partial response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available. Per-
centage may not total 100 because of rounding.
dexamethasone (BiRd) and lenalidomide-low-dose dexamethasone (Rd). Panel A: TTP; panel B: PFS; censoring patients at transplant date. Panel C: TTP; panel D: PFS,
not censoring patients at transplant date. Median TTP/PFS are provided in the figure (m: months). [Color figure can be viewed in the online issue, which is available at
Time-to-progression (TTP) and progression-free survival (PFS) in the intention-to-treat-population of patients treated with clarithromycin-lenalidomide-low-dose
666 American Journal of Hematology
median TTNT was not reached in the BiRd group compared
to 29.9 months in the Rd patients (HR 0.36 95% CI 0.20–
0.66; P < 0.001), (Fig. 2A).
Overall survival was not significantly different between
the two groups (3-year OS: 89.7% vs. 73.0% in the BiRd
and Rd groups, respectively, HR 0.48; 95% CI 0.17–1.37;
P 5 0.170), (Fig. 2B). Early deaths (during the first 4
months of therapy) were reported in 2/72 (2.8%) in BiRd
group and none in the Rd group, respectively (P 5 0.497).
According to ISS stage, in patients presenting with ISS
stage I/II, TTP (median: 48.3 vs. 23.2 months, HR 0.38;
95% CI 0.15–0.94; P 5 0.036), PFS (median: 48.3 vs. 23.2
months, HR 0.41; 95% CI 0.17–0.99; P 5 0.047), and
TTNT (median: 48.3 vs. 23.2 months, HR 0.34; 95% CI
0.16–0.71; P 5 0.004) were all significantly longer in BiRd
patients, compared to Rd patients; no significant differen-
ces in TTP, PFS, and TTNT were found among patients
with stage III ISS treated with BiRd or Rd. OS was not dif-
ferent between the two groups regardless of ISS stage.
By subgroup analyses, the OS was higher in BiRd
patients, both considering patients who received SCT (2
year OS: 93.5% vs. 80.9%, HR 0.35; 95% CI 0.06–2.17; P
5 0.262) and patients who did not (2 year OS: 86.6% vs.
64.7%, HR 0.56; 95% CI 0.16–2.02; P 5 0.375) (Fig.
Toxicity and deaths
Major grade 3–4 toxicities with BiRd and Rd are listed in
Table III. Fifty-five (76.4%) patients receiving BiRd and 42
(58.3%) patients receiving Rd experienced at least one
Grade 3 or higher toxicity (P 5 0.021). The frequency of
neutropenia was similar between the two groups while
thrombocytopenia was significantly more frequent with BiRd
(23.6% vs. 8.3%, P 5 0.012). One of the most common
extra-hematological toxicities reported with BiRd was ste-
roid related myopathy, which was significantly higher than
with Rd (9.7% vs. 0%, P 5 0.013).
The most common toxicities in patients treated with Rd
were infections (16.7% vs. 9.7%, P 5 0.218) and dermato-
logical toxicities (12.5% vs. 4.2%, P 5 0.129). The rate of
thromboembolic events (VTE) was similar in the two groups
(12.5% vs. 9.7%, respectively in Rd and BiRd, P 5 0.596).
Seven (9.7%) patients treated with BiRd discontinued treat-
ment for AEs compared with nine (12.5%) patients receiv-
ing Rd (P 5 0.596). There were two toxic deaths in BiRd
(pulmonary embolism  and myocardial infarction ) and
none in Rd.
In newly diagnosed MM patients, two randomized studies
have demonstrated the efficacy of the combination of lenali-
domide plus dexamethasone. Preliminary results showed
that RD resulted in a higher CR rate and 1-year PFS than
did high-dose dexamethasone . The Rd combination
tion-to-treat-population of patients treated with clarithromycin plus lenalidomide-
low-dose dexamethasone (BiRd) and lenalidomide plus low-dose dexamethasone
(Rd). Panel A shows TTNT; panel B shows OS. Median TTNT and OS are pro-
vided in the figure (m: months). [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Time to next treatment (TTNT) and overall survival (OS) in the inten-
ulation of patients treated with clarithromycin plus lenalidomide-low-dose dexa-
methasone (BiRd) and lenalidomide plus low-dose dexamethasone (Rd). Panel A
shows OS in patients who received transplant; panel B shows OS in patients who
did not receive transplant. Median OS is provided in the figure (m: months). [Color
figure can be viewed in the online issue, which is available at wileyonlinelibrary.-
Subgroup analysis of overall survival (OS) in the intention-to-treat-pop-
American Journal of Hematology 667
showed further benefit in terms of 2-year OS compared
with RD, with a lower rate of Grade 3 or higher toxic-
effects, related to the use of lower steroid doses. Therefore,
the trial was halted and RD patients were crossed over to
Rd. The Rd regimen was well tolerated in younger and
older patients .
The addition of clarithromycin to Rd has shown a CR
rate of 38.9%, and 2-year EFS of 97.2% . Clarithromy-
cin probably optimizes the pharmacologic effects of gluco-
corticoids, and this can in part explain why one of the
major corticosteroid-related toxicities reported was myopa-
thy. It has also an immunomodulatory effect and may have
direct antineoplastic properties. It is unclear if clarithromy-
cin can in some way affect the pharmacologic effects of
lenalidomide, but unlikely since lenalidomide is not target
for microsomal P450 or cytocrome 3A4. However, direct
pharmacokinetics studies to confirm this are warranted.
No formal comparison has been done so far between Rd
and BiRd. In an attempt to address this issue, to determine
the additive value of clarithromycin compared to a regimen
of lenalidomide plus low-dose corticosteroid, we performed
a case-match analysis that adjusted for age, gender and
transplantation status. The two groups were comparable for
baseline characteristics and for the main prognostic factors
known to affect outcome. With the exception of clarithromy-
cin, the treatment regimens were virtually identical; the
dose of dexamethasone was the same in both Rd and
BiRd with the exception of two extra doses of dexametha-
sone in the first cycle with BiRd. It is doubtful that two extra
doses of dexamethasone would explain the magnitude of
the differences observed.
On intention-to-treat analysis, CR and VGPR rates were
significantly higher with BiRd. Since duration of treatment
was significantly longer for BiRd patients, we evaluated
response rates after 6 months and 1 year of therapy, and
the results were unchanged. A longer duration of therapy
seems to be related in both groups to an increase in
response rates, however more pronounced in BiRd than in
Rd, resulting in a significantly higher response with BiRd
regardless of the duration of therapy. TTP, PFS, and TTNT
were also significantly better in patients treated with BiRd.
This translated in an increase in OS, even if the difference
lacks significance so far. We adjusted for the effect of
transplantation, by comparing the two regimens in patients
who received transplantation as well as in the subset of
patients who did not, and the findings were sustained. All
these finding suggest benefit in terms of both response
rate and survival, related to the addition of clarithromycin to
Rd. If this benefit is related to the optimization of the ste-
roid effects or to a direct antineoplastic activity it is still
The AEs reported were consistent with the established
toxicity profile for both regimens. The rate of Grade 3–4
AEs was higher in BiRd group, with an increase in both ste-
roid- and lenalidomide- related toxicity. The rate of steroid-
related toxicity (myopathy and neurological toxicity in partic-
ular) was higher with BiRd than with Rd, which supports
the hypothesis that the benefit of clarithromycin is due to
an increase in steroid effect. Hematological toxicity was
also higher with BiRd but this did not translate into an
increase in infections, in part likely related to the antibiotic
effect of clarithromycin. Except for hematological toxicity,
other lenalidomide-related toxicity (VTE and dermatological
toxicity) were not more frequent in the BiRd group. Despite
a higher rate of Grade 3–4 AEs, treatment discontinuation
due to AEs was similar in both groups. Duration of therapy
was definitely longer for BiRd patients. It is however hard to
say if the longer duration of therapy is due to a better toler-
ability of this regimen (despite a higher rate of AEs), supe-
rior efficacy, or is simply a consequence of a difference in
clinical practice between the two centers.
There are some limitations to our analysis. Since patients
treated with Rd were a mix of patients enrolled in clinical
trials and patients who received therapy outside of a clinical
study, the rates of toxicity in Rd may be underestimated.
Another limitation is that, since patients were treated in two
different institutions, a difference in clinical approach, such
as duration of therapy, could have affected the results. De-
spite these limitations, this is the first study to compare the
efficacy and safety of these two regimens.
In summary, results of this case-control analysis suggest
the superiority of BiRd compared with Rd in terms of
response rates and survival. It is worth noting that clarithro-
mycin is an excellent antibiotic, and that antibiotics are rou-
tinely recommended for patients receiving steroid-based
induction in almost all clinical trials and in practice. BiRd
treatment, although more active was associated with
increasedtoxicity, in particular
(without an increase in infections, at least in part related to
the effect of clarithromycin) and steroid-related toxicity;
treatment was overall well tolerated. Randomized prospec-
tive phase III studies are necessary to confirm these
results. Comparisons of BiRd with other active regimens
such as bortezomib/dexamethasone and bortezomib/thali-
domide/dexamethasone are also needed to determine the
optimum initial therapy for multiple myeloma.
1. Rajkumar SV, Kyle RA.Plasma cell disorders. In:Goldman L,Ausiello D, edi-
tors. Cecil Textbook of Medicine,23rd ed. Philadelphia: W. B. Saunders; 2008.
2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860–1873.
3. Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment
for multiple myeloma. Am J Hematol 1990;33:86–89.
TABLE III. Grade 3-4 adverse events
BiRd (N 5 72)
Rd (N 5 72)
N (%)P value
Grade 3/4 adverse events
Hematological adverse events
Leukopenia (no associated neutropenia)
Extra-hematological adverse events
Deep vein thrombosis
Steroid induced psychosis
Renal Failure/creatinine increase
55 (76.4) 42 (58.3)0.021
BiRd: clarithromycin/lenalidomide/low-dose dexamethasone; Rd: lenalidomide/
668American Journal of Hematology
4. Sirohi B, Powles R. Multiple myeloma. Lancet 2004;363:875–887.
5. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug
CC-5013 overcomes drug resistance and is well tolerated in patients with
relapsed multiple myeloma. Blood 2002;100:3063–3067.
6. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs over-
come drug resistance of multiple myeloma cells to conventional therapy.
7. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for
relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–
8. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone
for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–
9. Zonder JA, Crowley J, Hussein MA, et al. Superiority of lenalidomide (Len)
plus high-dose dexamethasone (HD) compared to HD alone as treatment of
newly-diagnosed multiple myeloma (NDMM): Results of the randomized, dou-
ble-blinded, placebo-controlled SWOG Trial S0232. Blood 2007;110(abstract
10. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial
therapy for newly diagnosed multiple myeloma: An open-label randomised
controlled trial. Lancet Oncol 2010;11:29–37.
11. Coleman M, Leonard J, Lyons L, et al. BLT-D (clarithromycin [Biaxin],
low-dose thalidomide, and dexamethasone) for the treatment of myeloma
and Waldenstrom’s macroglobulinemia. Leuk Lymphoma 2002;43:1777–
12. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin(R)[clarithro-
mycin]/Revlimid(R)[lenalidomide]/dexamethasone) combination therapy results
in high complete- and overall-response rates in treatment-naive symptomatic
multiple myeloma. Blood 2007;111:1101–1109.
13. Spahn JD, Fost DA, Covar R, et al. Clarithromycin potentiates glucocorticoid
responsiveness in patients with asthma: results of a pilot study. Ann Allergy
Asthma Immunol 2001;87:501–505.
14. Ohara T, Morishita T, Morishita T, et al. Antibiotics directly induce apoptosis in
B cell lymphomacells derived
15. Nakamura M, Kamimoto T, Yoshimori T, et al. Clarithromycin induces autoph-
agy in myeloma cells. Blood 2006;108:1001a abstract 3509.
16. Morris TC, Kettle PJ, Drake M, et al. Clarithromycin with low-dose dexameth-
asone and thalidomide is an effective therapy in relapsed/refractory myeloma.
Br J Haematol 2008;143:349–354.
17. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and
response assessment of multiple myeloma. Leukemia 2009;23:3–9.
18. National Cancer Institute: Common Terminology Criteria for Adverse Events,
v3.0, (CTCAE). 2003. Available at: http://ctep.cancer.gov/protocolDevelopment/
19. Kaplan E, Meier P. Nonparametric estimation from incomplete observations.
J Am Stat Assoc 1958;53:457–481.
from BALB/cmice. AnticancerRes
American Journal of Hematology 669