Annual Meeting Proceedings Part 1 - American Society of Clinical ...

534s Lymphoma and Plasma Cell Disorders
8098 General Poster Session (Board #38G), Mon, 1:15 PM-5:15 PM
A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib
(BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving
a BTZ-containing combination regimen. Presenting Author: James R.
Berenson, Institute for Myeloma and Bone Cancer Research, West Hollywood,
CA
Background: Recent data has shown that single-agent CFZ can produce
responses among MM pts refractory to previous treatment regimens
including those containing BTZ. We conducted an intrapatient Phase 1/2
trial investigating the safety and efficacy of CFZ as a replacement for BTZ in
BTZ-containing regimens to which pts have progressed. Methods: Eligible
pts had to have progressed while receiving their most recent BTZcontaining
regimen after at least 4 doses of BTZ at � 1.0 mg/m² in � 4
weeks per cycle. Combination regimens containing an alkylating agent,
anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in
each regimen via intravenous administration over 30 min on days 1, 2, 8, 9,
15, and 16 of each cycle. Treatment continued using the same dose(s) and
schedule(s) of each drug administered in the BTZ-containing regimen. CFZ
doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45
mg/m² or until a maximum tolerated dose (MTD) was reached for that
regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have
recently started treatment. Pts received a median of 7 (range, 1-18) prior
treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were
treated with CFZ and the following different combinations: bendamustine
(BEND) alone, BEND � methylprednisolone, dexamethasone (DEX) alone,
DEX � pegylated liposomal doxorubicin, ascorbic acid � cyclophosphamide,
and melphalan alone. Pts have completed a median of 3 cycles.
Clinical benefit was seen in 10 (77%) pts (complete response � 8%; very
good partial response � 8%; partial response � 31%; minor response �
31%) with another 23% showing stable disease. The median time to
progression (range: 2-8 months) has not been reached and only 2 pts have
progressed. The most common grade 3/4 adverse events were thrombocytopenia
occurring in 5 pts (all � grade 3 except 1 event) and fever occurring
in two pts (grade 3). Four pts experienced a serious adverse event but no
regimen has reached a MTD. Conclusions: These early results suggest that
CFZ is an effective and tolerable replacement for BTZ for pts who are
refractory to BTZ-containing combination regimens.
8100 General Poster Session (Board #39A), Mon, 1:15 PM-5:15 PM
Survival outcomes of early autologous stem cell transplant (ASCT) followed by
lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients
with high-risk multiple myeloma (MM). Presenting Author: Jonathan L. Kaufman,
Winship Cancer Institute, Emory University, Atlanta, GA
Background: Despite markedly improved survival rates for MM pts in the last
decade, 15-20% of pts with high risk genetics continue to have dismal outcomes
with a median PFS of 18.5 months (Kapoor P et al). In this subset of pts, efforts
are needed to improve response rates and prolong the response duration, but
doing so without genotoxic therapy as this has been shown not to improve
outcomes (Barlogie et al). Methods: We evaluated 37 pts with high risk features
[del17p (n�16), t(4;14) (n�1), t(14;16) (n�4) by FISH/CTG; hypodiploidy
(n�9), del 13 (n�16); complex karyotype (n�14) by CTG; PCL (n�7) and
atypical presentation (n�4)]. After completing induction therapy, all pts
underwent ASCT followed by RVD maintenance. 60 days after ASCT following
hematological recovery, pts began maintenance [lenalidomide 10 mg/day
(days1–21), bortezomib 1.3 mg/m2 and dexamethasone 40 mg once a week
(days 1, 8, 15) every 28 days]. Results: The response rates are summarized in the
table. 7/36 pts progressed while on RVD maintenance. The median PFS and OS
for pts on RVD maintenance has not been reached. Pts with �VGPR pre-ASCT
and with �VGPR on RVD maintenance have median PFS of 28 months and 11
months, respectively. 4 pts with prior h/o DVT received anticoagulation, while all
others received ASA for DVT prophylaxis. No thrombotic events were seen. There
were no grade 3/4 toxicities or treatment-related mortality. The most common
toxicities during maintenance schedule were: PN-40% (G1: 26%; G2:14%); G1
rash-10% and G1 fatigue in 78% pts. Cytopenias were seen in 25% pts and dose
reductions were made in 50% pts. There is no report of secondary malignancies.
Conclusions: Early ASCT followed by RVD maintenance delivers superior response
rates in this high risk segment achieving sCR in 47% and �VGPR in 73%
pts and prevents early relapses. The median PFS and OS have not been reached.
RVD maintenance regimen is well tolerated and promising.
Response rates.
Best response with
Pre-ASCT response Post-ASCT response RVD maintenance
n % n % n %
sCR 3 8 8 22 17 47
CR 3 8 8 22 5 14
sCR � CR 6 16 16 44 22 51
VGPR 13 35 16 43 8 22
>VGPR 19 51 32 77 30 73
PR 15 41 5 14 3 8
>PR 34 92 37 91 33 81
SD 1 3
PD 2 6 3 8
8099 General Poster Session (Board #38H), Mon, 1:15 PM-5:15 PM
Effect of matrix metallopeptidase 13 (MMP13) on multiple myeloma (MM)
cells, osteoclast (OCL) activity, and bone resorption. Presenting Author:
Jing Fu, Columbia University Medical Center, Department of Medicine/
Hematology-Oncology, New York, NY
Background: MM cells produce OCL-activating factors that induce excessive
bone resorption resulting in lytic lesions. The role of MMPs in invasion/
progression of solid tumors is well-known, but its function in MM has not
been well elucidated. Our group has shown that MMP13 is highly expressed
in primary MM cells and in sera of MM patients. Levels of MMP13
significantly correlate with the extent of bone disease. MMP13 is induced
by IL-6 via AP-1 activation in MM cells and enhances fusion of OCL
precursors resulting in excessive bone resorption. OCL formation using
MNCs of mmp-13-/- mice resulted in a fusion defect, significantly decreased
OCL size and activity, which could be reversed by exogenous
MMP13 (ASH 2009, IMW 2011). Methods: Methods will be presented in
the Results section. Results: RT-PCR and western blotting revealed that
IL-6 treatment of MM cells induced MMP13 transcription (30-fold) and
secretion (�1000-fold). Protein expression of the AP-1 members c-Jun
and c-Fos was induced by IL-6, which correlated with MMP13 upregulation.
Our data further indicate that the catalytic activity of MMP13 is not
required to enhance OCL formation and bone resorption. To prove this, we
generated the MMP13 activity-dead mutation MMP13-E223A construct by
site-directed mutagenesis PCR-based cloning. The mutated protein was
overexpressed in HEK293 cells and purified from the supernatant to
confirm whether loss of catalytic activity blocks MMP13 function. To
further investigate the in vivo role of MMP13 in MM bone disease, MMP13
expression was knocked down (KD) in murine 5TGM1-MM cells by pKLO. 1
puro lentiviral infection containing sh-RNA targeting mouse MMP13
sequence. MMP13-KD 5TGM1-MM cells or WT-5TGM1-MM cells were
intratibially injected into RAG2-/- mice. Development of lytic bone lesions
are monitored by micro-QCT and data will be available at the time of
presentation. Conclusions: Our data suggest that MMP13, secreted by MM
cells, plays a critical role in the development of lytic lesions. Targeting
MMP13 represents a promising approach to treat or to prevent bone
disease in MM.
8101 General Poster Session (Board #39B), Mon, 1:15 PM-5:15 PM
Efscalefect of lenalidomide, bortezomib, and dexamethasone (RVD) induction
therapy in transplant-eligible patients (Pts) with newly diagnosed
multiple myeloma (MM) on CR rates and survival. Presenting Author:
Charise Gleason, Winship Cancer Instiute, Emory University, Atlanta, GA
Background: Addition of lenalidomide to bortezomib and dexamethasone
(RVD) demonstrated to be an effective and well tolerated regimen in phase
II trials with overall response rate (ORR) �95% (Richardson P et al). Given
the lack of phase III data, we have evaluated our institutional experience of
pts treated with RVD induction therapy, to support this triplet combination.
Methods: 286 transplant-eligible pts with newly diagnosed MM were
treated with RVD induction therapy [R - 25 mg/day (days1–14), V-1.3
mg/m2 (days 1, 4 8, 11) andD-40mgonce/twice weekly as tolerated every
21 days] from January 2008 until January 2012. 148 pts underwent ASCT
and 138 pts opted for delayed transplant. Post-ASCT 56% pts are on
maintenance therapy tailored to their risk (R-40%; RVD-10%; V-6%).
Demographic and outcomes data for the pts that underwent ASCT were
collected and responses were evaluated per IMWG Uniform Response
Criteria. Results: Median age of the pts is 60 years (range 32-77). Other pt
characteristics include: M/F 55%/45%; ISS I/II/III 40%/30%/30%; Isotype
IgG/IgA/FLC/IgM 61%/20%/18%/1%; high risk/standard risk 13%/
87%. Pts received a median of 4 cycles (2-9) of RVD. Median CD34� stem
cell collection was 11.24 x 10 6 /kg. 18% pts required dose reductions
(R/V/D-5%/9%/2%) and discontinuation in 2% pts for progressive disease.
49%/8% pts had G1-2/G3-4 PN. Median estimated PFS is 47 months and
median OS has not been reached. Response rates are included in the table.
Conclusions: RVD is an active induction regimen with superior response
rates of � 80% �VGPR rates post-ASCT and is well tolerated in newly
diagnosed MM pts. Incorporation of lenalidomide did not impact the stem
cell collection. Until phase III data are available, our institutional experience
could provide a perspective in the choice of RVD as an effective
induction regimen in improving ORR and prolonging survival.
Post-induction response Post-ASCT response Best response
N (148) % N (146) % N (142) %
sCR 27 18 50 35 81 57
CR 10 7 18 12 8 6
nCR 15 10 12 8 10 7
sCR � CR � nCR 52 35 80 55 99 70
VGPR 40 27 36 25 26 18
>VGPR 92 62 116 80 125 88
PR 48 33 25 17 13 9
>PR 140 95 141 97 138 97
MR 3 2
PD 5 3 5 3 4 3
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