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

8086 General Poster Session (Board #37C), Mon, 1:15 PM-5:15 PM
Hematologic safety data from four phase II studies of single-agent
carfilzomib in relapsed and/or refractory multiple myeloma Presenting
Author: Ajay K. Nooka, Emory University Winship Cancer Institute, Atlanta,
GA
Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor
that is currently being evaluated in patients (pts) with multiple myeloma
(MM). Given that the majority of pts with MM exhibit either disease- or
therapy-related myelosuppression sometime in the course of their disease,
detailed evaluation of treatment-emergent hematologic safety data with
CFZ is of significant interest. In the following analysis, we report the
hematologic safety profile for single-agent CFZ from 526 pts treated in four
phase 2 studies. Methods: Pts treated with CFZ in trials 003-A0, 003-A1,
004, and 005 were included in the analysis. Pts with preexisting hematologic
abnormalities of Grade (G) 0–2 (G0–3 for 005) were eligible to enroll.
CFZ was dosed in all studies on Days 1, 2, 8, 9, 15, and 16 of a 28-day
cycle (C). Doses were 20 mg/m2 in C1 for all studies escalating to 27 mg/m2 in C2 per individual protocol, except 005 (15 mg/m2 in C1, 20 mg/m2 in
C2, and 27 mg/m2 in C3). Incidence, frequency, and severity of thrombocytopenia,
lymphopenia, neutropenia, and anemia were analyzed in terms of
adverse events (AEs) of interest. Laboratory data were analyzed for trends
over time. Results: See table below for summary of hematologic events. In
general, platelet counts trended down, reached a nadir by Day 8 of a 28-day
treatment cycle, and normalized before the start of next cycle. There was no
evidence of cumulative thrombocytopenia or clinically significant episodes
of bleeding associated with thrombocytopenia. Febrile neutropenia was
reported in 1% of pts. No mortality due to hematologic events was reported.
Conclusions: Hematologic AEs, although common with CFZ treatment, were
infrequently dose limiting. Clinically significant G3/4 cytopenias were both
infrequent and transient. In summary, the hematological safety profile of
CFZ was similar to or better than currently approved MM therapies,
providing further evidence of its acceptable safety profile in heavily
pretreated MM pts. Summary of hematologic events.
Total population
N�526, n (%) Thrombocytopenia Lymphopenia Neutropenia Anemia
Any AE 199 (37.8) 136 (25.9) 119 (22.6) 246 (46.8)
G3/4 AE 131 (24.9) 104 (19.8) 63 (11.9) 118 (22.4)
Dose reductions 6 (1.1) 0 6 (1.1) 2 (0.4)
Discontinuations 5 (1.0) 0 1 (0.2) 3 (0.6)
8088 General Poster Session (Board #37E), Mon, 1:15 PM-5:15 PM
A prospective clinical study evaluating current models for risk of progression
from smoldering multiple myeloma (SMM) to multiple myeloma (MM).
Presenting Author: Benjamin M. Cherry, Multiple Myeloma Section, Metabolism
Branch, National Cancer Institute, NIH, Bethesda, MD
Background: The updated (2010) International Myeloma Working Group
criteria emphasize individual follow-up and development of early treatment
trials for high risk SMM patients. To facilitate these goals, it is important to
have reliable models for risk of progression to MM derived from prospective
clinical studies. Current clinical risk models by the Mayo Clinic and the
Spanish PETHEMA group stratify SMM patients as low (LR), intermediate
(IR), or high risk (HR) of progression using bone marrow plasma cell
fraction and protein levels (Mayo) and abnormal plasma cell fraction on
flow cytometry with or without immunoparesis (Spanish). We report the first
comparison of these models in a prospective natural history study. Methods:
We evaluated 70 patients with SMM and determined the risk classifications
of each using the Mayo and Spanish models. P values of comparisons
between risk groups were calculated using Fisher’s exact test. Results:
Among SMM patients classified as HR by the Spanish model (n�31), 2
patients (6%) were HR by the Mayo model; the remaining 17 (55%) and 12
(39%) patients were classified as IR and LR by the Mayo model,
respectively. Among 2 SMM patients classified as HR by the Mayo model,
both patients (100%) were HR by the Spanish model. There was significant
disagreement between the models in identifying HR patients (HR v.
non-HR, p�0.0001). Similarly, of SMM patients classified as LR by the
Spanish model (n�17), 11 patients (65%) were LR by the Mayo model; 6
(35%) were IR and 0 (0%) were HR by the Mayo model. Among SMM
patients classified as LR by the Mayo model (n�36), 11 (31%) patients
were classified as LR by the Spanish model; 13 (36%) were IR and 12
(33%) were HR by the Spanish model. There was significant disagreement
between the models in identifying LR patients (LR v. non-LR, p�0.0016).
Conclusions: The significant discordance between the Mayo Clinic and
Spanish PETHEMA clinical risk models underscores the urgent need for
biologically derived models that rely on molecular markers to predict
disease progression. Such models are critical for counseling individual
patients and for the development of early treatment studies that seek to
prevent or delay progression to MM.
Lymphoma and Plasma Cell Disorders
8087 General Poster Session (Board #37D), Mon, 1:15 PM-5:15 PM
Natural killer (NK) cell activation, cytokine production, and cytotoxicity in
human PBMC/myeloma cell co-culture exposed to elotuzumab (Elo) alone
or in combination with lenalidomide (Len). Presenting Author: Balaji
Balasa, Abbott Biotherapeutics, Redwood City, CA
Background: Elo is a monoclonal IgG1 antibody targeting CS1, a cell surface
glycoprotein highly expressed on �95% of myeloma cells. In preclinical
models Elo exerts anti-myeloma activity via NK cell-mediated antibodydependent
cellular cytotoxicity. Len is an immunomodulatory agent that
may activate NK cells. The combination of Elo � Len synergistically
enhanced anti-tumor activity in myeloma xenograft models. We investigated
the mechanism of enhancing NK cell activation and myeloma cell
killing with Elo � Len. Methods: Human PBMC/OPM-2 co-cultures were
treated for 24-72h with Elo, Len, or Elo � Len. Activation markers and
adhesion receptors were evaluated by flow cytometry. Cytokines were
measured by Luminex and ELISpot assays. Cytotoxicity was assessed by
cell counting. Results: Elo � Len increased IFN-� secretion significantly
more than Elo or Len alone. IFN-� elevates ICAM-1 expression, and ICAM-1
surface expression on OPM-2 target cells increased synergistically with Elo
� Len. Elo, Elo � Len but not Len increased expression of CD25 (IL-2R�)
on NK cells. Len increased the levels of IL-2, but those were decreased in
the presence of Elo due to increased consumption by CD25 expressing NK
cells. Blocking uptake of IL-2 with anti-CD25 resulted in higher IL-2 levels
than with Len. ELISpot assays confirmed that Elo � Len significantly
increased the number of IL-2-producing cell colonies compared with Elo or
Len. Elo induced NK dependent myeloma cell killing, and the effect was
significantly higher with Elo � Len. Conclusions: Elo alone activated NK
cells and mediated the killing of myeloma cells in PBMC/OPM-2 cocultures.
Elo � Len synergistically enhanced myeloma cell killing and
increased expression/production of IFN-�, ICAM-1, IL-2, and CD25.
Treatment
No blocking (control mAb) ave n�6 Anti-CD25 blocking mAb ave n�6
IFN-� (pg/mL)
ave n�8
ICAM-1 on
OPM-2 (MFI)
n�4
CD25 on
NK cells
(MFI) n�8
IL-2 (pg/mL)
(Luminex)
# IL-2 positive
colonies
(ELISpot) n�9
531s
OPM-2
killing (%)
n�4
*Control 48 427 155 21 - 30 1
**Len 94 2040 131 50 - 71 15
Elo � Len 386 42,259 1546 14 134 191 67
Elo 65 3068 975 7.8 52 80 39
*cIgG1 (isotype); **plus cIgG1.
8089 General Poster Session (Board #37F), Mon, 1:15 PM-5:15 PM
Costimulatory molecule profiles and NK cell recovery after autologous
hematopoietic cell transplantation (HCT) in multiple myeloma (MM)
patients. Presenting Author: Myo Htut, City of Hope, Duarte, CA
Background: Increased immune responses post autologous HCT may be of
benefit in long term disease control. Responses may be mediated by NK
cell function and possibly other alternate pathways, including costimulatory
molecule pathways. This pilot study assesses the expression of
inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and
CD28) molecules on NK cells after auto-HCT in MM patients and evaluates
the effect of lenalidomide treatment on these pathways. Methods: 17
patients with MM undergoing HCT, median age 56.7 years (36 – 67), were
included in the study. Peripheral blood samples were taken 3 days prior to
HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17
patients were receiving lenalidomide with d91 as median start date. NK
cells and their costimulatory molecules were evaluated by flowcytometry
using 2 six color panels of antibodies. One way ANOVA test and Kruskal-
Wallis test (non-parametric) were applied to analyze the data using the
Graphpad Software. Results: See table below. NK cell number was highest
(median: 26% of total lymphocytes) at d14 (p: � 0.0001) compared to pre
and post HCT levels. At d180, TNF-R OX40 expression was significantly
increased in �PR group (n�5) (median: 9.5% of NK cells) compared to
�VGPR (n�12) (0.8%; p�0.0084). In addition, NK cell number was
higher in the lenalidomide group (n�13) (median: 15.15 % of total
lymphocytes) compared to the no lenalidomide group (n�4) (6.74%;
p�0.0108) at d180 post HCT. Significantly lower level of CTLA-4
expression was also found in the lenalidomide group (0.33% vs. 2.54%;
p�0.0362). Conclusions: We observed NK cell recovery to baseline values
at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was
higher in �PR group than �VGPR group. Lenalidomide treatment was
associated with higher NK cells number and decreased expression of
CTLA-4. This observation could be a possible marker of enhanced host NK
cell immune response against MM. Future clinical trials will explore
therapies that increase NK cell responses.
Pre-HCT d180
Very good partial response or better (> VGPR) 6 12
Partial response or worse (< PR) 11 5
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