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

518s Lymphoma and Plasma Cell Disorders
8033 Poster Discussion Session (Board #13), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Oral weekly MLN9708, an investigational proteasome inhibitor, in combination
with lenalidomide and dexamethasone in patients (pts) with previously
untreated multiple myeloma (MM): A phase I/II study. Presenting
Author: Paul Gerard Guy Richardson, Dana-Farber Cancer Institute, Boston,
MA
Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The
feasibility of combining a proteasome inhibitor with an immunomodulatory
drug and a steroid in previously untreated MM has been demonstrated with
the RVD regimen. This is the first study of MLN9708 in combination with
lenalidomide and dexamethasone (NCT01217957). Here we report the
phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with
previously untreated MM, aged �18 yrs with measurable disease received
oral MLN9708 (phase 1: 1.68–3.95 mg/m2 ) days 1, 8, and 15, lenalidomide
25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22,
for up to twelve 28-day cycles. Primary objectives were determination of
safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and
CR�VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had
been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82);
69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97
mg/m2 and the RP2D as 2.23 mg/m2 ; for Ph 2, the RP2D was converted to
a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received
a median of 6 treatment cycles (range 1–11), 8 received �6 cycles; 6
stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1
(range 1–2), all are ongoing. Grade �3 hematologic toxicity was reversible
and included anemia (n�2) and thrombocytopenia (n�1). Grade �3
nonhematologic toxicity included erythematous rash, syncope, and vomiting
(2 pts each). All-grade drug-related peripheral neuropathy was seen in 6
pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the
MTD). Two pts discontinued due to AE; there were 5 pts who had serious
drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 � Ph 2), all
achieved �PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in
response with duration of confirmed response of up to 9.5 months. Of 4
response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date.
Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears
well tolerated with manageable toxicity. These data show antitumor
activity at the RP2D in pts with previously untreated MM, with �PR in all
pts to date.
8035 Poster Discussion Session (Board #15), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Response rates to single-agent carfilzomib in patients refractory or intolerant
to both bortezomib and immunomodulators in trial PX-171-003-A1.
Presenting Author: David Samuel DiCapua Siegel, John Theurer Cancer
Center, Hackensack, NJ
Background: Patients (pts) with relapsed and refractory multiple myeloma
(RR MM) who are refractory or intolerant to both bortezomib (BTZ) and
immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie,
“double-refractory/intolerant”), have few therapeutic options and a poor
prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI),
has shown durable single-agent activity in clinical studies including
003-A1, an open-label, single-arm phase 2b trial in RR MM. The present
analysis describes clinical activity in pts from 003-A1 with double-refractory/
intolerant disease and in other groups of clinical interest including pts with
disease refractory to all 5 approved classes of anti-MM tx (alkylators,
anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory
to all approved tx”). Methods: Pts from 003-A1 with double-refractory/
intolerant disease were analyzed, as were pts with disease refractory to all
approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C),
(20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall
response rate (ORR). Secondary endpoints included duration of response
(DOR), overall survival, and safety. Results: The study ORR was 22.9% with
median DOR of 7.8 mo (N�266). 228 pts (86%) with double-refractory/
intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo.
Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable
responses in pts with double-refractory/intolerant MM or disease refractory
to all 5 approved classes of tx. The ORRs across groups of clinical interest
were generally consistent with results for the entire study population. These
results are notable for a next-generation PI and demonstrate the activity of
single-agent CFZ in pts with advanced stage MM.
Refractory status n ORR (>PR), % DOR, mo
Refractory/intolerant to BTZ and (>1 IMiD) 228 20.6 7.4
To BTZ in any prior regimen 194 16.5 7.8
To Thal in any prior regimen 118 17.8 5.6
To Len in any prior regimen 221 22.2 7.8
Refractory to all approved tx 44 20.5 7.8
8034 Poster Discussion Session (Board #14), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in
patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I
study. Presenting Author: Shaji Kumar, Mayo Clinic, Rochester, MN
Background: Phase 1 studies are evaluating IV and oral dosing of the
reversible proteasome inhibitor MLN9708 in multiple tumor types. We
report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and
preliminary responses with weekly oral MLN9708 in pts with relapsed/
refractory MM (NCT00963820). Methods: Pts aged �18 yrs received
MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase,
pts required �2 prior therapies (including bortezomib, thalidomide/
lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to
relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor
(PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have
been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation
phase (0.24–3.95 mg/m2 ) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI
naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation
cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and
median number of prior lines of therapy was 3.5 (range 1-13), including
92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide,
thalidomide, and carfilzomib, respectively. Pts have received a median of 2
cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable
pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs)
and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97
mg/m2 . Overall, 69% of pts had drug-related AEs, and 28% had related
grade �3 AEs, including thrombocytopenia (17%), diarrhea (11%),
nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had
drug-related peripheral neuropathy (PN; no grade �3). 2 pts discontinued
due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2 ,1
had a PR at 2.97 mg/m2 , and 8 have achieved SD durable for up to 9.5
mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2 ), Tmax of
0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active
hydrolysis product). There was a trend for a dose-dependent increase in
whole blood 20S proteasome inhibition. Conclusions: Current data suggest
weekly oral MLN9708 is generally well tolerated with infrequent PN, and
shows early signs of antitumor activity.
8036 Poster Discussion Session (Board #16), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or
refractory multiple myeloma. Presenting Author: Adriana C. Rossi, Weill
Cornell Medical College, New York Presbyterian Hospital, New York, NY
Background: Clarithromycin has been shown to enhance anti-myeloma
activity of lenalidomide�dexamethasone in the upfront treatment of
multiple myeloma (MM). Pomalidomide is an immunomodulatory agent
effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin
may similarly enhance pomalidomide � dexamethasone in RRMM.
We now report updated results from a phase 2 trial of ClaPD in RRMM.
Methods: 73 patients with RRMM were enrolled in a single-institution
phase 2 study of ClaPD. All subjects had � 3 prior lines of therapy, one of
which must have included lenalidomide. ClaPD is clarithromycin 500mg
twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days
1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin.
Monthly disease response evaluation included immunoelectrophoresis and
free light chain analysis; bone marrow biopsy with skeletal imaging was
used to confirm MM responses. Treatment continued as tolerated until
disease progression. Results: The 66 patients who completed � 1 cycle of
ClaPD are reported. Median number of cycles was 6 (range 1-17).
Responses were progressive disease: 10%, stable disease: 21%, minimal
response: 12%, partial response: 33%, very good partial response: 18%,
stringent complete remission: 5%, for an overall response rate (ORR) of
56% and �VGPR rate of 23%. Median time to PR was 1.25 cycles (range
1-8). Median PFS was 5 months. Response and PFS were not different in
patients refractory to lenalidomide (85%), bortezomib (82%), or doublerefractory
patients (76%). After a median follow up of 12 months,28 pts
(42%) remain on study without progression and 56pts (85%) are alive. Two
pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular
weakness). One patient withdrew consent. Conclusions: ClaPD is highly
effective for heavily pre-treated RRMM, particularly in lenalidomiderefractory
disesase and compares favorably to previously published Phase 2
data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess
toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7
months in most subjects. These data support the clinical efficacy of
pomalidomide based regimens in RRMM.
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