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

512s Lymphoma and Plasma Cell Disorders
8009 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly
patients with de novo multiple myeloma. Presenting Author: Brigitte Kolb,
University Hospital, Reims, France
Background: Melphalan-prednisone � thalidomide (MPT) or bortezomib
(MPV) are approved in frontline MM patients (pts) �65 years. Both
regimens demonstrated significant benefit over MP alone in terms of PFS
and OS but this benefit could be hampered by the risk of peripheral
neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has
demonstrated promising activity and favorable toxicity profile, with low
rates of PN. This phase I/II study was designed to determine the maximum
tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this
combination in newly diagnosed MM �65. Methods: In Phase I, Cfz was the
only escalating agent starting at 20 mg/m2 (level 1) with maximal planned
dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for
nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m²
were given on days 1 to 4, for all dose levels. Based on toxicity assessment,
the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD
determination was based on occurrence of Dose limiting toxicities (DLTs)
during the first cycle only. DLTs were defined as any grade 4 hematologic
toxicity or preventing administration of 2 or more of the 8 Cfz doses of the
first treatment cycle except grade 4 thrombocytopenia without bleeding or
grade 4 neutropenia lasting � 7 days; or grade � 3 febrile neutropenia; or
any other grade � 3 nonhematologic toxicity. Results: As of January 20th
2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6
at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There
were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the
MTD was considered to be 36 mg/m². Then, 16 additional pts were
included in the phase II at level 3. Overall, 40 pts have been enrolled into
the phase I/II study and 26 pts are evaluable for response. The ORR was
92% including 42% at least VGPR. These results compare favorably to
those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80
and 85%, respectively) in the same population. Conclusions: Frontline
carfilzomib (36 mg/m2) � MP is a tolerable and very effective combination
in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy
data to be presented at the meeting.
8011 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Stringent complete response (sCR) in patients (pts) with newly diagnosed
multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide
(LEN), and dexamethasone (DEX). Presenting Author: Andrzej J. Jakubowiak,
University of Chicago, Chicago, IL
Background: Combination treatment (tx) with CFZ, LEN, and DEX (CRd) is
well tolerated and highly active in NDMM. In a phase 1/2 study, CRd
provided rapid reduction of disease by 68% after cycle (C) 1 and 94%
�partial response (PR) at a median of 8C, including 65% �very good PR
and 53% �near CR (nCR), which improved to 79% �nCR after C12 (ASH
2011, Abstr 631). Here, we examine the clinical significance of the
response rates with longer follow-up. Methods: Pts with NDMM were treated
in 28-day (d) C with CFZ 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), LEN 25 mg
PO (d1–21) and DEX 40/20 mg PO weekly (C1–4/5–8). After C4,
autologous stem cell transplant (ASCT) candidates achieving �PR could
collect stem cells but then continued CRd with the option to proceed to
ASCT. After C8, pts received CRd maintenance, using the last tolerated
doses, with LEN/DEX at the same schedule but a modified CFZ schedule
(d1, 2, 15, 16). Response was assessed by IMWG criteria plus nCR.
Results: As of Nov 30, 2011, median follow-up was 14 mo (range 4–25)
with 33/53 (62%) pts achieving �nCR and 42% sCR. After a median of
13C (range 1–25), 36 pts completed C8 and continued CRd maintenance,
64% achieving sCR. 20/22 pts in CR evaluated for minimal residual
disease (MRD) by multiparameter flow cytometry had no MRD. Progressionfree
survival (PFS) rate was 97% at 12 and 92% at 24 mo. All pts who
achieved sCR have maintained response for a median of 9 mo (range
1–20). Extended CRd tx was well tolerated. During CRd maintenance, the
most common toxicities (all grades) were lymphopenia (30%), leukopenia
(26%), and fatigue (25%), and peripheral neuropathy remained limited
(11%, all G1/2). There were no tx discontinuations due to toxicity during
maintenance and limited dose modifications (CFZ 19%, LEN 28%, DEX
31%). Conclusions: CRd is highly active in NDMM, providing rapid and
deep responses. Extended tx was well tolerated and resulted in improved
depth of response with a high sCR rate and a significant proportion of pts
without evidence of MRD. Responses were durable with very promising
PFS. All pts who achieved sCR remained on CRd with sustained sCR. These
results compare favorably to other frontline regimens.
8010 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and
dexamethasone (CYCLONE) in patients with newly diagnosed multiple
myeloma. Presenting Author: Joseph Mikhael, Mayo Clinic, Scottsdale, AZ
Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its
target with favorable toxicity profile that has shown significant activity in
relapsed multiple myeloma (MM). Here we used carfilzomib as the center of
a 4 drug induction regimen designed for MM patients pre stem cell
transplant (SCT). Methods: We conducted a phase I safety run in 6 patients
with no DLT observed before expanding to phase II. The phase II regimen is
shown below. Treatment was for 4 cycles with expected SCT post induction.
For the phase II portion of this trial, the primary endpoint is the proportion
of patients who have � very good partial response to treatment. All patients
received herpes zoster prophylaxis and ASA daily. Results: Twenty seven
patients were enrolled. Median age was 65 (range 27-74). ORR for
evaluable patients (n�17) at phase II dosing is 100%: CR 35%, VGPR
48%, PR 18% after 4 cycles of CYCLONE. Grade 3 toxicity was reported in
52% of patients and 14% experienced a grade 4 toxicity. Grade 3/4
toxicities occurring in �5% of patients included fatigue, neutropenia,
lymphopenia, thromboembolism, myopathy. Toxicities of any grade seen in
�20% of patients included fatigue, constipation, lethargy, thrombocytopenia,
somnolence, creatinine increased, malaise. Four patients (20%)
developed grade 1 sensory neuropathy; no higher grade or painful neuropathy
was evident. All patients are alive. All patients advancing to SCT
successfully collected stem cells. One patient with t(4;14) disease who was
not transplanted has progressed. 94% remain progression free. Conclusions:
The 4 drug CYCLONE regimen has remarkable efficacy (83% �VGPR) and
manageable toxicity in newly diagnosed patients with multiple myeloma.
Especially notable was the low incidence of neuropathy and depth of
response (CR 35%) after only 4 cycles. Given the relative lack of toxicity an
extension of this regimen at higher doses of carfilzomib (20/45mg/m2 ) has
been initiated.
Agent Dose level Route Day Cycle length
Carfilzomib 20 mg/m2 cycle 1
27mg/m2 IV 1, 2, 8, 9, 15, 16 28 days
� cycle 2
Thalidomide 100 mg Orally 1-28 28 days
Cyclophosphamide 300 mg/m2 Orally 1,8,15 28 days
Dexamethasone 40 mg Orally 1,8,15,22 28 days
8012 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
PANORAMA 2: A phase II study of panobinostat in combination with
bortezomib and dexamethasone in patients with relapsed and bortezomibrefractory
multiple myeloma. Presenting Author: Melissa Alsina, H. Lee
Moffitt Cancer Center & Research Institute, Tampa, FL
Background: Patients (pts) with multiple myeloma (MM) refractory to
bortezomib (BTZ) and an immunomodulatory drug have limited treatment
options and a poor prognosis. In a phase I study of pts with relapsed or
relapsed/refractory MM treated with panobinostat (PAN) � BTZ, clinical
responses were observed overall and in pts with BTZ-refractory disease. We
report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts.
Methods: PANORAMA 2 is a single-arm, phase II study of PAN � BTZ �
dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment
phase 1 (TP1) consists of eight 3-week cycles of oral PAN �
intravenous BTZ � oral Dex. Pts demonstrating clinical benefit enter
treatment phase 2 (TP2) which consists of four 6-week cycles of PAN �
BTZ � Dex. The primary endpoint is overall response (� partial response
[PR]) in TP1. Results: Fifty-five pts with BTZ-refractory MM were enrolled
with 10 pts ongoing and 28 in follow-up. The median age was 61 years
(range 41-88 years). Pts were heavily pretreated: the median number of
prior regimens was 4 (range 2-11), and most pts (64%) received prior
autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts
had BTZ and Dex in their most recent prior line of therapy, respectively.
Eighteen pts achieved � PR for an overall response rate of 33% (1 near
complete response and 17 PR), and 13 pts achieved MR for a clinical
benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed
TP1 and entered TP2, and 2 have completed � 12 cycles. Common
adverse events (AEs) of any grade included thrombocytopenia (66%),
fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia
(38%), decreased appetite (36%), and dizziness (36%). Common grade
3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%),
pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt
(2%) experienced grade 3/4 peripheral neuropathy. Conclusions: PAN
synergizes with BTZ in recapturing responses in heavily pretreated,
BTZ-refractory MM pts. The combination of PAN and BTZ is a promising
treatment for pts with BTZ-refractory MM that is generally well tolerated,
with several pts receiving therapy long term.
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