CLINICAL NEWS
On Location Updates in Myeloma
potently inhibits the three proteolytic activities of the 20S
proteasome with specificity and activity distinct from that
of bortezomib and carfilzomib.” By irreversibly binding to
and inhibiting all three proteasome subunits, he and coauthors explained, the activity translates into longer duration of effect and potentially improved clinical activity.
Dr. Spencer and researchers enrolled 14 patients
(median age = 61 years; range = 31-69 years) into the 3
+ 3 dose-escalation section of the study. All patients had
received two or more prior therapies (including both
lenalidomide and bortezomib), and had been refractory
to their last therapy. Treatment was administered over
28-day cycles as follows:
• Marizomib – 0.3-0.5 mg/m2 delivered intravenously
over 120 minutes on days 1, 4, 8, and 11
• Pomalidomide – 3 or 4 mg once daily on days 1
through 21
• Dexamethasone – 10 mg once daily on days 1, 2,
4, 5, 8, 9, 11, 12, 15, 16, 22, and 23 of every 28-day
cycle
Safety, pharmacokinetics, proteasome inhibition, and
clinical response were assessed.
Five patients (36%) had high-risk cytogenetics, and all
patients were treated with a median of 4.5 prior therapies
(range=2-15). In addition to receiving prior bortezomib
and lenalidomide, 50 percent also had received prior
carfilzomib.
The most common marizomib-related adverse events
included: fatigue (5 patients), neutropenia (5), thrombocytopenia (3), anemia (3), and nausea (2).
One patient experienced tumor lysis syndrome (grade
2), and one patient had increased peripheral neuropathy (grade 1) related to pomalidomide. In addition, one
patient came off the study and subsequently died from
progressive disease.
All patients had a decrease in myeloma protein by the
end of their first treatment cycle.
Of the 11 patients with response data through the
third cycle of treatment, the researchers found that,
according to International Myeloma Working Group
criteria: six patients (54%) achieved partial response, two
(12%) experienced a minimal response, and three (27%)
achieved stable disease.
“Marizomib 0.4 mg/m2 caused near complete inhibition of the C-TL subunit as early as day 11 of the first
treatment cycle, with significant inhibition of the T-L and
C-L subunits evolving over time in whole blood assays
performed in all patients to date,” Prof. Spencer and colleagues wrote.
“Marizomib does not appear to add toxicity to the
established pomalidomide/dexamethasone safety profile,
and the combination of drugs demonstrated encouraging activity in some of the sickest patients with multiple
myeloma,” Prof. Spencer added during his presentation.
“I believe that this combination of drugs holds great
promise for the treatment of multiple myeloma.”
As no dose-limiting toxicity was observed in the preliminary results of this study, a dose-expansion stage of
the study is planned and will enroll 22 additional patients
who will receive marizomib (0.5 mg/m2), pomalidomide
(4 mg), and dexamethasone (10 mg). ●
REFERENCE
Spencer A, Spencer A, Badros A, et al. Phase 1, multicenter, open-label, dose-escalation,
combination study (NCT02103335) of pomalidomide (POM), marizomib (MRZ, NPI-0052), and
dexamethasone (DEX) in patients with relapsed and refractory multiple myeloma (MM); study
NPI-0052-107 preliminary results. Abstract OP-005. Presented at the 15th International Myeloma
Workshop, September 25, 2015; Rome, Italy.
48
ASH Clinical News
Pooled Analysis Shows Maintenance Therapy
Improves Survival in Multiple Myeloma
Though previous studies have indicated prolonged progression-free survival (PFS) with
maintenance therapy in patients with multiple
myeloma (MM), experts disagree about its effect
on overall survival (OS) and whether prolonged
treatment after complete response is necessary.
Chiara Cerrato, MD, from the University of Torino in Italy, and colleagues conducted a pooled
analysis of five clinical trials to clarify the role of
maintenance therapy in patients with a complete
response to treatment. The results were presented at the 15th International Myeloma Workshop.
Dr. Cerrato and researchers analyzed patient
data from five phase III trials: three including patients who were eligible for autologous
hematopoietic stem cell transplantation (AHCT)
and two including patients 65 years or older who
were ineligible for AHCT (TABLE 2).
TABLE 2.
conventional chemotherapy), Dr. Cerrato and
colleagues found that patients who continued
treatment after achieving CR had longer PFS
compared with those who did not receive maintenance therapy ac ross all subgroups, including:
• Patients who underwent AHCT (median
PFS=86 months vs. 40 months; HR=0.3;
p<0.0001)
• Patients <65 years old receiving conventional chemotherapy (median PFS=not reached
vs. 21 months; HR=0.2; p<0.0001)
• Patients ≥65 years old receiving conventional chemotherapy (median PFS=52 months
vs. 34 months; HR=0.5; p=0.003)
Phase III Trials Included in the Pooled Analysis
Trial
Induction
Maintenance
Patients eligible for AHCT
RV-MM 209
Melphalan/prednisone/lenalidomide and With or without lenalidomide
melphalan 200 mg/m2
RV-MM-EMN-441
Carfilzomib/revlimid/dexamethasone
and melphalan 200 mg/m2
HOVON-65/GMMG-HD4
Lenalidomide or lenalidomide/
prednisone
Bortezomib/doxorubicin/dexamethasone Bortezomib or thalidomide
Vincristine/doxorubicin/dexamethasone
Patients ≥65 years ineligible for AHCT
GIMEMA-MM0305
EMN01
Bortezomib/melphalan/prednisone/
thalidomide
Bortezomib/thalidomide
Bortezomib/melphalan/thalidomide
No further therapy
Lenalidomide/dexamethasone
Lenalidomide vs. lenalidomide/
prednisone
Cyclophosphamide/prednisone
Melphalan/prednisone
A total of 2,792 patients were analyzed: 2,330
patients (79%) received maintenance therapy;
503 (21%) of these patients had achieved a CR
prior to maintenance therapy (378 of whom
were transplant-eligible and 125 were transplantineligible). After a median follow-up of 47
months, the researchers identified a significant
advantage in terms of five-year OS and PFS (the
study’s primary endpoint) for patients who received maintenance therapy as part of the study
protocol:
• Five-year OS: 79% versus 59% (hazard ratio
[HR]=0.5; p<0.0001)
• Five-year PFS: 66% versus 20% (HR=0.3;
p<0.001)
“The role of maintenance therapy in MM has
been a subject of debate,” Dr. Cerrato noted
during her presentation, “but our study finds it
is really important to go on with treatment, with
a difference in OS and PFS in all patients with
drug-sensitive disease.”
In subgroup analyses by age (<65 vs. ≥65
years old) and type of treatment (AHCT vs.
In terms of OS, the researchers observed an advantage in both young and older patients receiving conventional chemotherapy (HR=0.4 and
0.5; p=0.06 and p=0.02, respectively). However,
there were no differences in OS among young
patients undergoing AHCT (HR=1.3; p=0.8).
In her presentation, Dr. Cerrato noted that
longer-term follow-up will be needed to confirm
whether maintenance therapy will improve OS
in younger patients.
In addition, the pooled analysis did not include
a crossover of patients from non-maintenance to
maintenance regimens, making it difficult to interpret the difference in OS.
“Maintenance treatment prolongs PFS, regardless of age and type of treatment, in CR patients,”
the authors concluded, “and maintenance is
particularly beneficial in patients with sensitive
disease.” ●
REFERENCE
Cerrato C, Gay F, Petrucci MT, et al. Continuous treatment improves survival of
newly diagnosed multiple myeloma patients achieving complete response: data
from 5 phase III trials including young and elderly patients. Abstract BP-017.
Presented at the 15th International Myeloma Workshop, September 23, 2015;
Rome, Italy.
November 2015