NEWS
Study Supports Use of AHCT Over VMP as Intensification
in Newly Diagnosed Myeloma
In patients with newly diagnosed myeloma, following
induction chemotherapy, early autologous hematopoietic
cell transplantation (AHCT) as intensification
therapy prolonged progression-free survival (PFS),
compared with the three-drug regimen of bortezomib,
melphalan, and prednisone (VMP), according to
findings published in The Lancet Haematology. Double
AHCT was better than single AHCT, and subsequent
consolidation therapy with bortezomib, lenalidomide,
and dexamethasone (VRD) also led to longer PFS,
compared with no consolidation.
“[This study] was designed to prospectively address
two widely debated issues in the field of multiple
myeloma: the role of upfront AHCT as intensification
therapy in the era of highly active novel agents,
and the role of consolidation therapy following the
intensification phase,” explained lead study author
Michele Cavo, MD, of the Bologna University School
of Medicine in Italy, and colleagues. Dr. Cavo told ASH
Clinical News that these findings may be relevant to
clinical care, as post-AHCT consolidation therapy is
not widely used in daily clinical practice and is not
uniformly recommended in E.U. national and international
guidelines. In the U.S., VMP is rarely used,
bortezomib, cyclophosphamide, and dexamethasone
(VCD) is uncommonly used as induction, and lenalidomide
or bortezomib maintenance are commonly
administered after AHCT.
The phase III study included 1,503 patients with
untreated myeloma from 172 academic and community
practice centers in Europe. Patients were between
18 and 65 years of age and presented with symptomatic
myeloma at stages 1 to 3. All participants had
measurable disease and a World Health Organization
performance status grade of 0 to 2.
A total of 1,197 participants received either 3 (n=635)
or 4 (n=562) cycles of VCD induction therapy. Following
induction, these patients were randomized to:
• VMP intensification (n=495)
• AHCT after high-dose melphalan 200 mg/m 2
(n=702)
In the VMP group, patients received four 42-day cycles
of intravenous or subcutaneous bortezomib 1.3 mg/m 2
(days 1, 4, 8, 11, 22, 25, 29, and 32) plus oral melphalan
9 mg/m 2 (days 1-4) and oral prednisone 60 mg/m 2 (days
1-4). In centers with a double AHCT policy, the first
randomization (1:1:1) was to VMP or single or double
AHCT, the researchers noted.
Patients then underwent a second randomization
to receive either:
• two 28-day cycles of VRD consolidation (n=449)
• no consolidation (n=428)
The VRD group received intravenous or subcutaneous
bortezomib 1.3 mg/m 2 (days 1, 4, 8, and 11), oral lenalidomide
25 mg (days 1-21), and oral dexamethasone
20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12). All patients in
both groups received maintenance therapy consisting
of oral lenalidomide 10 mg on days 1 through 21 of a
28-day cycle.
Patient characteristics were similar between the
study arms. The median ages were 58 years in the AHCT,
VMP, and no-consolidation groups and 57 years in the
VRD consolidation group. The median time from the initiation
of induction therapy to first randomization was
3.7 months. At time of data cutoff, the median follow-up
durations for the AHCT group and VMP group were 60.5
months and 59.4 months, respectively.
“ Upfront AHCT continues to
have an important role ...
even in the era of active
novel agents.”
—Michele Cavo, MD
The study’s primary endpoint was PFS, defined as
the time from randomization to either progression or
death from any cause. Secondary outcomes included
the proportion of patients who achieved a partial
response or higher, overall survival (OS), toxicity, and
quality of life.
In the first randomization, after a median follow-up
of 60.3 months, the investigators reported that AHCT
was associated with significantly longer median PFS,
compared with VMP intensification: 56.7 months vs.
41.9 months (hazard ratio [HR] = 0.73; 95% CI 0.62-
0.85; p=0.0001).
At the time of the first randomization, 485 of
1,197 patients (41%) had achieved a very good partial
response (VGPR) or higher, at similar proportions
in the AHCT and VMP groups (41% and 40%, respectively).
However, following intensification therapy, the
proportion of patients achieving at least a VGPR was
higher in the AHCT group: 64% versus 56% (p=0.020).
In addition, more AHCT recipients achieved at least a
VGPR as their best response (84% vs. 77%; p=0.002).
Some participating centers had a double AHCT
policy. The authors found that treatment with double
AHCT improved survival outcomes compared with
single AHCT. The 5-year PFS and OS rates were 53.5%
and 80.3% with double AHCT, compared with 44.9%
and 72.6% for single AHCT.
For the second randomization, consolidation with
VRD was associated with a significantly improved
median PFS versus no consolidation: 58.9 months
versus 45.5 months (p=0.014). However, there was no
significant difference regarding 5-year OS rates (77.2%
vs. 72.2%; HR=0.99 [95% CI 0.71-1.39]; p=0.96).
The investigators noted that grade ≥3 adverse
events (AEs) were more common in patients randomized
to AHCT compared with VMP, which included:
• neutropenia (79% vs. 29%)
• thrombocytopenia (83% vs. 16%)
• gastrointestinal disorders (12% vs. 5%)
• mucositis (16% vs. 0%)
• infections (30% vs. 4%)
At least 1 serious AE was reported in 34% of patients
randomized to AHCT and 27% of patients randomized
to VMP. The most common serious AEs were infection
and infestation in the AHCT (56%) and VMP (37%)
groups.
Approximately 12% of the deaths from the time of
first randomization were considered likely related to
treatment. Of these deaths, 68% (n=26) occurred with
AHCT and 32% (n=12) occurred with VMP. The most frequent
causes of death included infections (21%), cardiac
events (16%), and second primary malignancies (53%).
“AHCT seems to be more effective than VMP intensification,
and consolidation therapy following the
intensification phase seems to be more effective than
observation in terms of PFS,” the authors concluded,
noting that study follow-up was short. “[These findings]
further support and extend the existing body of
evidence suggesting that upfront AHCT continues to
have an important role in the management of patients
with newly diagnosed multiple myeloma who are fit
for high-dose chemotherapy, even in the era of active
novel agents.”
The lack of information on patients’ quality of life
represents a limitation of the study, and, according
to the investigators, these analyses are ongoing and
will be reported at a later date. Another limitation,
explained Dr. Cavo, was the use of VCD as induction,
which is now known to be a less optimal induction
strategy than VRD or VTD (bortezomib, thalidomide,
and dexamethasone).
Dr. Cavo also noted that these findings will need to
be considered against recent data about four-drug regimens
in this setting. “The benefits seen with upfront
AHCT and subsequent consolidation therapy may be
less clear in light of recent data showing unprecedented
rates and depth of response with quadruplet therapies
incorporating a monoclonal antibody,” he concluded.
“[This] remains an open question that should be prospectively
addressed in future trials.”
Study authors report relationships with Janssen and
Celgene, which funded the study.
Reference
Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus
bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone
consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple
myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet
Haematol. 2020;7:e456-e468.
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