FEATURE
The way I look at the question about
the optimal timing of transplant is to consider AHCT like any other drug that’s out
there. Just because it has been around for
a while does not mean that it is any less
effective – particularly for a patient who
would rather receive one transplant versus
multiple rounds of chemotherapy.
Dr. Landgren: I agree, but I would stress
that the map of myeloma treatment is
being redrawn, and it has to include these
new drugs. There are many questions
lacking answers; at the same time, though,
almost 25,000 people are being diagnosed
with multiple myeloma every year in the
United States. They do not have time to
wait for new trials to be developed – they
need therapy now.
The IFM/DFCI trial you referred to
demonstrated similar overall survival
rates between upfront and delayed AHCT,
and improved progression-free survival
in the upfront transplant group. In my
opinion, though, the most important part
of the results from this study were presented separately at the 2015 ASH Annual
Meeting.
In a sub-analysis of the IFM/DFCI
data presented by Herve Avet-Loiseau,
MD, PhD, immediate AHCT increased
three-year progression-free survival
compared with delayed AHCT, as well as
overall survival and complete response
rates.5 This difference in progression-free
survival was driven by the proportion
of “good” responders in the two treatment arms. Indeed, he showed that there
were more complete responders in the
transplant arm, and that several patients
achieved a complete response in the
non-transplant arm. Importantly, when
progression-free survival was assessed
among patients who were MRD-negative,
the results were similar, independent of
treatment arm.
Mortality rates were low, but we still
need to see how transplant will affect
quality of life in longer-term follow-up.
Dr. Kumar: Nearly 20 years ago, research-
ers attempted to answer this question in a
trial designed to assess the optimal timing
of high-dose therapy and AHCT, comparing the combination of upfront AHCT
and high-dose therapy with conventionaldose treatment followed by AHCT as
rescue treatment.6 Rates of overall survival
were similar, irrespective of the timing of
transplant. However, event-free survival
was longer in the early-transplant group.
Most importantly, the quality of life was
much better among patients who received
AHCT early, with a longer average time
without symptoms, treatment, and treatment toxicity.
So, even though the length of overall
survival was similar, performing AHCT
early clearly led to a better experience
for the patient and was associated with a
shorter period of chemotherapy. In my
ASHClinicalNews.org
opinion, the potential benefit of performing a transplant early on in the treatment
course is the ability to have less intensive
chemotherapy and a better quality of life.
With the newer drugs, this overall paradigm has not changed.
“Randomized
trials have
consistently
demonstrated that
patients do
benefit from
receiving
AHCT.”
—SHAJI KUMAR, MD
And again, though newer therapies
are leading to higher response rates
for the vast majority of patients, recent
studies have continued to show that
patients being treated with newer agents
do benefit from early AHCT followed by
some type of maintenance therapy. The
results of the IFM/DFCI 2009 trial, which
were presented at the 2015 ASH Annual
Meeting, have provided us with some
answers to this clinical question.2 The
IFM group conducted a randomized trial
comparing outcomes for patients treated
with conventional therapy (8 cycles of
lenalidomide, bortezomib, and dexamethasone [RVD]) with or without AHCT (3
induction cycles of RVD, followed by stem
cell collection and AHCT conditioned
with melphalan 200 mg/m2, followed by 2
cycles of RVD as consolidation) in 700 patients with previously untreated myeloma.
Patients in the RVD arm were to receive
delayed transplant at the time of relapse.
Immediate AHCT increased threeyear progression-free survival compared
with delayed AHCT, as well as overall
survival and complete response rates.
Mortality rates were low, but we still need
to see how transplantation will affect quality of life in longer-term follow-up.
Dr. Landgren: The results of the small subanalysis presented by Dr. Avet-Loiseau
– though not definitive – raise a key question: What role does high-dose melphalan followed by AHCT have in a newly
diagnosed multiple myeloma patient who
has obtained MRD-negative status after
combination therapy?
In the absence of a formal study,
I think a reasonable statement to tell
patients is: “We have no strong data either
way. Based on our current knowledge, it
seems very reasonable to collect stem cells
and to go right to maintenance therapy
without high-dose melphalan followed by
AHCT.” In this setting, I would monitor
MRD status longitudinally. Extrapolating
into the future, if formal results from clinical trials continue to confirm and expand
on these observations, I envision that
myeloma treatment for newly diagnosed
patients will become response-driven.
In countries with access to modern,
powerful therapies, I conjecture that the
role of high-dose melphalan followed by
AHCT most likely will change. Instead of
being offered upfront to every myeloma
patient who can tolerate it, transplantation may move to a treatment given to
myeloma patients who do not obtain a
deep response after modern combination
therapy or those who relapse. For these
settings, transplant should be considered
in the context of all available treatment
options, and not as the default, “go-to”
option.
Dr. Kumar: That’s true. One of the things
myeloma specialists have come to realize
over the past few years is that myeloma
is heterogeneous. To som RW