FEATURE
Drawing First Blood
or she needs to change treatment. That’s a
subtle point that is often lost in these discus-
sions. I find value in those endpoints; they
are prognostic endpoints more than anything
else and are laudable goals. However, I think
sometimes people – both patients and doc-
tors – get too hung up on achieving a certain
number, without realizing what that number
may or may not mean.
Also, many trials demonstrating the benefit of
achieving MRD negativity did so in the context of
limited or no maintenance; we may get different
results if we extrapolate those results to patients to
whom we give risk-adapted maintenance therapy
or continuous maintenance therapy.
Dr. Richardson: Keep in mind, though – these
endpoints are valid tools for regulatory ap-
proval, which is a different issue. The important
question is whether achieving these endpoints
should change our clinical practice. I don’t
think we can answer that yet. We don’t know
enough about exactly what these endpoints
mean clinically in terms of treatment choices.
But are they helpful from a regulatory point of
view? Yes, I believe they are.
Dr. Lonial: The randomized, phase III CASTOR
and POLLUX trials, which served as the basis
for the approval of daratumumab, demon-
strated early improvement in progression-
free survival (PFS) with the combinations of
daratumumab and either lenalidomide and
dexamethasone or bortezomib and dexametha-
sone. 3,4 The data also suggested improvement
in overall survival (OS), although those have
not yet been reported as clearly statistically
significantly different.
In both trials, more patients in the
daratumumab-treated groups achieved MRD-
negativity than in the comparator arms. In
POLLUX, 22.4 percent of daratumumab-treated
patients met criteria for MRD-negativity, at a
threshold of 10 -5 , compared with 4.6 percent
in the control group (p<0.001). In CASTOR,
18.3 percent, 10.4 percent, and 4.4 percent of
daratumumab-treated patients achieved MRD-
negativity at thresholds of 10 -4 , 10 -5 , and 10 -6 ,
respectively. What is often lost when people
look at these data, though, is the difference in
the methods for assessing MRD. Those are three
different benchmarks for MRD-negativity, and
not all levels of negativity are the same. When
thinking about MRD as a pathway to cure or to
achieving the longest-possible PFS and OS, we
want to use the most stringent response (10 -6 )
as an important endpoint. People need to read
these data critically and understand that every
MRD – and every study – is not the same.
Dr. Richardson: I completely agree with Dr.
Lonial, and I would add the following: What’s
so interesting in these trials is that, in com-
parisons of MRD-negativity rates between
the control groups and the triplet groups, the
outcomes for both groups correlated with each
other, which is an important validation. Having
said that, what’s even more clinically interesting
to me is that patients who are MRD-positive,
regardless of duration, did better with the trip-
let regimen than the two-drug regimen. You
126
ASH Clinical News
may think, “Well, that’s obvious.” But, I would
argue that this information gives us clues for
combining various therapeutic modalities. For
example, we may not need as much for MRD-
negative patients, but we absolutely need more
treatment for MRD-positive patients.
Newer treatments have offered us the op-
portunity to add more therapy when we need
to, without an adverse effect on quality of life.
They offer novel, entirely non–cross-resistant
mechanisms of action – be they antibodies, im-
munomodulators, proteasome inhibitors, other
small molecules, or a part of this whole emerging
platform of cellular therapy or immune therapies.
But it is remarkably plastic, even within one pa-
tient over time. For clinicians making treatment-
sequencing decisions, that’s an important factor
to understand because it means we have to be
particularly cautious to avoid a “one-size-fits-
all” treatment model.
Conversely, the best evidence we have for
length of treatment is that it should continue
until disease progression and/or treatment intol-
erance. However, monitoring MRD, for example,
may provide us with the opportunity to offer
patients a “drug holiday” at certain times. Per-
sonally, I am very cautious about that because, at
the end of the day, the disease may recur.
Dr. Lonial: That seems to be where our cur-
“[Myeloma] is
remarkably plastic,
even within one
patient over time.
... We have to
be particularly
cautious to avoid
a ‘one-size-fits-all’
treatment model.”
—PAUL RICHARDSON, MD
Dr. Lonial: Yes, the availability of new drugs and
new targets has given us the opportunity to talk
about cure versus control in a much different
way than we did before.
In plasma-cell disorders, we have settled
on a paradigm of continuous maintenance.
The new tools we have, though, mean that it
may be time for us to think about how we can
give treatment for a defined period of time. We
need to ask ourselves whether we are potential-
ly increasing the cure fraction, as opposed to
just keeping people on continuous therapy and
adding one drug, two drugs, and three drugs to
their maintenance approach.
Perhaps there is a growing subset of
patients in whom we have either eliminated
disease or caused remission long enough that
PFS and OS will be outstanding.
Dr. Richardson: I agree with that, but our chal-
lenge is to just remain cognizant of the fact
that maintenance is a standard of care. Every
patient probably will have an absolute need for
some form of continuous therapy to achieve
the goals that we have discussed. We may need
a backbone of specific drugs, to which we can
rationally add additional agents according to
specific patient needs, to achieve those goals. In
other words, we will be able to tailor therapy to
optimize outcome.
Myeloma is a complex disease. It’s not one
disease; it varies enormously between patients.
rent level of evidence stands, but I do think we
need to challenge ourselves to think beyond
that model. I have patients, as I’m sure you do,
who have been on continuous maintenance for
seven, eight, or nine years. There does come a
point when the patient and the clinician start to
ask, “Are we really doing any good here? Have
we already achieved the maximum benefit that
we’re going to get?” And we don’t know the
answer to that.
Yes, the present paradigm is treatment
until progression. The newly available tools and
drugs haven’t been fully incorporated into the
treatment model, though, so maybe we can start
to think about how to define when a patient can
stop therapy. Ultimately, that is a sustainable
model, while the continuous-treatment model
involving one-, two-, three-, or four-drug regi-
mens until progression becomes unsustainable
over time.
Dr. Richardson: Another factor to be aware of –
and it is a point that is relevant to all discussions
about treatment sequencing – is that, at the end
of the day, we have to face the reality of costs.
There’s an important distinction between
value of therapy and actual price, so we also
need to treat patients in a financially respon-
sible fashion. Going forward, we need to
consider costs, because we must be able to pro-
vide our patients with sustainable therapeutic
approaches. What I fear is a model where clini-
cians are constrained, not by clinical evidence
and good science, but by overzealous regula-
tory authorities worried about price alone.
As members of our academic and research
community, it behooves us to study real-world
combinations and strategies to provide cost-
effective options, because they increasingly
matter. We can, and need to, conduct elegant
studies with the best-available agents, but we
also must evaluate the most rational and least
financially toxic combinations. By doing so,
such real-world clinical research can be of
particular value to our community colleagues
and our patients. ●
REFERENCES
1. Holstein SA, Suman VJ, McCarthy P. Update on the role of lenalidomide in
patients with multiple myeloma. Ther Adv Hematol. 2018;9:175-90.
2. Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance
of response in multiple myeloma after stem cell transplantation. Blood.
2011;118:529-34.
3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and
dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31.
4. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and
dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-66.
December 2018