TRAINING and EDUCATION
How I Treat In Brief
Continued from page 29
the triplet combination of IMiD, PI, and dexametha-
sone and its favorable tolerability is now challenging
this paradigm. A rigid approach to AHCT upfront
use outside of clinical studies is now difficult to
justify and, given the acute and long-term toxicities
of AHCT, the role of transplant as part of upfront
treatment is an area of active research.
Again, participation in prospective trials is
encouraged as the treatment paradigm continues to
evolve and important unanswered questions remain.
Specifically, a key issue is the identification of patient-
and disease-specific markers, with the goal of expos-
ing only those who benefit from early AHCT to the
procedure.
For those who are ineligible for or decide not
to participate in clinical trials, AHCT remains
an appropriate option. For patients preferring to
delay AHCT after induction/remission therapy, we
encourage them to harvest stem cells as soon as a
sustained best response is reached (e.g., very good
partial response or better).
Tandem transplant
Randomized clinical trials have shown superior
response rates with tandem AHCT, but the effects
on survival have been less clear. Given these results
and the concerns of cumulative long-term marrow
toxicity from double high-dose alkylation, we do
not recommend routine tandem AHCT outside of a
clinical trial.
Allogeneic transplant
Given that the results of several trials comparing
AHCT and allogeneic hematopoietic cell transplan-
tation (alloHCT) in the upfront setting have failed
to show any consistent benefit with alloHCT, and
the non-relapse mortality rate has been significantly
higher with alloHCT, it is not recommended as a
firstline approach. However, a reduced-intensity
approach alloHCT can be considered in the salvage
setting for younger patients with good performance
status and high-risk cytogenetic features, preferably
in the context of a clinical trial.
Consolidation
Consolidation following AHCT consists of a short
course of multiagent therapy with a goal of improv-
ing the depth of the response and prolonging clinical
benefit. Several randomized trials have evaluated
different post-AHCT approaches, and all have
shown an improvement in depth of responses but
did not provide an OS benefit.
Ongoing trials like BMT-CTN 0702, which is
evaluating the addition of RVD consolidation or a
second AHCT versus a single AHCT followed by
lenalidomide maintenance, are still preliminary, and
other trials have shown a progression-free survival
(PFS) benefit with consolidation treatment. Given
the differing results, our approach is to offer two to
four cycles of RVD after AHCT in high-risk patients
and for those who do not achieve complete response
after transplant.
Maintenance and Continuous Therapy
Despite the improvement in PFS and OS with novel
approaches and AHCT, relapses are inevitable for
most patients with MM, primarily due to incomplete
eradication of residual disease. Maintenance therapy
is intended to prolong and deepen the response to
previous induction, with or without AHCT.
34
ASH Clinical News
Although first
Fast Facts
attempts at mainte-
✓ ✓ In younger patients with newly diagnosed MM, active treatment
nance therapy using
should be initiated as early as possible.
conventional chemo-
therapy, steroids, or
✓ ✓ Several factors should be considered during the planning of a
interferon-
treatment strategy, including logistics, out-of-pocket cost, drug
alpha proved
availability, social considerations, comorbidities, and patient
preference.
disappointing, the
introduction of
✓ ✓ Standard induction treatment should include a triplet regimen of
novel agents has
containing IMiD, PI, and steroids.
markedly restored
✓ ✓ Given the rapidly changing treatment paradigm and the efficacy
the potential of
of novel agent combinations, AHCT can reasonably be kept in
maintenance
reserve for patients who do not wish to initially pursue high-dose
therapy to improve
therapy.
clinical benefit.
✓ ✓ Postinduction continuous therapy with lenalidomide is
Our standard
recommended, with the addition of PIs as clinically appropriate.
of care for post-
AHCT consolida-
✓ ✓ New directions of research include the role of monoclonal
antibodies, vaccines, cellular therapy, and small molecules.
tion is lenalidomide
maintenance, which
is offered to all
patients undergoing
AHCT, with dose
adjustments and
schedule change
according to toler-
ability. Patients with high-risk disease characteristics,
When IMiDs are used, thromboprophylaxis
like del17p, are offered the addition of bortezomib.
should be initiated. For patients at a low risk for
For patients who are not willing to participate in
thrombosis, daily aspirin is associated with a low
clinical trials and who chose to delay AHCT, we of-
rate of deep vein thrombosis; for patients at higher
fer continuous therapy with both lenalidomide and
risk for deep vein thrombosis given other factors
bortezomib.
(such as prior history, immobility, and obesity),
Ideally, maintenance should be administered
therapeutic anticoagulation using low-molecular-
until disease progression; however, this approach
weight heparin or warfarin is recommended.
is not always feasible, and patients may require
Newer direct oral anticoagulants appear to be a
dose adjustment, schedule changes, and treatment
feasible new approach.
discontinuation if toxicity emerges.
To prevent skeletal events, we recommend
the use of intravenous bisphosphonates (such as
Minimal Residual Disease and Response zoledronic acid and pamidronate), regardless of
Assessment
whether bone lesions have been detected. Overall,
the benefits of bisphosphonate therapy should
Response criteria in MM rely on serum and urine
be weighed with their toxicities, and preventive
measurement of monoclonal proteins and bone
strategies must be instituted to avoid renal toxicity
marrow assessment. Recently, the IMWG has
or osteonecrosis of the jaw. The RANKL inhibitor
incorporated the measurement of minimal residual
denosumab was recently approved by the U.S. Food
disease (MRD), via multicolor immunofluorescence
and Drug Administration for the prevention of
flow cytometry and gene sequencing with sensitivity
skeletal-related events.
of up to 10 −5 , into MM response criteria.
Other measures of supportive care include
Meta-analyses have confirmed that MRD-
evaluation and management of neuropathy, cytope-
negative status after treatment of patients with
nias, and diarrhea common to PIs and IMiDs, with
newly diagnosed MM is associated with significant
neuropathy an area of particular importance.
improvement in survival and support the integra-
tion of MRD assessment in clinical trials. However,
Future Directions
another study showed that approximately 25 per-
cent of patients with MRD-negative disease still ex- The wide availability of options allows a tailored
perienced relapse at 36 months, despite better PFS
approach and also offers improved efficacy. Im-
and OS curves than patients with MRD-positive
mune function in MM has recently generated
disease. Newer approaches for measuring MRD,
great interest and is an active area of research, with
such as single-cell gene sequencing and serum cell-
several ongoing studies of checkpoint inhibition
free DNA, may more accurately assess MRD and
in combination with IMiDs, as well as monoclonal
complement existing methods.
antibodies, all of which have shown outstanding
activity in advanced disease.
Supportive Care
Other new directions for research include
vaccines,
cellular therapy, and small molecules,
For younger patients with newly diagnosed MM,
such as histone deacetylase inhibitors and other
general supportive measures include adequate hydra-
targeted therapies, as well as bone-targeting agents,
tion, low-impact exercise, weight control, avoidance
including denosumab. Participation in large phase
of nephrotoxic drugs, prevention of neuropathy, and
III trials investigating the best approach in younger
pain management.
patients with newly diagnosed MM is strongly
It is critical to monitor infection risk, and
recommended and should be considered for all
antiviral prophylaxis is recommended in patients
receiving PIs to minimize the development of herpes eligible patients. ●
zoster reactivation.
March 2019