Keywords
hematology - medical oncology - myeloma - transplant
Multiple myeloma is a malignant plasma cell disorder that has witnessed a steady improvement
in survival over the past two decades. The overall survival (OS) in the past 20 years
has nearly doubled due to the progress in supportive care, drug therapy, and the increasing
use of autologous stem cell transplantation (ASCT).[1]
[2] Although ASCT alone has directly not led to an increase in OS, for all eligible
patients, the choice of first-line of treatment includes induction therapy, followed
by high-dose melphalan and ASCT.[3]
However, the role of ASCT as first-line therapy has been questioned with advances
in drug therapy for myeloma. Novel agents are associated with unprecedented response
rates, including very good partial response (VGPR) or better responses in over 70%
of patients on bortezomib/lenalidomide-based triplets.[4] Newer agents, including carfilzomib and daratumumab, have enabled minimal residual
disease negativity as a viable target in a significant majority of patients, questioning
the need for upfront transplantation.[5]
[6]
[7]
[8]
We provide a snapshot of data affirming the utility of ASCT in the current era and
highlight how the importance of ASCT is further amplified in resource-constrained
settings.
A few randomized trials have compared ASCT with chemotherapy alone for eligible patients.
The randomized IFM2009 trial published in 2017 compared lenalidomide–bortezomib–dexamethasone
(RVD) alone versus RVD with autoSCT and found significantly better progression-free
survival (PFS) and measurable residual disease (MRD) negativity in the autoSCT arm.[9] The phase 3 HO95 study also found an improvement in the 3-year PFS with autoSCT
compared with chemotherapy alone.[10] Randomized control trials (RCTs) comparing newer novel agents (daratumumab, carfilzomib, pomalidomide) with ASCT are expected in the
near future. Randomized data comparing ASCT with chemotherapy alone has been evaluated
by two meta-analyses, both of which included similar studies. The first study from
China included four RCTs of ASCT versus novel agents and found a significant improvement
in the PFS (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.44 to 0.73) with
no significant change in OS.[11] A meta-analysis published in JAMA in 2019 found similar results and concluded that
even in the absence of an OS benefit, autoSCT in the first remission should be preferred
due to high rates of deeper responses including MRD negativity, low treatment-related
mortality (TRM), and PFS benefit.[12] As of now, no treatment option has shown enough benefits to replace ASCT as the
standard of care, which must be used for all eligible newly diagnosed patients.[13]
Nevertheless, the utilization of ASCT for myeloma worldwide has been less than ideal
but is slowly increasing with time. Data from the USA over 1995 to 2010 indicate the
utilization rates of less than 15%, being higher for younger patients.[14] Current data, derived from the SEER database, indicate a slight increase in the
utilization rate to ∼30% (8,371 transplants out of 30,000 newly diagnosed patients
in 2018). The Worldwide Network for Blood & Marrow Transplantation (WBMT) registry
also recorded a 107% increase in worldwide transplant activity for myeloma during
this period.[15] Increasing the use of first-line ASCT, even in settings with easy access to newer
drugs, indicates ongoing clinical benefits in the eligible patients. Additionally,
improving safety and reducing TRM with ASCT for myeloma over the past two decades
has allowed easier adoption of this treatment modality. The TRM in most centers in
India is less than 5% and typically averages 2 to 3%.[16]
In the absence of direct studies evaluating the utilization of ASCT for myeloma in
India, it is easy to realize that very few eligible patients proceed to transplant.
However, in resource-constrained settings, proceeding to transplant rather than continuing
on newer drugs has several tangible benefits.
Economic concerns and access to newer drugs play a significant role in treatment decisions
in low- and middle-income countries (LMICs). Compared with continued administration
of newer novel agents, ASCT is more cost-effective in the long run. ASCT has been
found to incur a cost of approximately Rs. 334,433 per QALY gained in India, and data
from India have demonstrated that it can be made more cost-effective with early initiation
of treatment.[18] Bortezomib and lenalidomide are now available as generics and available at a cost
of approximately USD 90 and USD 30 for a month of therapy, respectively.
However, the cost of newer agents such as carfilzomib and daratumumab is still formidable.
For instance, autoSCT in a public-sector hospital in India has been documented to
cost approximately INR 395,527 (USD 6,085), compared with approximately USD 33,000
for 16 doses of daratumumab and USD 9,333 for 6 months of carfilzomib alone (communication
with the drug company). The introduction of biosimilars or generic formulations may
make newer agents more cost-effective in the future but would need a detailed cost-effectiveness
analysis to guide the same.
Therefore, the best option for most patients is an early ASCT, with an aim to stall
a relapse for as long as possible. Eliminating a very effective treatment option such
as an ASCT is not a viable option for a resource-constrained setting such as India.
Another novel approach includes the use of outpatient transplantation, which now demonstrates
results similar to conventional transplants with a careful patient and site selection.[19] Various models of outpatient transplant, including total outpatient, mixed inpatient–outpatient,
or delayed admission can be adopted in an attempt to markedly reduce costs by reducing
the duration of hospital admission.
ASCT utilization is expected to be lower than Western data in India due to a multitude
of reasons including concurrent medical illness, lack of expertise or infrastructure
for ASCT at various centers, and financial factors, which can lead to withholding
this useful and cost-effective treatment for many patients. Inferring from daily practice,
several patients do not undergo this effective treatment due to the fear of complications
or after being advised against by family members and primary physicians.
Therefore, it is essential to compile collaborative data illustrating the rates of
the utilization of ASCT for myeloma and delineation of underlying reasons for the
same so that this efficacious and cost-effective therapy is provided to as many eligible
patients as possible.
