2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MAINTENANCE THERAPY FOR MULTIPLE MYELOMA
drugs other than lenalidomide may predispose to SPMs. In
the IFM 2005–02 trial, the cumulative incidence of SPMs
was 3.1 per 100 patient-years. Risk factors identified in
multivariate analysis were treatment with lenalidomide,
being over age 55, male gender, ISS III, and induction DCEP
(IFM 2005–01 protocol). In the MM 015 study, the cumulative
incidence was 2.5 per 100 patient-years.
Palumbo A and colleagues 28 recently presented the pooled
data of 1,798 patients from nine European protocols. The
risk/benefit of lenalidomide maintenance therapy was
largely in favor of the IMiDs, either regarding the risk of
progression or the risk of death as a result of myeloma.
Therefore, the strong efficacy of continuous therapy with
lenalidomide outweighs the potential risk of SPMs. Longer
follow-up is needed to definitively assess the risk of SPMs
in patients receiving lenalidomide, especially in context of
alkylating agents.
With respect to bortezomib maintenance, only sporadic
SPMs were reported with an incidence rate of 0.3 per 100
person-years. 29 This advantage proved partially abrogated
by its specific toxicity profile, in particular the neurotoxicity.
After ASCT, in the HOVON joint trial, 22 57% of patients
started maintenance, of which 27% required dose reductions
and 9% discontinued bortezomib because of toxicity, mainly
peripheral neuropathy. Less than half of the patients could
receive the planned 2 years of maintenance.
In elderly patients, similar limitations were observed. In
the UPFRONT study, 24 50% of patients effectively received
the maintenance with 13% to 25% requiring dose reductions.
Surprisingly, maintenance with single-agent bortezomib was
well tolerated, with limited additional toxicity compared
with induction. In the Spanish trial GEM2005MAS65, 25 up
to 10% of patients experienced grade 3/4 peripheral neuropathy
and nearly 60% of patients discontinued bortezomib
Authors’ Disclosures of Potential Conflicts of Interest
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because of adverse events. Of note, 5% of deaths were
related to drug toxicity. The median duration of bortezomib
maintenance was 20 months (range: 1–36 months).
Overall, the neurotoxicity related to bortezomib will likely
limits its use as a maintenance agent and dose adjustments
as well as a limited administration are therefore suggested.
Conclusion
Currently, maintenance therapy with novel agents is not
approved in most countries. Thalidomide and bortezomib
effectively increase response rates and prolong PFS, but that
benefit is hampered by their neurologic toxicity likely making
them more useful as consolidation agents rather than
long-term maintenance.
Maintenance therapy with lenalidomide is clearly effective
in prolonging the duration of response and diminishing
the risk of relapse in frontline multiple myeloma patients
irrespective of their age. However, patients treated with
lenalidomide have the ongoing risk of new cancer and a clear
OS benefit has yet to be shown. In the case of elderly
patients, where one hopes to maximize the response to
upfront treatment, the current robust data supports the use
of lenalidomide maintenance in these patients, this balancing
the potential risk of SPMs.
In younger patients, whether lenalidomide maintenance
therapy should be routinely offered to patients is controversial.
The increased incidence of SPMs is an important risk
and we await for more mature survival data before making
firm recommendations in this regard.
Acknowledgment
We are indebted to Christopher P. Venner, MD, for his critical
reading of the manuscript.
Stock
Ownership Honoraria
Michel Attal Celgene;
Janssen-Cilag
Murielle Roussel Celgene;
Janssen
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REFERENCES
Research
Funding
Celgene;
Janssen-Cilag
Expert
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Other
Remuneration
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