Consensus panel opinion

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Review
Optimizing the use of lenalidomide in relapsed or
refractory multiple myeloma: consensus statement
Leukemia (2011) 25, 749–760; doi:10.1038/leu.2011.3; published online 4 February 2011
Presenter:R4劉耀中 醫師
Supervisor : 高志平 醫師
Aug 15, 2011,VGH
財團法人台灣癌症臨床研究發展基金會
Outline
 Brief introduction
 Optimal timing and duration of the therapy
 Use in special populations
 Prevention and management of adverse
events
 Consensus summary
About multiple myeloma
 Thalidomide, lenalidomide and bortezomib
positive effect on survival in MM.
 Treatment goal: the best possible response with
cytoreductive therapy or sustainment of disease
control.
 Lenalidomide: direct tumoricidal and
immunomodulatory effects quality of response,
and prolong the time to relapse and OS.
Mechanism of lenalidomide
Richardson P et al. Blood 2009;114:772-778
©2009 by American Society of Hematology
Treatment response
 Monotherapy of Len.: moderately active in relapsed or
refractory multiple myeloma (RRMM).
Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009
 Superior efficacy in Len/Dex for least one previous
therapy (Table 1).
 Approval of lenalidomide on the results of two
multicenter, randomized, placebo-controlled trials
comparing Len/Dex with placebo/Dex in patients with
RRMM.
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007
Approval of Len/Dex
13.5 months
4.7 months
13.5 months
8.4 months
4.7 months
4.6 months
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007
Subgroup analysis of Len/DEx
Subgroup analysis of Len/DEx
Subgroup analysis of Len/DEx
 In light of these emerging data, there is a need for
refinement of the recommendations regarding the
optimal use of Len/Dex in daily practice.
 In July 2010, an expert panel convened in Munich,
Germany, to discuss the available data and provide
practical recommendations.
 The following report summarizes the key points on
which the expert panel reached a consensus
regarding the use of lenalidomide in RRMM.
Outline
 Brief introinduction
 Optimal timing and duration of the therapy
 Use in special populations
 Prevention and management of adverse
events
 Consensus summary
What is the optimal time to initiate Len/Dex in
relapsing patients?
 More effective at first relapse
J Haematol 2009; 82: 426–432 Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince MH, San Miguel JF et al. Lenalidomide in combination with dexamethasone at first relapse in
comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur
What is the optimal time to initiate Len/Dex in
relapsing patients?
Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior
thalidomide exposure. Blood 2008
What is the optimal time to initiate Len/Dex in
relapsing patients?
 In VISTA trial: effective at first relapse who had or had not
received bortezomib as a part of the first-line therapy.
VISTAL trial: Mateos MV et al. J Clin Oncol 2010; 28: 2259–2266
 High-dose chemotherapy and ASCT does not appear to
affect the efficacy of Len/Dex
Reece D et al. Blood 2009; 114: 522–525.
 Advanced age, poor performance status, IgA-type disease
and advanced disease stage: not influenced
Lonial S, et al.. Haematol 2007; 92
 The efficacy in pts with/without RI and neuropathy:
comparable
Delforge M et al. Blood 2009; 114:
Consensus panel opinion
 Len/Dex is most effective when used at first
relapse.
 Len/Dex can be administered regardless of
the type of previous therapy.
What is the optimal starting dose of Len. when
combined with Dex.?
 25 mg once daily orally on days1–21 of each 28-day cycle.
 Based on two key factors: renal function and the presence of
cytopenias at baseline
What is the optimal starting dose of Len. when
combined with Dex.?
 Is G-CSF used concomitantly or very soon after
treatment initiation?  a short course of G-CSF (3
days) in certain cases, such increased bone marrow
infiltration.
Mateos MV et al. Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing
neutropenia under lenalidomide-based therapy? Br J Haematol 2008; 140: 324–326
Consensus panel opinion
 For renal impairment and cytopenia, the
starting dose of Len. should be reduced,
depending on the degree of impairment.
What is the optimal starting dose of
dexamethasone?

Len/Dex regimen, use of a lower total dose of dexamethasone:
1. Reduction in serious adverse events and early deaths, particularly
within the first 4 months, in newly diagnosed MM.
Rajkumar SV et al. Lancet Oncol 2010; 11: 29–37
2. Dex. enhances the tumoricidal effects of lenalidomide but partly
antagonizes its immunomodulatory effects,
Gandhi AK, et al. Curr Cancer Drug Targets 2010; 10: 155–167.
3. Association with improved tolerability and efficacy.
4. Standard, high-dose dexamethasone for certain cases, such as
cord compression, hypercalcemia or renal failure.
European Medicines Agency evlimid. Available from: http://www.emea.europa.eu. Accessed July 2010
High dose VS. low dose Dex.
Rajkumar SV et al. Lancet Oncol 2010; 11: 29–37
Recommendations on Dex. dose
Consensus panel opinion
 Low-dose Dex./Len. : better tolerability
without loss of efficacy.
 The recommended dose of Dex./ Len.
according to age in patients with RRMM is
shown in Table 3.
What is the optimal duration of Len/Dex
therapy?
 In MM-009/010, study treatment continued until
progression or unacceptable toxicity.
Dimopoulos M, . N Engl J Med 2007
 50% of patients with initial PR later achieved a CR or
VGPR and better longer median TTP and OS with
continued treatment.
Harousseau JL, et al.. Haematologica 2010; 95: 1738–1744
.
 Continuous therapy has a lower risk of death.
San Miguel JF, et al.. Clinl Lymphoma Myeloma Leuk 2010; E-pub ahead of print 26 October 2010
 Lenalidomide maintenance therapy after ASCT or as a
continuous therapy: prolong TTP
Attal M, et al. J Clin Oncol (ASCO Ann Meet Proc) 2010; 28
Figure 1. Accumulated maximum serum M-protein reduction
after lenalidomide plus dexamethasone by treatment cycle for
all patients achieving at least a partial response as best
response
Figure 2. Cumulative response by
treatment cycle for patients with
complete response (CR)/very good
partial response (VGPR) to
lenalidomide plus dexamethasone
(n=114)
Copyright ©2010 Ferrata Storti Foundation
Harousseau, J.-L. et al. Haematologica 2010;95:1738-1744
Consensus panel opinion
 Len/Dex may continue in responding patients
until evidence of disease progression.
 Treatment should continue at the best-
tolerated dose of each agent.
 Caution with long-term dexamethasone use
is required.
How often should patients be monitored
during therapy?
Consensus panel opinion:
 Pts without cytopenias may be monitored every 2
wks for the first C2–3.
 Pts with neutropenia or thrombocytopenia may
require more intensive monitoring.
 For continuous Len/Dex, monitoring at the start of
each new treatment cycle.
 Pts with RI may require more intensive
monitoring.
Outline
 Brief introinduction
 Optimal timing and duration of the therapy
 Use in special populations
 Prevention and management of adverse
events
 Consensus summary
Advanced age
 Pts into three groups (<65, 65–75 and >75
years), comparing Len/Dex with Dex alone:
1. RR to Len/Dex: similar in three groups and
higher than Dex alone.
2. Median TTP: higher in Len/Dex than in Dex
alone.
Consensus panel opinion:
Len/Dex is an appropriate treatment option for patients
with RRMM, regardless of age.
Lonial S, et al. Effect of Len/Dex in MM in different age groups. Haematol (EHA Annu Meet Abstr) 2007; 92(Suppl 2): (abstract PO-663).
Renal impairment
 In MM-009/010 study, pts with SCr>2.5mg/dl were
excluded.
 When assessed by CCr, however, 82 pts (24%) treated with
Len/Dex were deemed to have moderate RI (CCr 30–
60 ml/min) and 16 patients (5%) had severe RI (CCr
<30 ml/min) at baseline.
Dimopoulos M, et al. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple
myeloma patients with impaired renal function. Cancer 2010; 116: 3807–3814.
OS in severe RI: 18.4m
in moderate RI: 29.0m
in mild or no RI: 38.9m
Consensus panel opinion
 Len/Dex is safe and effective in patients with RI,
provided that the dose of lenalidomide is adjusted
appropriately according to the creatinine clearance at
each cycle.
Cytogenetic abnormalities
 Cytogenetic abnormalities such as del(13q), t(4;14) and del(17p):
poor prognostic factors in MM ongoing research with novel
agents
 Reece et al : RR and OS in Len/Dex with del(13q) and t(4;14)
were similar to normal pts. (Pts with del(17p): worse than those
without del(17p))
Reece D,et al. Blood 2009; 114: 522–525
Reece D,et al. Blood 2009; 114: 522–525
Cytogenetic abnormalities
 Avet-Loiseau et al.: PFS and OS with del(13q) and t(4;14)
were lower. Results according to del(17p) status could
not be evaluated because of the low number of patients
with del(17p) (n=8).
Avet-Loiseau H, et al. Leukemia 2010; 24: 623–628.
Cytogenetic abnormalities
 OR and survival outcomes were lower in those with del(13q),
del(17p), t(4;14) and amp(1q21).
Dimopoulos MA, et al. Leukemia 2010; 24: 1769–1778.
 Response rates were similarly high in high-risk and standard-risk
patients (81 and 89%; P=0.56), but median PFS was lower in highrisk patients (18.5 vs 36.5 months; P<0.001).
Moreau P et al. Leukemia 2007; 21: 2020–2024
 Novel combinations of lenalidomide and bortezomib : overcome
the negative effects of certain cytogenetic abnormalities. (but
del(17p) remains poor)
Richardson P et al. Blood (ASH Annu Meet Abstr) 2008; 112
Consensus panel opinion
 More data are needed before definitive
recommendations can be made regarding the
influence of cytogenetic abnormalities on the
efficacy of Len/Dex.
 Enrollment in a clinical trial is recommended for
patients with del(17p).
Outline
 Brief introinduction
 Optimal timing and duration of the therapy
 Use in special populations
 Prevention and management of adverse
events
 Consensus summary
Myelosuppression
 In MM-009/010, neutropenia occurred early in the
course of treatment: the most severe within 6 months
(52%) and within 12 months (76%)
Lonial S, et al.. Blood (ASH Annu Meet Abstr) 2009; 114
Consensus panel opinion
 Neutropenia and thrombocytopenia often occur in
patients treated with Len/Dex, but are predictable and
manageable.
 Neutropenia can be managed with a combination of
growth factor support, lenalidomide dose
modifications or discontinuation.
 Thrombocytopenia can be managed with a
combination of platelet transfusions, lenalidomide
dose modifications or discontinuation.
Venous thromboembolism
 The risk of VTE is low as monotherapy with Len., but increases in
Len/Dex in elderly patients.
Rajkumar SV,et al.. Lancet Oncol 2010; 11: 29–37
 Concomitant use of EPO increase the risk of VTE
Rizzo JD,et al. J Clin Oncol 2008; 26: 132–149
 VTE in MM-009/010 was 16% : thromboprophylaxis was not a
requirement.
Dimopoulos M, . N Engl J Med 2007
 Prophylaxis with LMWH or low-dose aspirin effectively reduces VTE to
2–5%.
Klein U, et al.. Ann Hematol 2009; 88: 67–71.
 In previously untreated pts, aspirin prophylaxis: reduce the risk of VTE
from 75% (9 of 12 patients) to 15% (4 of 26 patients).
Zonder JA, et al. Blood 2006; 108: 403
Venous thromboembolism
a.High risk includes immobilization and previous history.
Consensus panel opinion
 Thromboprophylaxis for pts with Len/Dex.
 Aspirin for standard risk; LMWH for higher risk
 LMWH prophylaxis should continue for at least the
first four cycles and then switch to aspirin.
 Prophylaxis for the entire duration of treatment
 Len/Dex should be resumed in pts considered stable
on anticoagulation therapy.
Rash
 Rash has been reported in 16% of pts and more
likely occurrs during the first cycle.
Dimopoulos M, . N Engl J Med 2007
 Consensus panel opinion:
1. Antihistamines and topical steroids can use.
2. Len. discontinue permanently in pts with diffuse,
desquamating, exfoliative or bullous rash.
Other adverse events
 Infection was reported in 14% of pts in MM-009/010
Dimopoulos M, . N Engl J Med 2007
 Muscle cramps was reported in 30% pts.
European Medicines Agency. Available from: http://www.emea.europa.eu. Accessed July 2010
 Dexamethasone-related myopathy, chronic non-
neutropenic infections, fatigue, psychological changes or
hyperglycemia.
Outline
 Brief introinduction
 Optimal timing and duration of the therapy
 Use in special populations
 Prevention and management of adverse
events
 Consensus summary
Consensus summary
 Len/Dex. is an effective and well-tolerated treatment
option for RRMM.
 Use as early lines of MM therapy and continue until
disease progression.
 In responding/stable pts, continuing Len/Dex is
associated with further improvement in the quality of
response and improved outcomes.
 Effective and safely in pts with RI (adjusted dose).
 Independent factor: age, PS and disease stage.
Consensus summary
 Resistance to previous MM therapies reduces response to
Len/Dex.
 More data are needed to determine the efficacy in pts with
cytogenetic abnormalities
 VTE can be minimized with proper prophylaxis, particularly in
high-risk
 Neutropenia and thrombocytopenia can be managed (G-CSF
support, platelet transfusions).
 Further, in pts with RRMM, Len/Dex is most effective when
administered at first relapse as a continuous long-term
treatment
Thank you for your listening
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