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Lenalidomide (Revlimid ®)
Lenalidomide in Relapsed/Refractory Multiple Myeloma
Studies with lenalidomide among patients with relapsed and refractory MM
demonstrate that this analogue can overcome drug resistance, including
thalidomide resistance.1,2 Two phase I trials of lenalidomide demonstrated
promising activity as well as decreased toxicity in heavily pretreated patients
with relapsed, refractory myeloma. From a phase I study published by Richardson
and colleagues, the safety and tolerability of lenalidomide at doses of 5-50 mg
daily was investigated in patients with refractory/relapsed MM.1 These patients
failed to respond to ≥ 2 previous chemotherapy regimens. Patients with MM with
prior thalidomide therapy were allowed, provided no intolerance or
hypersensitivity had occurred. Dose levels were 5, 10, 25 or 50 mg daily of oral
lenalidomide for 21 days followed by a 1-week rest period and repeated every 28
days. Twenty-seven patients (median age, 57 years) had received a median of 3
previous regimens (range, 2-6 regimens); all had relapsed disease, and 18 (72%)
were refractory to salvage treatment. Two patients were removed from the study
on day 1 because of rapid disease progression. Fifteen of the remaining 25
patients (60%) had undergone previous high-dose chemotherapy with peripheral
stem cell transplantation, and 16 (64%) had received previous thalidomide
therapy. The first cohort (receiving 5 mg daily; n = 3) was treated for 28 days
without any dose-limiting toxicity (DLT). In the second cohort (10 mg daily), 1
patient had dose-limiting grade 3 leukopenia and neutropenia. Three additional
patients were enrolled on the second cohort and tolerated therapy without
significant toxicity. No patients on the third (25 mg daily; n = 3) or fourth
(50 mg daily; n = 13) cohorts developed DLT in the first 28 days. However, 2
patients from the third cohort did develop grade 3 thrombocytopenia and grade 4
neutropenia, respectively, during the second month or therapy and were
subsequently removed from the study. The overall median duration of therapy was
6 months. The side effects related to thalidomide, namely, somnolence,
constipation, and neuropathy, were not encountered; however, other adverse
events included grades 1 and 2 rash, fatigue, lightheadedness, and leg cramps.
As a result of grade 3/4 myelosuppression developing beyond the first 4 weeks of
therapy in 12 of the 13 patients at the 50-mg-daily cohort, the authors
concluded that 25 mg daily was the maximum tolerated dose (MTD) for lenalidomide.
Stable disease (SD) or minor response ( 25% reduction in myeloma protein) was
observed among 19 of 24 patients (79%) who received ≥ 28 days of therapy,
including 11 patients (46%) who had received previous thalidomide. The median
time to best response with the use of single-agent lenalidomide was 2 months
(range, 1-11 months), with a median duration of response of 6 months (range,
2-14 months). In another phase I trial by Zangari et al of 15 patients with
advanced MM, the MTD of 25 mg daily of lenalidomide was confirmed. These studies
established the MTD and a firm foundation for continuing trials with
lenalidomide alone or in combination with other active agents in MM.2
Combination of Lenalidomide and Dexamethasone and Chemotherapy
Preliminary results of a randomized, phase III, double-blind, placebo-controlled
study (North American trial MM-009) of lenalidomide/dexamethasone versus
dexamethasone alone in patients with relapsed/refractory MM was reported at the
10th International Myeloma Workshop in Sydney, Australia.3 The MM-009 trial
enrolled 341 patients (170 on the combined arm and 171 on the dexamethasone
alone arm). Lenalidomide 25 mg daily was administered along with dexamethasone
40 mg orally on days 1-4, 9-12, and 17-20 every 28 days versus dexamethasone
(same dose as outlined above) with placebo in the other group. The combination
yielded a significantly higher response rate (RR; 61% vs. 23%; P < 0.001). In
the combination arm, 27% of patients exhibited a complete response (CR), 35%
exhibited a partial response (PR), and 28% exhibited SD. Time to progression (TTP)
was significantly prolonged by the addition of lenalidomide to dexamethasone (>
15 months vs. 5.1 months, respectively; P < 0.0000001). Toxicities included
grade 3/4 neutropenia (24%), thrombocytopenia (11%), anemia (11%), and VTD
(10%). The incidence of VTD was comparable with the general MM population
observed in retrospective analyses.4 In an updated report at the 41st Annual
Meeting of the American Society of Clinical Oncology in Orlando, Florida, Weber
et al presented data from the European sister study (MM-010).5 In this study,
351 patients were enrolled (176 on the combination and 175 on the dexamethasone
alone arm). The overall RR was similar at 58%. Complete response and TTP rates
were lower compared with the MM-009 study (14% vs. 27% and 13.3 months vs. > 15
months, respectively). The incidence of VTD was also lower compared with the
North American study (8.5% vs. 15% [updated]). The toxicity profile revealed
very low incidence of fatigue, constipation, and neuropathy but increased grade
3/4 hematologic events. Due o the increased incidence of VTD, the authors
recommended consideration of prophylactic anticoagulation.
Pegylated Doxorubicin (Doxil ®) in combination with Lenalidomide
At Cleveland Clinic, we combined pegylated doxorubicin (Doxil®), vincristine,
and dexamethasone regimen with lenalidomide in a phase I/II study of patients
with refractory/relapsed MM.6 Study objectives included MTD, safety, and
efficacy. Lenalidomide was administered orally at doses of 5, 10, and 15 mg
daily for 21 days every 28 days in cohorts of 3-6 patients. Patients were
treated for ≥ 4 cycles and a maximum of 2 cycles after best response.
Maintenance therapy included continuation of lenalidomide with the addition of
prednisone 50 mg every other day until disease progression. Low-dose
acetylsalicylic acid (81 mg) was administered for VTD prophylaxis. Twenty-four
patients were enrolled on the study (18 of whom had refractory disease). The
overall RR was 70% (CR or near CR, 36.5%). An additional 32.5% of patients
exhibited SD. Grade 3/4 adverse events included neutropenic fever (9%),
neurologic events (14%), VTD (9%), and tumor lysis (9%). This novel combination
appears to be active with manageable toxicities.
Lenalidomide and Dexamethasone in the First-Line Setting
The encouraging results in the relapsed/refractory setting resulted in a phase
II trial to assess the response rate and toxicity of the lenalidomide/dexamethasone
combination in the first-line setting.7 In this recent phase II trial,
lenalidomide was combined with dexamethasone in 34 newly diagnosed, previously
untreated patients with MM. Lenalidomide 25 mg daily was administered orally on
days 1-21 of a 28-day cycle. Dexamethasone 40 mg daily was given orally on days
1-4, 9-12, 17-20 of each cycle. Thirty-one of 34 patients attained an objective
response; 2 patients (6%) exhibited a CR, and 11 (32%) met criteria for both
very good PR and near CR, resulting in an overall objective RR of 91%. Of the 3
patients without an objective response, 2 experienced a minor response and 1
exhibited SD. Forty-seven percent of patients developed grade ≥ 3 nonhematologic
toxicity, including fatigue (15%), muscle weakness (6%), anxiety (6%),
pneumonitis (6%), and rash (6%).
Myelosuppression was minimal, most likely reflecting the preserved bone marrow
reserve in this group of previously untreated patients. All patients were placed
on acetylsalicylic acid prophylaxis, based on the efficacy of acetylsalicylic
acid in preventing VTD among patients treated on the thalidomide/dexamethasone
regimen.8 Only 1 patient developed a VTD. No disease progression was noted to
date (10 months after the last patient was enrolled). The lenalidomide/dexamethasone
combination appeared to be a useful pre-transplantation conditioning regimen,
because there was no adverse effect on stem cell mobilization among these
patients.
With successful responses and better tolerability obtained from early phase I
trials, as well as in large randomized trials, lenalidomide is rapidly being
incorporated into first-line regimens. The Southwest Oncology Group and Eastern
Cooperative Oncology Group (ECOG) have ongoing randomized trials assessing
lenalidomide/dexamethasone as primary therapy in the first-line setting. The
ECOG compares lenalidomide/dexamethasone versus lenalidomide with low-dose
dexamethasone in an attempt to further diminish adverse events, while
maintaining the response rate.
Conclusion
IMiDs appear to have a different safety profile from thalidomide. Significant
sleepiness, constipation, or neuropathy is much less frequent. From the
published data, lenalidomide appears to have manageable side effects. The most
common grade 3/4 toxicities include myelosuppression (neutropenia,
thrombocytopenia) and VTD. Mild side effects include diarrhea, fever, muscle
cramps, rash, and fatigue.
Multiple myeloma has become a paradigm for translational research in the past
few years, with significant advances in the translation of novel biologically
derived therapies from bench to bedside. Studies of lenalidomide and CC-4047
have shown a significant clinical benefit in MM, along with an improved safety
profile and probable improved activity compared with thalidomide. It is
anticipated that lenalidomide and other IMiDs will become a significant addition
to the therapeutic armamentarium for MM therapy because of their more potent
immunomodulatory properties and their better tolerability. Further studies of
these orally bioavailable agents in patients with MM are warranted not only in
combination with other biologics and chemotherapeutic agents but with
thalidomide as well.
References
1. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug
CC-5013 overcomes drug resistance and is well tolerated in patients with
relapsed multiple myeloma. Blood. 2002;100:3063-3067.
2. Zangari M, Tricot, G, Zeldis, J, et al. Results of a phase I study of CC-5013
for the treatment of multiple myeloma (MM) patients who relapse after high dose
chemotherapy (HDCT). Blood. 2001;98:3226a.
3. Weber D, Chen C, Niesvizky R, et al. A Multicenter, Randomized,
Parallel-Group, Double-Blend, Placebo-Controlled Study of Lenalidomide Plus
Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects with
Multiple Myeloma. The 10th International Myeloma Workshop. Sydney, Australia;
2005:Abstract #738.
4. Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein
MA. Monoclonal gammopathy of undetermined significance and multiple myeloma are
associated with an increased incidence of venothromboembolic disease. Cancer.
2004;101:558-566.
5. Weber D. IMiDs- Results of Phase III studies in relapsed/refractory myeloma.
American Society of Clinical Oncology. Orlando, FL; 2005.
6. Hussein MA, Karam M, Brand C, et al. Doxil (D), Vincristine (V), Reduced
Frequency Dexamethasone (d) and Revlimid(R) (DVd-R) a Phase I/II Trial in
Advanced Relapsed/Refractory Multiple Myeloma (RMM) Patients. Blood (ASH Annual
Meeting Abstracts), Nov 2004; 104(11):208.
7. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide
plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood. 2005
(preprinted ahead online).
8. Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention
of thrombotic complications of thalidomide and anthracycline-based chemotherapy
for multiple myeloma. Mayo Clin Proc. 2005;80:1568-1574.
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