Palumbo_EU Haematology 03/03/2010 15:24 Page 86
Haematological Malignancies Lymphoproliferative Disorders
studies have assessed the association of dexamethasone-based Lenalidomide and Dexamethasone-based Regimen
regimens with the new drugs for the treatment of new MM patients The association of lenalidomide with steroids (RD) has been approved
who are not suitable for ASCT. in the US and Europe as treatment for relapsed/refractory myeloma.
Thalidomide and Dexamethasone-based Regimen In a newly diagnosed setting, a phase II trial evaluated the efficacy
Recently, two randomised clinical trials have compared thalidomide and safety of RD as initial therapy for MM (see Table 1).
13
Thirty-four
and dexametasone (TD) with dexamethasone alone
7,8
in newly patients were enrolled and were treated with an oral daily dose of
diagnosed MM patients ineligible for high-dose therapy (see Table 1). lenalidomide (25mg on days one to 21 of each 28-day cycle) and
dexamethasone (40mg/day on days one to four, nine to 12 and 17
The RR was high, about 65%, including a high CR/very good partial to 20). In order to prevent thrombosis, patients also received once-
remission (VGPR) rate (4–8% according to the studies). One of these daily aspirin (81 or 325mg at the discretion of the physician). The
studies also showed better long-term outcome in the TD arm, with combination was found to be highly effective, and among patients
time to progression (TTP) and progression-free survival (PFS) of 22.6 who did not receive high-dose therapy, the CR or VGPR rate was
and 14.9 months, respectively, versus 6.5 months for both in the 67%, including 24% CR. Two-year PFS and three-year OS were 59
dexamethasone-only arm.
8
and 85%, respectively. Half of the patients had grade 3 or greater
non-haematological toxicities (mostly fatigue). Myelosuppression
The TD regimen has also been compared with MP,
9
showing a non- was minimal.
statistically significant longer PFS (20.7 versus 16.7 months,
respectively) but a shorter overall survival (OS) (41.5 versus 49.4 Another phase III study compared RD with dexamethasone alone in
months, respectively) and shorter post-relapse survival (three versus 198 newly diagnosed patients.
14
The combination therapy was
6.7 months, respectively). superior in terms of RR (85.3 versus 51.3%, respectively) and one-
year PFS (77 versus 55%, respectively). The toxicity was higher in the
TD-related toxicity is generally high: deep-vein thrombosis (DVT), RD arm, especially in terms of neutropenia, infection and DVT (see
peripheral neuropathy (PN) and infection are the most frequent Table 1).
adverse events. Moreover, in patients ≥75 years of age a high early-
death rate and a high discontinuation of therapy was also observed.
9
In an attempt to evaluate the balance between safety and efficacy with
In patients ineligible for ASCT, TD is an effective regimen, but its toxicity different treatment schedules, a randomised phase III study compared
is very high and may explain the high incidence of adverse events, lenalidomide plus low-dose dexamethsone (Rd) versus lenalidomide
discontinuation of therapy and early death, which may influence long- plus high-dose dexamethasone (RD).
15
The OS was significantly
term outcomes. superior with Rd than with RD (96.5 versus 86%, respectively). As
expected, in the arm with high-dose dexamethsone there was an
The UK Medical Research Council (MRC) Myeloma IX study added higher incidence of grade ≥3 thromboembolism (22 versus 6%),
cyclophosphamide to TD combination (CTD) and compared it with the infection/pneumonia (15.7 versus 7.5%) and hyperglycaemia (9.7
conventional induction regimen MP in elderly newly diagnosed MM versus 6.6%) (see Table 1).
patients.
10
The ORR and CR rates were higher (see Table 1), but more
time is needed to evaluate the PFS and OS. Low-dose dexamethasone and lenalidomide was also combined with
clarithromycine, an antibiotic that seems to optimise the effect of
Offidani and co-workers presented the results of a phase II study in steroids and that appears to have immunomodulant properties,
which pegylated liposomal doxorubicin was added to TD (ThaDD) for especially the suppression of interleukin (IL)-6, interacting with IMiDs
the treatment of newly diagnosed and relapsed elderly MM such as lenalidomide.
16–18
Seventy-two patients have been enrolled
patients
11,12
(see Table 1). (see Table 1).
Patients presenting at least a minor response after six courses of Autologous transplantation was allowed for eligible patients. The
ThaDD were randomised to receive interferon-α plus dexamethasone responses were higher and rapid, with 70% of patients achieving at
(ID) or thalidomide plus dexamethasone (TD) until recurrence of least 50% paraprotein reduction after the first cycle. Among the 52
disease or intolerable toxicity. After six cycles of therapy, the overall patients who did not receive ASCT, 37% achieved a CR and 33% a
response rates (ORRs) included 30% of patients who achieved a CR, VGPR. At the moment of analysis, the two-year EFS was 97.2%. The
with a slight improvement of the response with maintenance in most common grade 3 or higher haematological adverse events were
both arms. neutropenia (19.4%), anaemia (13.8%) and thrombocytopenia (22.2%).
Among the more frequent non-haematological grade 3 or higher
After a median follow-up of 30 months, the two-year OS probability adverse events were myopathy (11.1%) and thrombosis (9.7%); the
was significantly better in the maintenance TD arm than in the ID arm latter occurred mainly in the context of aspirin interruption.
(84 versus 68%, respectively). Haematological toxicities related to
induction regimen were seen in 42% of patients, including 12% grade In a phase II trial, cyclophosphamide was added to lenalidomide and
3–4. Severe side effects related to thalidomide were DVT (14%), low-dose dexamethasone (RCd) for the treatment of newly diagnosed
fatigue (6%), constipation (4%) and tremors (4%). This regimen was MM patients, both eligible and not for ASCT.
19
The ORR was 83%,
shown to be effective for the treatment of elderly patients with newly including CR 2%, VGPR 38% and PR 43%. Grade 3–4 toxicity was
diagnosed MM. The toxicity was manageable in older fragile patients mainly haematological, while the non-haematological toxicities were
as well, and complications such as infection and DVT may be lower-grade and included neuropathy, diarrhoea, cystitis and
prevented with adequate antibiotic and antithrombotic prophylaxis. thrombosis. The RCd combination showed excellent activity in the
86
EUROPEAN HAEMATOLOGY
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100