Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy

Disclosures

Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

IMiDs as Maintenance Therapy

Transplant in MM is not curative and virtually all patients relapse. Maintenance therapy after transplant has been studied for more than three decades. Previous studies with interferon showed improvement in PFS but only a small survival benefit, if any. Because of its toxicity and inability to select patients who are likely to benefit from it, maintenance therapy with interferon has largely been discontinued.[80] With the availability of IMiDs that are better tolerated, their role in maintenance was explored.

Maintenance with thalidomide after ASCT has been associated with prolonged PFS in many studies,[36,81–83] although OS benefit has not been consistently demonstrated.[36,83] The MRC Myeloma IX study showed late survival benefit in patients with favorable interphase FISH defined by hyperdiploidy, t(6;14) and t(11;14) and absence of cytogenetic abnormalities gain(1q), t(4;14), t(14;16), t(14;20) and del(17p). The group conducted a meta-analysis of thalidomide maintenance trials and demonstrated similar late OS benefit in patients on thalidomide maintenance.[84] Long-term use of thalidomide is associated with considerable risk and high discontinuation rates related to toxicities such as severe neuropathy. For example, in the MRC Myeloma IX study, among patients who discontinued thalidomide maintenance, more than half of them (52.2%) discontinued before progression due to treatment-related AEs.[84]

Lenalidomide is better tolerated and may be more suited as a maintenance agent compared with thalidomide. Maintenance with lenalidomide has been evaluated in nontransplant and transplant settings. A randomized Phase III study MM-015 compared MPR-R versus fixed-duration MP or MPR in transplant-ineligible patients ≥65 years.[62] A total of 459 patients were randomly assigned in a 1:1:1 ratio to receive oral MPR-R (152 patients), MPR (153 patients) or MP (154 patients). The induction therapy consisted of nine 28-day cycles of melphalan 0.18 mg/kg (days 1–4), prednisone 2 mg/kg (days 1–4) and lenalidomide 10 mg (days 1–21) (MPR-R and MPR) or melphalan and prednisone with placebo (MP). After induction, MPR-R patients received lenalidomide 10 mg (days 1–21) maintenance until progression; MPR and MP patients received placebo.[62] Those with progressive disease could enroll in an open-label extension phase to receive lenalidomide 25 mg (days 1–21) ± dexamethasone 40 mg (days 1–4, 9–12 and 17–20). Both MPR and MPR-R regimens were superior to MP. With a median follow-up of 30 months, MPR-R reduced progression risk by 66% and significantly prolonged median PFS compared with MP (31 vs 13 months; p < 0.001) and MPR (31 vs 14 months; p < 0.001). Analysis showed that maintenance with lenalidomide reduced the risk of progression by 66% (p < 0.001). MPR-R however did not improve PFS in patients older than 75 years of age, which could be related to increased rate of AEs requiring frequent dose modifications in older patients than in <65 year individuals (74 vs 85% of planned dose intensity, respectively). The most common induction grade 4 hematologic AEs for MPR-R, MPR, and MP were neutropenia (35, 32 and 8%) and thrombocytopenia (33, 12 and 4%). Lenalidomide maintenance was generally well tolerated, with little evidence of cumulative toxicities. The 3-year risk of second primary tumor was 7% with MPR-R and 3% with MP (acute myeloid leukemia [AML] or myelodysplastic syndrome).

Two randomized controlled trials have evaluated the role of lenalidomide maintenance after ASCT. In Intergroupe Francophone du Myélome (IFM) 2005–02 study, 614 patients aged under 65 years with stable disease after firstline ASCT were randomized to receive two cycles of consolidation (25 mg/day on days 1–21 for 2 months) followed by maintenance with either lenalidomide (10–15 mg/day) until relapse or placebo.[85] Consolidation with lenalidomide improved the rate of CR or VGPR (58% before consolidation vs 69% after consolidation; p > 0.001). Maintenance therapy significantly improved the median PFS compared to placebo (41 vs 23 months with placebo; hazard ratio: 0.50; p < 0.001). The OS 3 years after randomization was however similar in the two groups (80% in lenalidomide group and 84% in the placebo group; p = 0.29).[85]

In another study (CALGB 100104) with very similar study design except that there was no consolidation phase, 460 patients were randomized after ASCT to receive lenalidomide or placebo.[86] Maintenance with lenalidomide was associated with a 63% reduction in risk of disease progression at 18-month follow-up with significantly fewer events compared to placebo (20 vs 44%; p < 0.001). TTP was 39 months for lenalidomide versus 21 months for placebo, leading to unblinding of the study by the Data Safety Monitoring Committee and crossover for those receiving placebo (86 of 128 eligible patients). At follow-up of 34 months, median TTP in the lenalidomide group was significantly higher than placebo group (46 vs 27 months in placebo; p < 0.001). Maintenance therapy with lenalidomide was associated with improved OS compared with placebo (85% in lenalidomide vs 77% of patients in placebo group were alive at 3 years; p = 0.03). More patients on the lenalidomide arm experienced grade 3 or higher AEs (p < 0.0001). There was higher incidence in second primary cancers in lenalidomide arm compared to placebo (8 vs 3% in placebo).[86]

These studies provide strong evidence of improvement in PFS with maintenance lenalidomide. However, many important questions remain – what is the magnitude of survival benefit, if any; are all patients eligible for maintenance or only those with less than a certain degree of response; significance of prognostic factors in selection of patients for maintenance; duration of therapy and long-term toxicities related to maintenance. Further studies are needed to answer these questions before long-term maintenance can be routinely recommended.

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