Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy

Disclosures

Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

Thalidomide

The clinical activity of thalidomide in relapsed MM was first reported in 1999 by Singhal et al..[21] Eighty four previously treated patients received single-agent oral thalidomide at doses ranging from 200 to 800 mg/day and an overall response rate (ORR) of 32% was observed. Lambda-type myeloma and presence of cytogenetic abnormalities were identified as predictors of poor outcome on multivariate analysis. Patients who received cumulative thalidomide doses in excess of 42 g in the first 3 months had a superior overall survival (OS).[22] Several other Phase II trials further confirmed its efficacy with response rates ranging from 28 to 66%.[23–25] Systematic review of Phase II clinical trials involving 1674 patients with relapsed/refractory MM showed an ORR of 29% and a median OS of 14 months with thalidomide monotherapy. Grade III/IV adverse events (AEs) included somnolence (11%), constipation (16%), peripheral neuropathy (6%), thromboembolism and rash (3%).[26]

In vitro studies showed that thalidomide enhances the anti-MM activity of dexamethasone.[27] On the basis of this observation, several Phase II studies tested the efficacy of the combination and response rates of 45–75% were reported in relapsed/refractory myeloma.[28–30] Rajkumar et al. conducted a double-blinded, placebo-controlled trial comparing thalidomide plus dexamethasone (TD) versus placebo plus dexamethasone (D) as induction therapy in previously untreated patients.[31] Patients in the TD arm received oral thalidomide 50 mg daily, escalated to 100 mg on day 15 and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dexamethasone 40 mg was administered on days 1–4, 9–12 and 17–20 during cycles 1 through 4 and on days 1–4 only from cycle 5 onwards. A total of 470 patients were enrolled and significantly higher response rates (63 vs 46%; p < 0.001) and time to progression (TTP; median: 22.5 vs 6.5 months) were observed favoring the TD arm. Grade 4 AEs were more frequent with TD than with D (30.3 vs 22.8%) and higher incidence of deep vein thrombosis (DVTs) was reported in the TD arm (18.8 vs 5.6%). The findings in this study led to accelerated approval of TD by the FDA in 2006 in newly diagnosed MM.

Thalidomide-based Regimens in Patients Eligible for Transplantation

ASCT is an important treatment strategy for eligible myeloma patients. Patients are typically treated with 2–4 cycles of induction therapy prior to stem cell harvest and either undergo ASCT as frontline or resume induction therapy, reserving ASCT as a delayed option at progression.[32]

Combination of TD demonstrated superior response in comparison to vincristine, doxorubicin (adriamycin) and dexamethasone (VAD) as induction therapy in preparation for ASCT and, as a result, emerged as the preferred induction regimen.[33–35] This was first demonstrated in a retrospective matched case–control analysis of 200 patients who entered two consecutive studies and received TD (n = 100) or VAD (n = 100) administered for 4 months before collection of peripheral blood stem cells and autologous transplantation. TD resulted in a significantly higher response rate in comparison to VAD (76 vs 52%; p < 0.001). DVT emerged as a significant toxicity, seen in 15% of patients receiving thalidomide.[33]

Inclusion of thalidomide into double-ASCT approach improved outcomes.[36,37] A trend for extended OS was seen among thalidomide-treated patients in one of the studies but this did not reach statistical significance (69 vs 53% at 5 years respectively; p = 0.07).[37] However, the incidence of thromboembolic events and peripheral neuropathy was higher in the thalidomide-treated group, in particular, with thalidomide maintenance leading to its discontinuation in 30 and 60% of the patients within 2 and 4 years of enrollment, respectively.[36]

The activity of thalidomide has been explored in combination with doxorubicin and cyclophosphamide as an induction regimen in transplant candidates. In the Phase III HOVON-50/GMMG-HD3 trial designed to evaluate the effect of thalidomide during induction treatment and as maintenance, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate compared with patients randomized to VAD (88 vs 79%; p = 0.005) and complete remission rates of 31 and 23% (p = 0.04), respectively, in favor of the thalidomide arm.[38] Thalidomide significantly improved the progression-free survival (PFS) from median 25 to 34 months (p < 0.001) and median survival from 60 to 73 months (p = 0.77). Superior rates of complete response (CR) were observed both before and after ASCT with TD and cyclosphosphamide compared with cyclophosphamide–VAD (post-transplant CR: 50 vs 37.2%; p = 0.00052) in MRC Myeloma IX randomized controlled trial.[39] There was a trend toward an OS advantage with cyclophosphamide–TD in a subgroup of patients with favorable interphase FISH.

Preclinical studies suggesting synergy among the novel agents provided rationale for combining thalidomide with bortezomib and dexamethasone (VTD).[40] High response rates seen in a small cohort of patients[41,42] led to a Phase III study comparing VTD versus TD as induction therapy before and consolidation therapy after ASCT.[43,44] Four hundred and eighty patients were randomly assigned to receive VTD or TD. Two hundred and thirty six on VTD and 238 on TD were included in the intention-to-treat analysis after six patients withdrew consent. Patients received three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days but not consecutively; total of 320 mg per cycle) either alone (TD) or in combination with bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8 and 11 (VTD). After double ASCT, patients received two 35-day cycles of their assigned regimen as consolidation therapy. After induction therapy, CR or near-CR (nCR) was achieved in 73 patients receiving VTD, and 27 patients on TD (31 vs 11%; p < 0.0001). Although CR/nCR rates before starting consolidation were not significantly different among the two groups (63.1% in VTD and 54.7% in TD), the response rates were significantly higher in VTD arm (CR: 60.6 vs 46.6% and nCR: 73.1 vs 60.9% respectively) postconsolidation. The rates of AEs observed with consolidation therapy were lower than that with induction therapy; grades 2 and 3 peripheral neuropathy in VTD versus TD groups of 8.1 vs 2.4%, respectively, with no other significant differences in frequency of overall and grade 3/4 AEs. PFS at 3 years was significantly longer for the VTD group (60 vs 48% for the TD group), suggesting that the superior outcome of VTD as induction therapy was retained and consolidation therapy after ASCT with the same regimen further contributed to improved clinical outcomes. Of note, the superiority was maintained in poor-prognosis patients including high International Staging System disease stage and adverse cytogenetic profile (t 4;14 and/or del 17p).[43,44]

Thalidomide Regimens in Patients Not Eligible for Transplantation

For patients not suitable for transplant, melphalan and prednisone (MP) were the mainstay of treatment for many years. After the availability of thalidomide, many trials compared the combination of thalidomide and MP (MPT) to MP. A meta-analysis of 1685 individual patients from six randomized controlled trials comparing MP and MPT (melphalan, prednisone and thalidomide) showed a significant benefit in OS favoring the MPT group (median OS time: 39.3 vs 32.7 months in MP group; p = 0.004).[45] The thalidomide regimen was also associated with superior PFS (hazard ratio: 0.68; 95% CI: 0.61–0.76; p < 0.0001) and better 1-year response rates (partial response [PR] or better was 59% on MPT and 37% on MP).[45] Subsequently, other studies have also shown better outcomes with the addition of a novel agent, IMiD or proteasome inhibitor to MP.[46–48] MP can no longer be regarded as the standard of care in transplant-ineligible patients. Improved response rates of MPT over MP were reported in two other meta-analyses supporting the use of MPT in elderly myeloma patients.[49,50] In all the studies, the improved responses came at the cost of increased toxicity with a significantly higher incidence of grade 3 or 4 hematologic toxicity, thromboembolism, peripheral neuropathy and neurologic AEs.[45,46]

TD was shown to be more effective than dexamethasone or VAD as induction therapy in transplant-eligible patients.[31] When this combination was compared with MP in the elderly patient population, although the CR and ORRs were better in the TD group (68 vs 50%; p = 0.002), the OS was significantly shorter (41.5 months in TD vs 49.4 months in MP; p = 0.024) along with increased thalidomide-related toxicity in the TD group.[51] Almost twice as many patients died in the first year of therapy in the TD group compared with MP arm from nonmyeloma-related causes, in particular infections and cardiovascular toxicity (28 vs 16%; p = 0.014). The OS was markedly shorter in patients older than 75 years in TD arm (median: 19.8 vs 41.3 months; p = 0.071). TD, therefore, is not recommended as a standard therapy in an elderly patient population ineligible for high-dose therapy and ASCT.[52]

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