Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy

Disclosures

Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

Lenalidomide

Studies assessing lenalidomide as secondline therapy in MM showed potent clinical activity including in thalidomide-treated patients.[53,54] Subsequent studies in newly diagnosed MM patients demonstrated improved efficacy with better safety profile, in particular, lower risk of neuropathy and thrombosis.

Relapsed or Refractory Myeloma

Richardson et al. conducted a Phase I dose-escalation trial of lenalidomide in 27 patients with relapsed or refractory MM in which the current dose of 25 mg/day was established.[55] ORR of 71% (17 of 24 patients had at least 25% reduction in paraprotein) was observed with no significant somnolence, constipation or neuropathy seen in any cohort. Lenalidomide demonstrated activity in drug-resistant patients including those with prior ASCT or thalidomide exposure. Phase II studies confirmed good tolerance and efficacy of lenalidomide providing basis for future studies in combination with dexamethasone and as monotherapy.[56]

Lenalidomide was approved for MM on the basis of data from two double-blinded placebo-controlled Phase III studies, MM-009 and MM-010.[53,54] Participants in both of the trials were >18 years of age and had received at least one prior therapy. Patients were randomly assigned to receive either 25 mg of lenalidomide or placebo on days 1–21 of 28-day cycle. All patients received 40 mg of oral dexamethasone on days 1–4, 9–12 and 17–20 for the first four cycles and only on days 1–4 with the subsequent cycles. Lenalidomide in combination with dexamethasone was associated with ORR of 60–61%, which was significantly better than the placebo arm (20–24%). The median TTP was longer in the lenalidomide group at approximately 11 months compared with 4.7 months in the placebo group (p > 0.001). Overall, 83.3% of patients treated with lenalidomide plus dexamethasone and 69.7% of patients in dexamethasone–placebo group experienced at least one grade 3 or 4 AE (p < 0.0001).[57] Neutropenia and hyperglycemia were the most common grade 3/4 AEs observed in the lenalidomide–dexamethasone and dexamethasone–placebo arms, respectively.

In a pooled update of these pivotal trials, which included 704 patients, treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%; p < 0.001), CR rate (15.0 vs 2.0%; p < 0.001), TTP (median: 13.4 vs 4.6 months; p < 0.001) and duration of response (median: 15.8 vs 7 months; p < 0.001) compared with placebo–dexamethasone group.[57] At a median follow-up of 48 months for surviving patients, a significant benefit in OS (median of 38.0 vs 31.6 months in placebo arm; p = 0.045) was retained despite the fact that 47.6% of patients assigned to dexamethasone plus placebo received lenalidomide plus dexamethasone at progression or study unblinding. Low β2-microglobulin and low bone marrow plasmacytosis were associated with longer survival. Of 704 patients, 39% were previously exposed to thalidomide. ORR was higher in the thalidomide-naive group compared with thalidomide-exposed patients (65 vs 54%; p = 0.04) with longer median TTP (median: 13.9 vs 8.4 months; p = 0.004) and PFS (13.2 vs 8.4 months; p = 0.02).[58] Lenalidomide also improved the TTP and PFS of patients previously treated with thalidomide, suggesting that thalidomide and lenalidomide are not cross resistant.

Newly Diagnosed MM

The Phase II trial by Rajkumar et al. showed a high ORR of 91% when lenalidomide was used in combination with dexamethasone in patients with newly diagnosed MM.[59] Thirty four patients were enrolled in the study. They were treated with 25 mg per day of lenalidomide on days 1–21 of a 28-day cycle and 40 mg per day of dexamethasone on days 1–4, 9–12 and 17–20 of each cycle. All patients received aspirin for thromboprophylaxis. Patients had an option to pursue ASCT after four cycles of treatment. Stem cells were successfully collected after four cycles of treatment. After initial therapy, 13 of 34 patients proceeded to ASCT. Long-term update of results reported 31 patients achieved an objective response defined as PR or better (95% CI: 79–98%) with a CR plus very good PR (VGPR) rate of 56%.[60] Among the 21 patients who did not proceed with ASCT, the depth of remission improved over time; CR and VGPR of 67% was observed.[60] The median time to response was 1 month. Grade 3 or more neuropathy was not seen (grade 1 and 2: 21%). Thrombosis was uncommon (3%). Fatigue, muscle weakness, anxiety and pneumonitis were the most common nonhematologic AEs, largely caused by dexamethasone.

Since a large proportion of toxicities in Phase II were related to high-dose dexamethasone, a Phase III trial was conducted to compare the efficacy of lenalidomide in combination with either high- or low-dose dexamethasone in newly diagnosed MM.[61] Patients were randomly assigned to lenalidomide (25 mg/day for 21 days) with high-dose dexamethasone (RD-40 mg/day on days 1–4, 9–12 and 17–20) or low-dose dexamethasone (RD: 40 mg/day on days 1, 8, 15 and 22). The overall response to therapy after four cycles was higher with high-dose dexamethasone (79%) than with low-dose dexamethasone (68.3%; p = 0.008). However, at second interim analysis at 1 year, the OS was significantly better in the low-dose dexamethasone group at 96% compared with 87% in the high-dose group (p = 0.0002) as a result of which the study was stopped based on the recommendations from independent data-monitoring committee. Patients in the high-dose group were crossed over to the low-dose group. The median PFS was 19.1 months (15.7–26.3 months) with high-dose dexamethasone versus 25.3 months (22.3 months, not reached) with low-dose group (p = 0.026). Most common toxicities were DVT (26 vs 12%) and infections. Thromboembolic events caused five (9%) deaths in the high-dose group and one (2%) in the low-dose group. Fifty six (27%) of 223 patients in the high-dose group and 37 (19%) of 222 in the low-dose group discontinued treatment due to AEs. Grade 3 or greater side effects were higher in the high-dose group in the first 4 months (52 vs 35%; p = 0.0001). These data established low-dose dexamethasone as the preferred regimen for most patients with MM.

MP had long been the treatment of choice in patients older than 65 years. Palumbo et al. evaluated the efficacy of combination of MP with lenalidomide (MPR) in transplant-ineligible patients aged ≥65 years.[62] There were improved response rates in MPR followed by lenalidomide maintenance therapy (MPR-R) and fixed duration MPR compared with MP alone (77 and 68%, respectively, vs 50% with MP alone; p < 0.001). The median PFS was significantly longer with MPR-R (31 months) than with MPR (14 months) or MP (13 months). Maintenance with lenalidomide reduced the risk of progression by 66% (p < 0.001), providing sustained disease control and suggesting that MPR-R is an effective treatment for patients with newly diagnosed MM not eligible for transplantation.

Multidrug Combination Therapy with Lenalidomide

Several novel agent combinations have proved to be superior to the traditional VAD. A pivotal trial by Rajkumar et al. established the efficacy of lenalidomide in combination with low-dose dexamethasone in newly diagnosed MM.[61] The 3-year OS of patients who received four cycles of induction with lenalidomide and dexamethasone followed by ASCT was 92%, compared with 55% who did not undergo ASCT.

Lenalidomide has been combined with other agents to further enhance efficacy, particularly in patients with adverse prognostic genetic factors. Lenalidomide–bortezomib–dexamethasone (RVD) combination was investigated in a Phase I/II trial and showed remarkable activity. Sixty six patients were enrolled in the study and received eight 3-week cycles of bortezomib 1.0 or 1.3 mg/m2 (days 1, 4, 8, 11), lenalidomide 15–25 mg (days 1–14) and oral dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12).[63] Phase II dosing was determined as bortezomib 1.3 mg/m2, lenalidomide 25 mg and dexamethasone 20 mg. All patients received thrombosis prophylaxis unless contraindicated. The regimen was the first of its kind to result in 100% response rate, most with deep responses with VGPR of 67% and CR–nCR of 39%. While VGPR is defined as ≥90% reduction in serum M-component plus urine M-component <100 mg/24 h (M-component is detectable by immunofixation but not on electrophoresis), negative immunofixation of serum and urine and <5% plasma cells in bone marrow is considered CR.[64] Responses were seen independent of cytogenetics though the sample size was small. Responding patients proceeded to maintenance or ASCT (28 patients, 42%). With median follow-up of 21 months, estimated 18-month PFS and OS for the combination treatment with or without transplantation were 75 and 97%, respectively. Post-hoc landmark analysis showed a low risk of progression after 1 year regardless of ASCT status. No treatment-related mortality was observed. Most common toxicities included sensory neuropathy (80%) and fatigue (64%) with mainly grade 2 neuropathy (23%; no grade 4 neuropathy was noted). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%) and thrombocytopenia (6%). Thrombosis was rare (6%).[63]

A Phase II trial by Kumar et al. examined the efficacy of addition of cyclophosphamide to lenalidomide and dexamethasone.[65] Treatment cycles consisted of lenalidomide 25 mg by mouth (p.o.) daily day 1–21, dexamethasone 40 mg p.o. weekly and cyclophosphamide 300 mg/m2 p.o. days 1, 8, 15 every 28 days. PR or better was seen in 85% of patients including 47% with a VGPR or better and CR of 2%. The toxicities were manageable with more than 80% of planned doses delivered; six patients went off study due to toxicity. Stem cells were collected successfully in all 31 patients in whom collection was attempted (75% with granulocyte-colony stimulation factor [G-CSF] mobilization alone and 25% with chemotherapy and G-CSF or plerixafor and G-CSF mobilization). The median PFS for the entire group was 28 months (95% CI: 22.7–32.6) and the OS at 2 years was 87% (95% CI: 78–96). Fourteen patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39).[65] The ORR was better for the high-risk patients, at 93% compared with 79% for the standard-risk patients. The 2-year PFS were comparable at 57 and 61% for the high- and standard-risk patients, respectively.[65] The ORR in high-risk MM patients in this study was better compared with those who received lenalidomide–dexamethasone combination in the study by Kapoor et al., suggesting that addition of an alkylating agent such as cyclophosphamide to lenalidomide-based regimens may improve the outcomes in MM with adverse genetic factors.[65,66]

Other combination therapies have included quadruplet regimens like VDCR, where cyclophosphamide was added to bortezomib, dexamethasone and lenalidomide (VDR). The EVOLUTION study evaluated bortezomib, dexamethasone and cyclophosphamide (VDC), VDR and VDCR in previously untreated MM. All the regimens were highly active and well tolerated but no significant advantage was observed with VDCR over the three-drug combinations. Higher incidence of hematologic toxicity was seen with the VDCR regimen despite a lower dose of lenalidomide (15 mg).[67]

Another quadruplet regimen that has been explored is incorporation of liposomal doxorubicin in RVD.[68] Seventy two patients received a median of 4.5 cycles. The maximum tolerated doses (MTDs) were lenalidomide 25 mg, bortezomib 1.3 mg/m2, pegylated liposomal doxorubicin 30 mg/m2 and dexamethasone 20/10 mg in 3-week cycles. Response rates after 4 and 8 cycles were 96 and 95% Pr or better, 57% and 65% ≥ VGPR, and 29 and 35% CR and nCR, respectively. At a median follow-up of 15.5 months, median PFS and OS were not reached. The estimated 18-month PFS and OS were 80.8 and 98.6%, respectively. The most common AEs were fatigue (83%), constipation (69.4%), sensory neuropathy (65.3%) and infection (56.9%); incidences of fatigue, constipation, neuropathy and infection were relatively higher in doxorubicin in RVD compared with the lenalidomide–dexamethasone-treated patients in the MM-009 and MM-010 trials.[53,54] Grade ≥3 AEs included neutropenia (19.4%), infections (13.9%), thrombocytopenia (11.1%) and DVT/pulmonary embolism (2.8%); 25% of patients had grade 1–2 palmar–plantar erythrodysesthesia. There was no treatment-related mortality.[68]

Combination with clarithromycin or biaxin showed promising data in a Phase II study (Table 2).[69] Clarithromycin has immunomodulatory properties partially mediated by suppression of IL-6 and other inflammatory cytokines in addition to a direct antitumor effect.[70] Of the 72 patients enrolled, 65 had an objective response (90.3%) with CR rate of 38.9%. Fifty two (72%) of the patients who did not go on to receive ASCT continued therapy to achieve CR and VGPR of 37 and 33%, respectively. The AEs were comparable to other combination regimens. The most common grade 3 or higher hematologic toxicities were neutropenia (19.4%), anemia (13.8%) and thrombocytopenia (22.2%). The most common grade 3 or higher nonhematologic AEs were myopathy (11.1%), rash (5.6%), diverticular abscess (5.6%), hypocalcemia (4.2%) and thrombosis (9.7%). Thromboembolic events occurred in nine patients (12.5%), of which five events (55.5%) occurred as a result of aspirin interruption or poor compliance.[69]

Transplant is an important component of overall treatment plan for MM in eligible patients. The general approach is 3–4 months of cytoreductive therapy followed by stem cell collection and transplant.[4,71] Due to excellent responses seen with novel agents, there has been a shift in therapeutic paradigm with a tendency to defer transplant in patients who get very good responses. Early versus delayed ASCT was shown to result in comparable OS in randomized controlled trials in patients with MM who receive alkylator-based regimens.[72] This paradigm was tested in context of IMiD-based initial therapy in sequential cohorts of 123 patients who received TD and 167 patients who received RD induction prior to ASCT. The median estimated time to ASCT was 5.3 months in early- and 44.5 months in delayed-ASCT groups. The 4-year OS rate for both the groups was 73%. Treatment with RD compared with TD was associated with better OS whether ASCT was performed early (82 vs 68%) or late (86 vs 64%).[73] Although this was not a prospective randomized study, these data strongly suggests that ASCT can be safely deferred in patients who get good responses with induction therapy.

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