Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy


Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

Safety & Tolerability

Teratogenicity is the most notorious and dreaded toxicity of thalidomide. Strict prescribing regulations and an educational program for patients and physicians were instituted to ensure safety of IMiDs. Additionally, thalidomide is frequently associated with toxicities such as somnolence, fatigue, peripheral neuropathy, thromboembolism, skin rash and constipation. Less common AEs are neutropenia, hypothyroidism, Stevens–Johnson syndrome and neurologic toxicities such as confusion and tremors. The incidence of the toxicities can be managed with lower dosage of thalidomide (200 mg or less).[87]

A large body of experience from trials and clinical use demonstrates that lenalidomide has a better toxicity profile than thalidomide. In 2005, the FDA instituted an expanded access program for lenalidomide prior to its approval in part to obtain additional safety information.[88] A total of 1438 patients with refractory or relapsed MM were enrolled in that program. The most common AEs noted were hematologic (49%), gastrointestinal (59%) and fatigue (55%), and the most serious AEs reported were pneumonia, pyrexia, venous thromboembolism (VTE) and thrombocytopenia. Similar spectrum of side effects was noted in two randomized trials.[53,54] While neutropenia and thrombocytopenia were the primary reasons for dose modification in the two trials, the frequently reported nonhematologic side effects were fatigue, diarrhea, muscle cramps, peripheral neuropathy, infections and insomnia (Table 3).[53,54] Rare AEs include skin toxicity (rash, Stevens–Johnson syndrome), atrial fibrillation and thyroid abnormalities.[89]

In MM-009 and MM-010 trials, VTE was carefully monitored because of the high risk of this complication with thalidomide. On the basis of analyses of pooled data from both the trials, VTEs were infrequent but more common in the lenalidomide group compared with placebo arm. Risks for VTE were affected by the dose of dexamethasone and erythropoietin administration. The incidence of VTE was 26% in the high-dose dexamethasone and 12% in the low-dose group (p = 0.0003).[61] Concomitant administration of erythropoietic agents significantly increased the risk of VTE (23 vs 5%).[90] Arterial thromboembolic events such as myocardial infarction, transient ischemic attack, cerebrovascular accident and thrombotic stroke occurred in a small percentage (2.9%) of patients.[88] With increasing use of IMiD combinations in treatment of MM, thromboprophylaxis has come to play a crucial role. Individual risk factors for thrombosis associated with IMiDs include age, history of VTE, central venous catheter, comorbidities such as cardiac disease, obesity and diabetes, immobilization, surgery and inherited thrombophilia; myeloma-related risk factors include diagnosis and hyperviscosity. The International Myeloma Working Group has recommended a risk-based thromboprophylaxis approach: aspirin prophylaxis for patients with one or less VTE risk factors and low-molecular weight heparin (equivalent to enoxaparin 40 mg/day) for those with more than one risk factor.[91] Recent studies showed similar efficacy of low-dose aspirin and low-molecular weight heparin in reducing serious thromboembolic and cardiovascular events in previously untreated myeloma.[92,93]

An important consideration for MM patients who are potential transplant candidates is to choose induction therapy that will allow successful stem cell mobilization. On the basis of anecdotal observations of impaired stem cell mobilization after lenalidomide treatment, this issue was evaluated in larger studies. In patients mobilized with G-CSF alone after treatment with lenalidomide, significant decrease in total CD34+ cells per kg, average daily yield and day-1 yield was observed.[94] Higher number of apheresis was required compared with controls treated with dexamethasone alone, TD or VAD chemotherapy.[94] Risk of impaired mobilization was minimal in lenalidomide-treated patients who had their stem cells collected within 6 months of initiation of therapy. In another study, mobilization failed in 25% of patients who had previously received lenalidomide compared with 4% of patients who did not receive lenalidomide (p < 0.001).[95] Prior use of lenalidomide and mobilization more than a year after diagnosis of MM were independent factors affecting the stem cell yield. In majority of the patients, remobilization was successful with filgrastim and chemotherapy.[95] With these observations, recommendations are to do stem cell harvest after four cycles in patients receiving lenalidomide-based induction.[96] Among those treated with RD for fewer than four cycles and younger than 65 years, G-CSF alone is considered adequate. Use of cyclophosphamide along with G-CSF should be considered among patients who have received more than four cycles of lenalidomide therapy.[32]

There is ongoing debate regarding increased risk of developing second primary malignancies (SPM) with the use of lenalidomide, in particular AML and myelodysplastic syndrome. Palumbo et al. reported 3-year SPM of 7% with MPR-R, 7% with MPR and 3% with MP. Hematologic malignancies included AML (four patients in the MPR-R and two in the MPR group), myelodysplastic syndrome (one patient in the MPR-R, three in the MPR and one in the MP arm), T-cell lymphoblastic leukemia (one in the MPR-R group) and chronic myelomonocytic leukemia (one in the MPR-R arm).[62] Similar increases in incidence of SPMs were reported in IFM 2005–02 and CALGB 100104 studies.[85,86]

The authors lack clear data at the current time, and longer follow-up is needed to confirm the risk of SPMs associated with lenalidomide use. Better characterization of the molecular features of the patients who develop SPMs in myeloma versus SPMs with lenalidomide use is needed.