The past several decades have witnessed a dramatic improvement in the treatment of patients with multiple myeloma (MM), the second most common type of hematologic malignancy. A better understanding of the biology of this disease and the introduction of a wealth of novel drug classes has more than doubled median survival times. In a single month in 2015, the FDA approved 3 new drugs, each with a unique mechanism of action.
Amid these changes, the immunomodulatory drugs (IMiDs), consisting of thalidomide and its analogs, remain the backbone of MM treatment. Most of the newly approved drugs are administered as a triplet in combination with an IMiD and the steroid dexamethasone.
IMiDs have proved their worth across the spectrum of treatment settings in MM, both in triplet and doublet regimens and even as single agents, from the newly diagnosed patient to those with relapsed or refractory disease and in the maintenance setting, to achieve deep and durable remissions.
Increasingly, evidence also suggests that IMiDs have therapeutic potential beyond MM, in other B-cell malignancies, notably in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), and possibly in solid tumors. The 2 leading FDA-approved drugs and a new generation of agents are being evaluated in many tumor types (Table
Although they are dubbed IMiDs, these drugs have a wide range of cellular effects, many of which were recently tied together by the discovery of their shared mechanism of action. In a noteworthy development, researchers now believe that IMiDs represent the first clinically approved agents in a novel class of drugs, targeting an enzyme involved in the regulation of protein levels in the cell. This understanding opens the door to a unique drug mechanism that could expand the reach of our anticancer armamentarium to targets previously thought to be undruggable.
Table. Experimental IMiD Combination Regimens in Selected Ongoing Clinical Trials
ABC indicates activate B-cell; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; DLBCL, di use large B-cell lymphoma; FL, follicular lymphoma; HCC, hepatocellular carcinoma; IMiD, immunomodulatory drug; MCL, mantle cell lymphoma; MM, multiple myeloma; MZL, marginal zone lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SLL, small lymphocytic leukemia.
Rewriting a Turbulent History
Thalidomide is infamous for the disastrous teratogenic effects that manifested themselves as severe birth defects in thousands of newborn babies after it was used to ease morning sickness in pregnant women in the 1950s. Although its anticancer properties were noted at the time, it wasn’t until the 1990s that it was reinvented as an IMiD when its anti-inflammatory properties were revealed.
In 2006, the FDA approved thalidomide (Thalomid) for the treatment of newly diagnosed MM in combination with the steroid dexamethasone. The agency stringently controls thalidomide’s marketing through a Risk Evaluation and Mitigation Strategy (REMS) program to prevent fetal exposure during pregnancy.
Although responses were observed in more than half of patients with MM treated with thalidomide and dexamethasone, the combination was associated with severe adverse events, including an increased incidence of venous thromboembolism. Modification of its chemical structure resulted in the development of lenalidomide (Revlimid), a more potent and safer analog.
Initially approved for myelodysplastic syndromes, lenalidomide gained an MM indication in 2006 for use in combination with dexamethasone in patients who had received 1 prior therapy. Like thalidomide, it is only available under a REMS program.
A third IMiD, pomalidomide (Pomalyst), joined the market in 2013, also with evidence of stronger anti-myeloma activity and an improved toxicity pro le. Pomalidomide in combination with dexamethasone has been added to the MM armamentarium for use in patients who have relapsed after 2 prior treatment regimens, including lenalidomide and the proteasome inhibitor bortezomib (Velcade).
Pomalidomide was granted accelerated approval by the FDA based on the results of the CC-4047-MM-002 trial, a multicenter, open-label phase II study. Among 221 patients, the overall response rate (ORR) was 29.2% for patients treated with the combination of pomalidomide plus low-dose dexamethasone compared with 7.4% for pomalidomide alone, with a median duration of response (DOR) of 7.4 months with the doublet.