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The past several decades have witnessed a dramatic improvement in the treatment of patients with multiple myeloma, 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.
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).
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
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.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.
New Mechanism of Action Discovered
The drug subsequently gained full FDA approval in the relapse setting based on the results of a follow-up phase III trial, MM-003, in which the combination of pomalidomide and low-dose dexamethasone significantly improved median progression-free survival (PFS) to 3.6 months versus 1.8 months with high-dose dexamethasone alone (HR, 0.45; P <.001), which translated to a 55% reduction in the risk of progression. Doublet therapy also improved overall survival (OS), with a 30% reduction in the risk of death, notably despite of the fact that more than half of patients in the dexamethasone arm had previously received pomalidomide.Thalidomide and its analogs are described as IMiDs because of their reported effects on immune cells. A major part of their anticancer efficacy is thought to be related to their immune stimulatory properties, which may help to boost the antitumor immune response.
IMiDs were first reported to have an anti-inflammatory effect, mediated by an inhibition of tumor necrosis factor alpha, a cytokine with a major role in inflammation. Subsequently, they have also been shown to increase the production of interleukin-2 (IL-2) and interferon-gamma, which stimulate the activity of cytotoxic T and natural killer (NK) cells, and to enhance antigen uptake by dendritic cells and promote more effective antigen presentation, among other reported effects.
Despite their moniker, however, they have a diverse range of cellular effects to which their anticancer activity might also be attributed. IMiDs have been shown to have antiangiogenic properties since they reduce the production of proangiogenic factors such as vascular endothelial growth factor and broblast-like growth factor. In addition to these effects, which predominantly impact the tumor microenvironment, they also may directly affect MM cells by influencing the cell cycle, proliferation, cell migration, and metastasis (Figure).
In 2010, the discovery of a common molecular target for IMiDs tied together many of these observed effects into a common mechanism of action. It was discovered that all 3 IMiDs bind a protein called cereblon, a protein that forms part of a ubiquitin ligase complex. In normal cells, this complex adds ubiquitin molecules to proteins, marking them as old, damaged, or unwanted and targeting them for destruction in the proteasome—the cell’s “garbage disposal.” Cereblon is responsible for recruiting to the complex the target proteins that will be tagged for destruction.
When bound by an IMiD, the types of proteins that cereblon recruits are altered. In MM, 2 transcription factors of the ikaros family of zinc finger (IKZF) proteins appear to be most relevant to the cellular effects of IMiDs. IMiD-bound cereblon in MM cells targets the IKZF1 and IKZF3 proteins, leading to their ubiquitination and degradation. These proteins have been shown to regulate the transcription of numerous genes that are important for MM cell survival. Therefore, IMiDs exert their anticancer activity in MM cells by reducing the expression of IKZF1 and IKZF3 and essentially switching off their transcriptional activity.
Intriguingly, thalidomide and its analogs have now been transformed from simple IMiDs into the first members of a novel class of anticancer drugs. They represent the first clinically available inhibitors of a ubiquitin ligase and offer a way to target transcription factors, which are the master regulators of the dysregulated gene expression programs of cancer cells, and have, until now, been considered largely undruggable.
Backbone of Multiple Myeloma Therapy
Since the discovery of this mechanism of action, a new generation of non-thalidomide—based IMiDs are in development that have been specifically designed to target cereblon. Celgene Corporation, which has developed all 3 approved IMiDs, is now studying avadomide (CC-122), CC-220, and CC-90009, all of which are in early-stage clinical trials.Since its approval, lenalidomide has gone on to form the backbone of therapy for patients with relapsed and refractory MM. The doublet regimen of lenalidomide and dexamethasone is highly effective in itself but, in general, it is used in combination with a third drug in patients who are able to tolerate it.
There are a growing number of FDA-approved triplet therapies for patients with relapsed/ refractory disease. Lenalidomide and dexamethasone can be combined with the proteasome inhibitors carfilzomib (Kyprolis) and ixazomib (Ninlaro), with the latter marking the approval of the first all-oral treatment regimen for MM; the monoclonal antibodies elotuzumab (Empliciti) and daratumumab (Darzalex), and the histone deacetylase inhibitor panobinostat (Farydak). Bortezomib has also shown significant efficacy in combination with lenalidomide and dexamethasone, although its approval in MM is currently only for use as a single agent.
As with many other effective agents, investigators are pairing IMiDs with PD-1 inhibitors. Lenalidomide is being evaluated in combination with pembrolizumab (Keytruda) and low-dose dexamethasone in the phase III KEYNOTE-185 trial in patients with newly diagnosed, treatment-naïve MM (NCT02579863). The triplet combination demonstrated a 50% ORR in 40 heavily pretreated evaluable patients in a phase I trial, including 13% with a very good partial response (VGPR).
Pomalidomide currently is approved only for use as doublet therapy as a treatment option in MM after the failure of 2 prior regimens. However, pomalidomide is also proving to be a very promising partner with a wide spectrum of drugs in triplet therapy, including carfilzomib, ixazomib, elotuzumab, and daratumumab. Many clinicians choose to use these combinations off-label when presented with highly refractory patients.
Additionally, pomalidomide also is being paired with PD-1 inhibitors. At the 2016 American Society of Hematology (ASH) Annual Meeting, the results of a study evaluating the combination of pembrolizumab with pomalidomide and dexamethasone were presented.
Moving Toward Front Line
Among 48 patients with relapsed/refractory MM treated in this phase II, single-center trial, the ORR was 65% with triplet therapy, with 29% of patients experiencing VGPR or better and 2% complete remission (CR) rate over a median follow-up of 9.6 months. The median DOR was 16.3 months. The ORR was 68% among 38 patients with double- refractory disease and 56% among 27 patients with high-risk cytogenetics. The most common grade 3 or higher AEs were neutropenia, hyperglycemia, anemia, upper respiratory tract infections, lymphopenia, fatigue, rash, and thrombocytopenia. An ongoing phase III trial is currently evaluating this combination (KEYNOTE-183).Both lenalidomide and pomalidomide as part of doublet and triplet regimens are also finding therapeutic success in other settings beyond relapsed/ refractory MM. Studies have shown that patients with newly diagnosed disease, including those who are eligible for a stem cell transplant and those who are transplant ineligible, can also benefit from IMiDs.
In 2015, FDA approval for lenalidomide-dexamethasone was expanded to include all patients with MM, following the results of the phase III FIRST trial. That study compared continuous lenalidomide-dexamethasone treatment until disease progression with the use of melphalan, prednisone, and thalidomide in newly diagnosed patients who were not candidates for stem cell transplantation.
Patients taking continuous lenalidomide-dexamethasone had a 28% reduction in the risk of disease progression or death compared with melphalan, prednisone, and thalidomide, time to progression was 25.5 versus 21.2 months, respectively, and median OS was 58.9 versus 48.5 months, respectively.
The combination of bortezomib-lenalidomide-dexamethasone has also been shown to be effective as frontline therapy and, although not FDA approved, is one of several preferred options for patients who are transplant candidates and those who are transplant ineligible. Phase III studies of a variety of other drugs, currently approved in the relapsed/refractory setting, are also ongoing in patients with newly diagnosed disease, such as the ELOQUENT-1 study of elotuzumab-lenalidomide-dexamethasone.
Finally, lenalidomide has also recently proved its worth as maintenance therapy to help prolong remissions following stem cell transplantation in patients with MM. There has been a significant amount of buzz surrounding this potential use in recent years, following encouraging findings from several phase III trials. A meta-analysis, with pooled results from randomized trials concluded that lenalidomide maintenance should become standard of care in this setting, since it appears to improve OS.
Exploration in More Tumor Types Based on its success in MM, lenalidomide has also been tested in clinical trials in different tumor types and have proved effective for the treatment of other B-cell malignancies.
In 2013, the FDA approved lenalidomide-dexamethasone doublet therapy for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). Recently published data from a phase II multicenter study suggest that lenalidomide-dexamethasone also is highly effective in combination with the CD20-targeting monoclonal antibody rituximab (Rituxan) as initial treatment for patients with MCL. Thirty-eight patients have been treated so far and the ORR is 92%, with a complete response rate of 64%.
Lenalidomide also shows promise when added to rituximab in FL and as maintenance therapy in CLL. Interim results from the phase III German CLL M1 study suggested that lenalidomide maintenance therapy lowered the risk of progression by 80% among 89 patients with CLL who achieved partial response or better after receiving chemoimmunotherapy.A new generation of IMiDs that exploit the recently developed knowledge about cereblon protein activity is being explored. The most advanced of these agents is avadomide.
The results of an ongoing phase Ib study of avadomide in combination with the CD20-targeting monoclonal antibody obinutuzumab (Gazyva) were presented at the 2016 ASH Annual Meeting. Among the 26 patients with relapsed/refractory diffuse large B-cell lymphoma and indolent non-Hodgkin lymphoma enrolled so far, the combination was well tolerated and the ORR was 53.8%, with most responses occurring in patients with FL.