Pomalidomide is a next-generation immunomodulatory agent in development for relapsed/refractory multiple myeloma, designed to follow in the footsteps of its siblings, Revlimid (lenalidomide, Celgene) and Thalomid (thalidomide, Celgene). The first evidence that pomalidomide could be a true successor to Revlimid came from the Phase II MM-002 trial, which randomized 221 patients to pomalidomide plus low-dose dexamethasone (LoDEX) versus pomalidomide alone. Patients enrolled in that trial were heavily pre-treated with a median of five prior therapies, including Velcade (bortezomib, Millennium/Johnson & Johnson) and Revlimid. Results from this study were first presented at ASH 2011 (Richardson, Abstract 634) and were updated at ASCO 2012 (Vij, Abstract 8016). A partial response (PR) or better was observed in 30% of patients treated with pomalidomide plus LoDex compared with 9% for patients treated with pomalidomide alone, and responses of minor response (MR) or better were 45% compared to 25%. The median progression-free survival (PFS) of pomalidomide plus LoDex was associated 3.8 months versus 2.5 months for patients treated with pomalidomide monotherapy (HR 0.73, p=0.037), and the overall survival (OS) was 14.4 months versus 13.6 months (HR 0.85, p=0.449). The regimen was well-tolerated with a discontinuation rate due to adverse events of 6% in the pomalidomide plus LoDex arm versus 12% in the pomalidomide-alone arm. The most common Grade 3/4 toxicities in the pomalidomide plus LoDex arm versus pomalidomide alone were neutropenia (38% and 47%, respectively), anemia (21%, 22%), pneumonia (19%, 14%), thrombocytopenia (19%, 22%), and fatigue (10%, 10%). Based on these encouraging data, Celgene has filed for accelerated approval in the United States and for conditional approval in Europe. The U.S. Food and Drug Administration (FDA) has accepted this application for standard review, with a PDUFA date of February 10, 2013. These data also created a lot of buzz in the myeloma community – the recent approval of Kyprolis (carfilzomib, Onyx) has started to close a gap in the treatment armamentarium, but a hole still exists that pomalidomide could help fill.
To confirm the activity seen in MM-002, Celgene initiated the Phase III NIMBUS study (MM-003; NCT01311687), which randomized 455 patients with relapsed/refractory multiple myeloma 2:1 to treatment with pomalidomide plus LoDEX versus high-dose dexamethasone (HiDEX). Patients must have received at least two prior lines of therapy, which had to have included prior Revlimid and prior Velcade. A first look at the data from NIMBUS came in the late-breaking abstract session on the last day of the 2012 ASH conference (Dimopoulos, Abstract LBA6).
The use of pomalidomide plus LoDEX significantly improved PFS compared to HiDEX (3.6 months versus 1.8 months, HR 0.45, p<0.001) with very clear separation of the Kaplan-Meyer curves. The response rates were also significantly improved in the combination arm (24% versus 3%, p<0.001). Importantly, OS was significantly improved in the combination arm (median not reached versus 7.8 months, HR 0.53, p<0.001), a result that is even more impressive when we consider that 29% of patients on the HiDEX arm received pomalidomide upon progression, and that these patients were heavily pre-treated, with a median of five prior therapies. Additionally, the level of benefit was also maintained in patients refractory to both Revlimid and Velcade: PFS (3.2 months versus 1.7 months, HR 0.48, p < 0.001) and OS (median not reached versus 7.4 months, HR 0.56, p < 0.001). These results are only loosely tempered by an increase in Grade 3/4 neutropenia (42% versus 15%) and febrile neutropenia (7% versus 0%). All other reported Grade 3/4 toxicities (thrombocytopenia, infections, hemorrhage, glucose intolerance, neuropathy and venous thromboembolism) were similar between the two arms. The minimal increase in toxicity is reflected in the low discontinuation rates due to adverse events (7% versus 6%).
The data were undeniably impressive, but pomalidomide will enter an increasingly crowded market space. Kyprolis, a next-generation proteasome inhibitor, was given an accelerated approval in the U.S. based on results from a Phase II trial. Onyx has initiated three Phase III trials: ASPIRE (NCT01080391; RevDex with or without Kyprolis in relapsed myeloma), FOCUS (NCT01302392; Kyprolis versus best supportive care in heavily pre-treated myeloma patients) and ENDEAVOR (NCT01568866; Kyprolis plus dexamethasone versus Velcade plus dexamethasone in relapsed patients). Further behind in development are the pan-deacetylase inhibitor panobinostat (Novartis), the PI3K/AKT inhibitor perifosine (Æterna Zentaris) and the anti-CS1 monoclonal antibody elotuzumab (Bristol-Myers Squibb/AbbVie). Elotuzumab is being examined in combination with Revlimid plus dexamethasone in both newly diagnosed (ELOQUENT-1; NCT01335399) and relapsed patients (ELOQUENT-2; NCT01239797).
In spite of the increased competition, pomalidomide will be eagerly included into the drug armamentarium for myeloma patients. Physicians are excited about these new agents, as represented by the large number of Phase I or II trials presented at ASH 2012 examining new drug combinations, including one Phase I/II study that showed impressive efficacy (56% MR or better, 70% six-month PFS) with the combination of both Kyprolis and pomalidomide with LoDEX in heavily pre-treated patients (Shah, Abstract 74). After a five-year dry-spell, the introduction of Kyprolis this year and the data for pomalidomide at ASH 2012 portend to a new era in multiple myeloma therapy.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Arnold DuBell, PhD, Associate Consultant, Kantar Health
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