Insights into the OPTIMISMM study presented at the 23rd Congress of the European Haematology Association, 14–17 June 2018, Stockholm, Sweden
The introduction of immunomodulatory agents and proteasome inhibitors (PIs) has transformed the management of multiple myeloma (MM) in recent years.1 However, relapse inevitably occurs, and the disease becomes more aggressive with each relapse.2 Treatment of relapsed/refractory MM represents a therapeutic challenge, because of the heterogeneity of disease at relapse and the absence of clear recommendations regarding the choice of therapies at various time points of disease progression.3 As most patients receive lenalidomide-based therapy upfront, followed by consolidation and maintenance therapy,4 patients who are no longer receiving benefit from lenalidomide represent a growing unmet need. There is, therefore, a need for new combinations in relapsed and refractory MM.
A number of strategies have emerged as useful combinations that can overcome lenalidomide resistance. Pomalidomide (Pomalyst®, Celgene, NJ, US) is an oral immunomodulatory drug that has become standard of care for patients for patients with MM who have received two or more prior therapies including lenalidomide and a PI, and have had disease progression within 60 days of completing their last therapy.5,6 It has therefore been suggested that using pomalidomide at an earlier stage of disease relapse would result in outcomes as good or even better that those achieved after two or more treatment failures. Phase I/II studies have shown that the combination of pomalidomide, bortezomib, and low-dose dexamethasone (PVd) is safe and highly active.7,8
The OPTIMISMM study aimed to study a real-word combination that could provide patients with the best outcome after lenalidomide therapy.9 The randomised, open-label, international, phase III clinical study investigated the combination regimen of PVd in 559 patients with relapsed or refractory MM who had received at least one prior treatment including lenalidomide. Eligibility criteria included 1–3 prior regimens and 2 or more cycles of prior lenalidomide therapy. Patients were randomly assigned to receive PVd or bortezomib plus dexamethasone (Vd) treatment in 21-day cycles: pomalidomide 4 mg/day on days 1–14 (PVd arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1–8 and on days 1 and 8 of cycle 9 and beyond; and dexamethasone 20 mg/day (10 mg/day for patients aged over 75 years) on the days of and after bortezomib. Both arms received induction and then maintenance therapy as part of continuous treatment until progression and/or intolerance. This is an important difference to some other phase III studies, which have had fixed treatment durations and do not reflect real world practice. Around 70% of the study participants were refractory to lenalidomide. The primary endpoint was progression-free survival (PFS).9
Results of the OPTIMISMM study were presented at the 54th Annual American Society of Clinical Oncology Scientific Sessions (ASCO) in Chicago, Illinois on 1–5 June 2018, and also at the 23rd Congress of the European Haematology Association (EHA), on 14–17 June 2018, in Stockholm, Sweden. After a median follow-up of 16 months, PVd treatment significantly reduced the risk of progression or death by 39% and resulted in earlier, deeper and more durable responses in these patients compared to Vd treatment. The median PFS was 11.2 versus 7.1 months (p<0.0001) in the intention-to-treat population. The PFS benefit was also observed lenalidomide-refractory, lenalidomide-nonrefractory, prior PI exposure or high-risk cytogenetics patient subgroups.
Overall response rate (ORR), one of the study’s secondary endpoints, was also significantly higher in the PVd treatment arm compared to those receiving Vd (82.2% versus 50.0%, p<0.001). In addition, time to treatment response was shorter in the PVd arm (0.9 months PVd versus 1.4 months Vd), complete response was higher in the PVd arm (15.7% PVd versus 4.0% Vd) and those receiving PVd experienced a longer duration of response than those in the Vd arm (13.7 months PVd versus 10.9 months Vd).9
In an exploratory sub-group analysis, patients who had received only one prior line of therapy reported longer PFS (20.73 months in the PVd arm versus 11.63 months in the Vd arm) and ORR (90.1% in the PVd arm versus 54.8% in the Vd arm) with a 46% reduction in the risk of disease progression or death in the PVd treatment arm compared with Vd. This was a striking finding; the almost 10-month PFS benefit was larger than expected. Other secondary endpoints included overall survival and safety. Data for the overall survival analysis are not yet mature.9
The most common grade 3/4 treatment-emergent adverse events were neutropenia (PVd: 42% versus Vd: 9%), infections (PVd: 31% versus Vd: 18%) and thrombocytopenia (PVd: 27% versus Vd: 29%.) Rates of grade 3 or 4 deep vein thrombosis in the PVd versus Vd arms were 0.7% versus 0.4% and rates of grade 3 or 4 pulmonary embolism were 4.0% versus 0.4%. No events were fatal. Secondary primary malignancies, a known risk of lenalidomide treatment, occurred in 3.2% (2.7 per 100 person years) of patients treated with PVd and 1.5% (1.2 per 100 person years) of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease.9
In a press release, lead investigator Paul Richardson of the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, said: “In the early relapse setting, there remains a need for a deeper understanding of potential treatment options, and in particular for patients who have received prior lenalidomide-based therapy. These are the first phase III clinical findings to report a significant and clinically meaningful PFS improvement in patients who have previously received lenalidomide, a majority of whom are lenalidomide refractory.”10
Other PI-based combinations such as pomalidomide plus carfilzomib11 or ixazomib12 and dexamethasone hold great promise, However, in an interview with Touch Medical Media at the EHA meeting, Paul Richardson described this combination as a “real world value proposition” to which we can rationally add other drugs—an important consideration since 4–5 drug combinations can become very expensive. View the full interview here.
These data have shown that pomalidomide-based combination therapy regimens represent an important new treatment option for patients with relapsed/refractory MM for whom effective new therapies are urgently required.
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6. US Food and Drug Administration. Pomalyst: highlights of prescribing information, 2013. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf (accessed 28 June 2018).
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8. Richardson PG, Hofmeister CC, Raje NS, et al. Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. Leukemia. 2017;31:2695–701.
9. Richardson P, Rocafiguera AO, Beksac M, et al. OPTIMISMM: Phase III trial of pomalidomide, bortezomib and low-dose dexamethasone vs bortezomib and low-dose dexamethasone in lanalidomide-exposed patients with relapsed/refractory multiple myeloma. Presented at the 23rd Congress of theEuropean Haematology Association (EHA), 14–17 June 2018, Stockholm, Sweden.
10. Celgene. Press Release: Results of Phase III OPTIMISMM Study Presented at ASCO 2018 Showed the PVd Triplet Improved PFS in Early Lines of Relapsed or Refractory Multiple Myeloma. Available at: http://ircelgenecom/releasedetailcfm?releaseid=1069084 (accessed 28 June 2018).
11. Zou Y, Ma X, Yu H, et al. Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma: a meta-analysis of 37 trials. Oncotarget. 2017;8:39805–17.
12. Krishnan A, Kapoor P, Palmer JM, et al. Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Leukemia. 2017; doi: 10.1038/leu.2017.352. [Epub ahead of print].