The evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial involving 559 patients comparing pomalidomide/bortezomib/dexamethasone (PVd) with bortezomib/dexamethasone (Vd) alone in patients with multiple myeloma who had received 2-3 previous regimens, including a lenalidomide containing regimen for at least two consecutive cycles (OPTIMISMM).r
Between January 7, 2013 and May 15, 2017, 281 patients were randomised to receive pomalidomide (4mg daily days 1 - 14), bortezomib (1.3mg/m2 intravenously (IV) or subcutaneously (SC) days 1, 4, 8, 11 for the first eight cycles and subsequently on days 1 and 8) and dexamethasone (20 mg or 10 mg if aged ≥ 75 on the same days as bortezomib and the day after). The cycle length was 21 days.r
The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response (partial response or better) according to the International Myeloma Working Group (IMWG) criteria, duration of response and safety. PVd significantly improved PFS compared to Vd alone.r
Since the availability of lenalidomide maintenance therapy post autologous stem cell transplantation, the treatment landscape of relapsed refractory MM has changed, and consideration of outcomes for patient’s refractory to lenalidomide is a more important consideration than previously. To address this question, further analysis from the OPTIMISMM Studyrr has been undertaken and published.
Once-weekly bortezomib (as opposed to twice-weekly) is a practice widely used in the Australian Myeloma landscape. There is data to support this approach in terms of efficacy, safety and convenience. Using the dosing schedule outlined in by Paludo et al.r, of pomalidomide (4 mg oral (PO) days 1 - 21), bortezomib (1.3 mg/m2 IV or SC on days 1, 8, 15, and 22), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) given every 28 days, it was concluded from this phase 2 study that once-weekly bortezomib (IV or SC in this paper) offered greater convenience without compromise in efficacy. Safety was improved with mild cytopenias being the major toxicity and no dose-limiting neuropathy from their small study (N = 50).
After a median follow up of 15.9 months, the median PFS was significantly improved in the PVd group compared with Vd alone (median 11.2 months [95% CI 9.66-13.73] vs. 7.0 months [95% CI 5.88-8.48], hazard ratio 0.61, 95% CI 0.49-0.77; p < 0.0001) (Figure A).r OS data was not mature at time of data cut-off but no difference in OS was seen between the two groups (HR 0.98, 95% CI 0.73-1.32, p = 0.89).r
Figure 1: PFS for intention to treat population
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Figure 2: Response in the intention to treat population according to IMWG criteria
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Median age of patients was 67 years. 70% of enrolled patients were lenalidomide refractory, approximately 72% had received previous bortezomib therapy and approximately 10% were refractory to previous bortezomib therapy.r
Health related quality of life (HRQOL) was assessed using the global health status/QoL domain of the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire on day 1 of every 21 day cycle before treatment administration and at the end of treatment. HRQOL could be assessed in 85% of patients randomised to PVd and 75% of patients allocated Vd. The study reported no statistically significant or clinically meaningful differences recorded between treatments at any cycle.r
Dimopoulos et al.r, stratified patients according to prior lenalidomide refractoriness versus non-refractory. The results in terms of PFS (primary endpoint) were encouraging in that second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) (Figure 3, A) and lenalidomide non-refractory patients (22.0 vs 12.0 months; P = 0.0491) (Figure 3, B). PFS advantage was also seen in patients with prior bortezomib exposure as well as patients regardless of prior SCT status. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including after upfront lenalidomide treatment failure.
Figure 3: PFS in patients at first relapse (1 prior line of therapy) by lenalidomide-refractory status. A. Patients who were refractory to lenalidomide at first relapse. B. Patients who were non-refractory to lenalidomide at first relapse.
HR hazard ratio, NE not evaluable, PFS progression-free survival, PVd pomalidomide, bortezomib, and dexamethasone, Vd bortezomib plus dexamethasone.
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Adverse events are demonstrated in Figure 3. 86 deaths occurred in each group during the treatment and follow-up periods. Eight treatment related deaths occurred: 6 (2%) in the PVd group (pneumonia, 2; unknown cause, 2; cardiac arrest, 1; cardiorespiratory arrest, 1) and 2 (1%) in the Vd group (pneumonia, 1 and hepatic encephalopathy, 1).r Serious adverse events occurred in 57% of the patients in the PVd group and 42% of the Vd group. 30% of patients receiving PVd compared with 15% of patients treated with Vd had at least one drug-related serious adverse event, primarily infections (14% vs 8%); venous thromboembolism (4% vs < 1%); cardiac arrhythmia (3% vs none) and neutropenia (2% vs none).r
The most common grade 3 or 4 haematological event was neutropenia (42% in the PVd arm versus 9% in the Vd arm).r Grade 3 or 4 febrile neutropenia was seen in 3% of patients receiving PVd compared with no patients receiving Vd. Grade 3 or 4 thrombocytopenia was seen in 27% (PVd) and 29% (Vd) of patients.r
With regards to non-haematological grade 3 or 4 toxicities, comparing PVd with Vd: infection was seen in 31% vs. 18%; peripheral sensory neuropathy in 8% vs 4%, DVT in 1% vs < 1% and PE in 4% vs <1%.r
Second primary malignancies occurred in 3% of patients receiving PVd versus 1% in those receiving Vd. Invasive secondary primary malignancies were seen in 2 patients with PVd (1%) and 1 patient treated with Vd (>1%).r
11% of patients in the PVd arm stopped pomalidomide and 24% stopped bortezomib due to at least one adverse event. 19% of patients in the Vd arm stopped bortezomib. Dose reductions of any study drug were reported in 72% of patients in the PVd arm and 51% of patients in the Vd arm.r
Table 1: Adverse Eventsr
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