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First line VMP for patients who are not eligible for conventional treatment
BM BS MCRP FRCPath
Guy’s & St Thoma’s NHS
Foundation Trust, London
Multiple myeloma (MM) is a malignancy of the plasma cells. MM accounts for 1% of all cancers and the annual incidence in the EU is 5.72 per 100,000 people. Traditional chemotherapeutic strategies have involved various combinations of melphalan, steroids and cyclophosphamide. Recently, the introduction of novel agents such as bortezomib (Velcade), thalidomide and lenalidomide (Revlimid) to the portfolio of treatment options has improved response rates.
Bortezomib is a first-in-class proteasome inhibitor. Proteasomes manage regulatory proteins. Inhibition of the proteasome impairs nuclear factor kappa B (NF-kB) activation which is required for cell growth and survival. Initial clinical data demonstrated the efficacy of bortezomib in the relapsed/refractory setting; however data are emerging on its use as a first-line agent.
The choice of treatment for newly diagnosed MM depends on age and co-morbidities. Patients under 65 years should be considered for induction therapy followed by autologous stem cell transplantation (ASCT). Patients 65-75 years, full-dose conventional therapy or a reduced-dose ASCT should be considered. Patients >75 years or patients with significant heart, lung, renal or liver dysfunction should have the dose of any therapy reduced accordingly.
Patients who are deemed suitable for ASCT should not receive melphalan as a component of their front-line therapy. Current treatment options include thalidomide in combination with cyclophosphamide and dexamethasone (CTD). Bortezomib, in combination with doxorubicin and dexamethasone (PAD), in the first-line setting, has been shown to be an effective induction regimen for patients in whom ASCT has been deemed appropriate. Data on the combination of bortezomib, cyclophosphamide and dexamethasone (CVD) is currently emerging as another option for induction therapy followed by ASCT.
The combination of melphalan, prednisolone and thalidomide (MPT) has become a recommended option for elderly patients with newly diagnosed MM for whom an ASCT is not deemed appropriate. Data from five randomised studies comparing MPT with melphalan and prednisolone (MP) have consistently reported a higher overall response rate (ORR) with MPT compared to MP (42%-76% vs 28%-48%) and longer progression-free survival (PFS) (13-27.5 months vs10-19 months). However, an improvement in overall survival (OS) attributable to MPT has only been demonstrated in two studies (45.3-51.6 months vs 27.7-32.2 months). In addition, MPT administration is associated with increased rates of neutropenia and venous thromboembolic events compared with MP.
The combination of bortezomib, melphalan and prednisolone (VMP) was first examined in a phase 1/2 study of 60 untreated elderly (> 65 years) patients with MM.4 Treatment comprised of 46-week cycles of bortezomib 1.0 or 1.3mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32 followed by a 10-day rest period, in combination with melphalan 9mg/m2 and prednisolone 60mg/m2 both on days 1 to 4. Following completion of 46-week cycles, patients went on to receive a maintenance phase consisting of 55-week cycles of 1.0 or 1.3mg/m2 on days 1, 8, 15 and 22 followed by a 13 day rest period in combination with melphalan 9mg/m2 and prednisolone 60mg/m2 both on days 1 to 4. No dose limiting toxicities occurred during phase 1 (bortezomib 1.0mg/m2), therefore 1.3mg/m2 of bortezomib was used for phase 2. The median number of cycles administered was 7 (range, 2-9 cycles). Responses to VMP were rapid; 70% of patients demonstrated a response after the first cycle (6 weeks). 53 patients completed at least the first cycle and the response rate was 89%. Of these 32% achieved complete response (CR) and 11% near complete response (nCR). After a median follow-up of 26 months (range, 15-38 months) median time to progression (TTP) was 27.2 months for VMP and 20.0 months for MP.
A subsequent randomised phase 3 study comparing VMP with MP has recently been reported (VISTA Trial).6 682 patients who were not candidates for ASCT were randomly assigned to receive VMP (n=344) orMP (n=338). MP was administered day 1 to 4 every 6 weeks for nine cycles and in the VMP arm, in addition to MP, bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29 and 32 during cycles 1 to 4 and on days 1, 8, 22 and 29 during cycles 5 to 9. The ORR was significantly higher for VMP compared to MP (71% vs 35%). CR was seen in 30% of the VMP group and 4% of the MP group. Of particular interest, the median time to subsequent therapy was significantly longer for patients who had received VMP; 35% of patients compared with 57% of the MP group started second line treatment within 2 years. After a median follow-up of 16.3 months, 13% who received VMP and 22 % of patients who received MP had died. The total number of adverse events during treatment were similar for both treatment arms (99% VMP, 97% MP) and haematological toxicity was comparable. Peripheral sensory neuropathy was reported in 44% of patients receiving VMP compared to 5% of patients receiving MP. Herpes zoster infection occurred more frequently in the VMP arm (13% vs 4%). Anti-viral prophylaxis was not initially mandatory for patients randomised to receive VMP but following increased reports of VZV reactivation (13% VMP, 4% MP) anti-viral prophylaxis became mandatory resulting in a marked reduction in patients affected (3%).
The VISTA Trial reported subset analysis of 3 groups of patients who had poor prognosis. These were patients 75 years or older, patients with impaired renal function and those with adverse cytogenetics (t(4;14),t(14;16) translocation or 17p deletion). For patients 75 years or older, the median time to progression was identical to those patients <75 years. There was no reduction in benefit for patients with impaired renal function. The patients with high-risk cytogenetics had the same rate of complete response (28%) with similar times to progression and OS as patients with standard cytogenetic profile. The results of the VISTA Trial cannot be directly compared to the studies of MPT vs MP; however the data does indicate that both VMP and MPT are appropriate front-line therapies for patients who are not suitable for ASCT. MP can no longer be considered standard care. A trial directly comparing the efficacy of MPT vs. VMP in the first-line setting had not been reported.
Thalidomide and bortezomib are both licensed for first-line treatment of MM in combination with MP.
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6. San Miguel JF et al. N Engl J Med 2008; 359: 906-917