It is recognised that more evidence is needed on how and in which sequence treatments for multiple myeloma (MM) should be administered in order to achieve the best outcome. A recent meta-analysis found that first line bortezomib plus melphalan/prednisone (VMP) resulted in the highest complete response (CR) (33%) versus MP plus lenalidomide (17%), MP plus thalidomide (10%) or MP alone (3%).¹ 

This analysis supports the idea that starting with a novel agent in combination with MP increases survival compared to starting with MP alone. The combination of VMP is a considered the new standard of care for elderly patients newly diagnosed with MM. However, outcomes may be improved even more by the addition of thalidomide in the induction phase.

Results from a Phase 3 study comparing bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) versus VMP alone found that VMPT-VT resulted in a 3-year PFS of 55% versus 38% for VMP in elderly patients.²

Various other treatment regimens for MM that included bortezomib were presented at this year's ASH meeting in Orlando, Florida.

 A Phase III study compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed MM.³ 

This study found that VTD induction optimises outcomes for ASCT and consolidation improves responses, including CR and molecular remissions. Double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities.

The HOVON-65/GMMG-HD4 randomised Phase III trial compared bortezomib, adriamycine and dexamethasone (PAD) versus vincristine, doxorubicin and dexamethasone (VAD) as induction treatment prior to high dose melphalan (HDM) in patients with MM. In the first interim analysis of this trial the investigators found that PAD was a safe and effective induction regimen.⁴

Around 80% of patients completed three cycles without a dose reduction and 42% of patients achieved at least a very good partial response (VGPR) after three PAD cycles. With HDM plus ASCT, a VGPR was achieved in 80% of patients. PAD improved CR and VGPR significantly compared with VAD after induction and after HDM plus ASCT. Stem cell apheresis was successful in all PAD treated patients and 87% of patients achieved HDM/ASCT.

A subgroup analysis of the impact of cytogenic abnormalities confirmed a significant negative prognostic impact of del17p13 and gain 1q21 on PFS and OS.⁵ The negative impact of t(4;14) on PFS could almost completely be overcome by the bortezomib-based treatment. Patients with t(4;14) also showed improved OS when treated with bortezomib, but still had an inferior prognosis compared to patients without this cytogenetic aberration. Similarly, bortezomib significantly prolonged OS in patients with gain 1q21 but only partially overcame the adverse effect of this aberration.

Results of a comparison of bortezomib versus bortezomib plus dexamethasone in relapsed/refractory MM patients from the international, non-interventional, Electronic Velcade Observational Study (eVOBS) were also presented.⁶ This ongoing observational study to assess the clinical and health economic outcomes in MM patients treated with bortezomib in the clinical-practice setting found that the addition of dexamethasone to bortezomib monotherapy appeared to increase the CR rate in relapsed/refractory MM patients.

Consistent with the higher CR rate, addition of dexamethasone was associated with trends to improved PFS and time to disease progression, but the differences were not significant in both unadjusted and adjusted analyses. Although more data from a larger patient population may be needed to confirm these results, it was concluded that the addition of dexamethasone to bortezomib did not appear to increase OS in these relapsed/refractory patients.

As an alternative to the normal intravenous (IV) delivery, subcutaneous (SC) administration of bortezomib may be a good option for some patients, particularly those with poor venous access. This would eliminate the need for repeated IV access or insertion of long-term central venous access devices and improve convenience for some patients and physicians. In a randomised Phase 1 trial of SC versus IV bortezomib in 24 relapsed or refractory MM patients, both routes of administration demonstrated similar systemic drug exposure and proteasome inhibition, good local tolerability and, importantly, comparable response rates and safety profiles.⁷ The results of a follow on Phase 3 open-label trial were presented at ASH 2010.⁸ 

This large, multicentre, international, randomised study included 222 patients from 53 centres in 10 countries across Asia, Europe and South America. The study results demonstrated that the efficacy of bortezomib in patients with relapsed MM was similar with SC and IV administration with respect to complete and partial response rates, time to disease progression, PFS, 1-year survival, time to response and duration of response. The data highlight the efficacy of bortezomib irrespective of its route of administration. Median PFS was 10.2 months in the SC arm compared to 8.0 months in the IV arm, and 1-year OS was 72.6% in the SC group and 76.7% in the IV arm. Some safety advantages were also observed with SC administration. The incidence of Grade ≥3 treatment emergent adverse events was 57% for SC versus 70% for IV administration.

Although bortezomib has demonstrated complete clinical responses in patients with refractory or rapidly advancing MM, it is recognised that the type of cytogenetic abnormality can have a significant impact on treatment outcomes. In a large series of newly diagnosed MM patients receiving bortezomib-based induction treatments it was found that del(13q) alone had no adverse effect on both progression free survival (PFS) and overall survival (OS), and that the presence of t(4;14) and/or del(17p) also did not adversely influence PFS.⁹ However, t(4;14) and/or del(17p) was associated with a shorter OS, due at least in part to a worse outcome after relapse. In comparison with t(4;14), del(17p) alone did not predicted for shorter PFS and OS, possibly as a result of the relatively long-term exposure to bortezomib. The presence of both del(17p) and t(4;14) was likely to confer a particularly dismal clinical outlook, a finding which needs to be confirmed in larger series of patients.