NPC Archive Item: Bortezomib▼ plus melphalan and prednisone beneficial for initial treatment of multiple myeloma

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San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Eng J Med 2008;359:906–17

Disease progression in multiple myeloma is slowed by adding bortezomib▼ to melphalan and prednisone in previously untreated patients who are not suitable for bone marrow transplant.

Action: NICE have issued guidance on the use of bortezomib▼ in multiple myeloma as monotherapy in those where initial therapy has failed. This study suggests that bortezomib can provide additional benefit when added in to existing regimens in those who are not suitable for bone-marrow transplant. PCTs will need to consider whether and how to incorporate this new evidence into the commissioning of services for people with multiple myeloma.

What is the background to this?
Multiple myeloma is a cancer of the plasma cells. In 2004 3,353 patients were diagnosed with multiple myeloma in England and Wales. Around three quarters of newly diagnosed patients are over 65 years of age. Bortezomib is already licensed as monotherapy for progressive multiple myeloma in patients who have received at least one prior treatment and who have undergone or are unsuitable for bone marrow transplantation – NICE have issued guidance on this and a ‘response-rebate’ scheme is in place whereby the manufacturer refunds the NHS for the drug costs in those who do not respond according to the defined criteria. Bortezomib, in combination with melphalan and prednisone, was given a positive opinion by the European Medicines Agency in July 2008 for patients with previously untreated multiple myeloma who are not suitable for high dose chemotherapy with bone marrow transplantation.

What does this study claim?
This open-label trial (see below for details) found that bortezomib in combination with melphalan and prednisone was more effective than melphalan and prednisone alone. The primary endpoint, median time to disease progression, was 24.0 months for bortezomib  patients and 16.6 months in the control group (hazard ratio [HR] 0.48, P<0.001). After a median follow-up of 16.3 months, 13% in the bortezomib group and 22% of the control group had died (HR= 0.61; P=0.008; NNT=11).

Similar proportions of patients discontinued therapy due to adverse events – 15% vs. 14% respectively. Haematological adverse events were seen in around half of all patients in both groups.  Gastrointestinal effects (19% vs 5%) and peripheral neuropathy (44% vs 5%) were more likely with bortezomib. (P values not given).

How does this relate to other studies?
Both thalidomide▼ and lenalidomide▼ have been assessed in multiple myeloma trials. Published head-to-head studies of those agents compared with each other and bortezomib for newly diagnosed patients are awaited.

So what?
Bone marrow transplantation is the preferred treatment in patients with multiple myeloma under the age of 65 years. Some patients under this age may not be suitable for bone marrow transplantation and so may be considered for first-line bortezomib. However, the majority of patients in this study were over the age of 65 years. An age restriction has not been published as part of the positive opinion.

Bortezomib would cost in the region of £39,600 per patient if used for nine treatment cycles as in this trial. Thalidomide Pharmion▼ in combination with melphalan and prednisone, has recently been licensed as a first-line option for patients with untreated multiple myeloma, aged 65 years or over or who are ineligible for high dose chemotherapy. Thalidomide Pharmion costs approximately £20,000 if given in a similar way to the IFM 99-06 trial.

Study details
Design: randomised, open-label, multi-national. Allocation was not concealed.

Patients: 682 patients (median age 71 years) with newly diagnosed, untreated, symptomatic, measurable multiple myeloma and not suitable for bone marrow transplant due to being 65 years of age or older or having co-existing conditions.

Intervention: nine six-week cycles of bortezomib (n=344) plus melphalan and prednisone. The median number of treatment cycles administered was 8.

Comparator: nine six-week cycles of melphalan and prednisone alone (n=338). The median number of treatment cycles administered was 7.

Outcomes: Primary end point – time to disease progression as validated according to criteria from the European Group for Blood and Marrow Transplantation (EBMT). 24.0 months for bortezomib patients and 16.6 months in the control group (hazard ratio [HR] 0.48, P<0.001).

Pre-specified secondary end points included the rate of complete response (30% vs. 4% (P<0.001), the median duration of response (19.9 vs. 13.1 months) and the proportions of patients with a partial response or better (71% vs. 35% (P<0.001). After a median follow-up of 16.3 months, 13% in the bortezomib group and 22% of the control group had died (HR= 0.61; P=0.008).

Adverse effectsGrade 3 (severe) adverse events were more common in the bortezomib group (53% vs. 44%, P=0.02); no significant differences in grade 4 (life-threatening) events (28% vs. 27%) or treatment-related deaths (1% and 2%).

Haematological adverse effects were commonly seen in both groups. For example thrombocytopenia occurred in 52% of the bortezomib patients and 47% of the control group; neutropenia in 49% and 46% respectively. Gastrointestinal adverse events were more common in patients given bortezomib (e.g. nausea 48% vs. 28%, diarrhoea 46% vs. 17%, respectively). Peripheral sensory neuropathy occurred in 44% of bortezomib patients compared to 5% of the control group. This had either resolved or decreased within a median of two months in 74% of the patients. Herpes zoster was seen in 13% of bortezomib patients and 4% of those in the control group. P values were not given for any of these differences.

Sponsorship: Johnson and Johnson Pharmaceutical Research and Development. Millennium Pharmaceuticals.

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