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Addition of Thalidomide Improves Event-Free Survival in Multiple Myeloma Patients: Presented at EHA

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 19, 2006 -- Improved response rates and longer event-free survival are obtained with addition of thalidomide to a melphalan plus prednisone regimen (MP) as first-line treatment in elderly patients with multiple myeloma.

Principal investigator Antonio Palumbo, MD, chief, myeloma unit, department of haematology, University of Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy, presented this multicentre, prospective, randomised, controlled trial here on June 17^th at the 11^th Congress of the European Hematology Association (EHA).

For many years, there have been no major improvements in outcomes beyond those achieved with oral MP for patients aged 65 years with multiple myeloma. Thus, Dr. Palumbo and colleagues conducted their study to contribute towards the urgent need for new treatments for these patients.

The 255 patients were randomised to receive either MP (n = 126) or thalidomide plus MP (MPT, n = 129). With a median age of 72 years in both arms, the age distributions within them were similar (< 70 years, 41% vs 43%; 71-75 years, 34%, 29%; > 75 years, 25% vs 28%, respectively).

The 2 treatment arms had similar baseline levels of median beta2-microglobulin (3.7 mg/L in each arm), haemoglobin (10.6 vs 10.2 g/L), creatinine (0.8 mg/dL in each arm) and Ca2+ (2.25 vs 2.27 nmol/L) were also similar.

Treatment comprised 6 4-week cycles of oral melphalan 4 mg/m² (days 1-7) and prednisone 40 mg/m² (days 1-7) accompanied by thalidomide 100 mg/day continuously until relapse or progressive disease. Initially (first 65 patients), no anticoagulation prophylaxis was administered; subcutaneous enoxaparin 40 mg/day was then used during the first 4 cycles of therapy.

In the intention-to-treat analysis, there was a significantly higher response rate with the inclusion of thalidomide (47% vs 76% for MPT; P < .001); this comprised improved complete (2% vs 16%), near complete (5% vs 12%), and partial (4% vs 60%) responses for the MPT combination, with a corresponding improvement in median time to response (MP, 3.1 months; MPT, 1.4 months).

At a median follow-up of 16.3 months the event-free survival was significantly prolonged by 16 months for MPT (P < .001). This did not result in an improved 3-year overall survival rate between MP and MPT (64% vs 80%; P = .20; respectively).

However, Dr. Palumbo noted that the survival curves crossed at 9 months of treatment, whereby the initially higher deaths due to adverse events with MPT (4 vs 11) was later seen as a benefit of decreased death due to disease progression (20 vs 8). Thus, there was an improved overall survival for MPT after 9 months of treatment that represented a 65% decrease in risk of death (P = .014).

Dr. Palumbo also noted another important issue: the use of beta2-microglobulin as a prognostic factor in MP treatment (P = .005) was lost by the inclusion of thalidomide (P = .5). "This means that high beta2-microgobulin could be a selective population that should be treated with this combination," he said.

Grade 3/4 adverse events were similar for haematologic toxicities across the MP and MPT arms (25% vs 22%, respectively), with significant increases with thalidomide seen for thrombosis (2% vs 12%; P = .001), neurological toxicity (1% vs 10%; P = .001), and infection (2% vs 10%; P = .01).

When the MPT group was divided according to enoxaparin prophylaxis (first 65 vs last 64 patients), the reduction in grade 3/4 adverse events from 56.9% to 39.1% was mainly due to the significant reduction in the incidence of thrombosis, from 16.9% to 3.1%, respectively (P = .005).

Division of the MPT arm by age demonstrated higher levels of grade 3/4 adverse events in patients > 70 years -- infections, 2% versus 8%; cardiac events, 0% versus 7%; early death, 1% versus 5%.

The other specific change that Dr. Palumbo stressed was after thalidomide reduction. "All grades of neurological toxicities were around 30% at the dose of 100 mg[/day], but then, when we reached a neurological toxicity of grade 2, according to protocol the dose of thalidomide was reduced to 50 mg[/day] -- and the incidence of all-grade neurological toxicities was just one third of that seen with the full dose."

He thus concluded that oral MPT is superior to MP as first-line treatment for elderly patients with multiple myeloma, while noting the need for anticoagulant prophylaxis and a longer follow-up to assess the full effects on OS.

Drugs used in the trial were supplied by Pharmion.


[Presentation title: A Prospective Randomized Controlled Trial of Oral Melphalan, Prednisone, Thalidomide Versus Oral Melphalan, Prednisone in Elderly Newly Diagnosed Myeloma Patients. Abstract 0490]

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