Alternating, sequential combination drug administration feasible in elderly with multiple myeloma

NEW ORLEANS — The combination of bortezomib, melphalan and prednisone alternately or sequentially added to lenalidomide plus dexamethasone was feasible in elderly patients with newly diagnosed multiple myeloma, according to study results.

The alternating dosing was associated with superior response rate and outcome, although further follow-up is necessary, results showed.

Maria-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca in Spain, and colleagues compared the two dosing regimens in 241 patients aged 65 to 89 years.

Maria-Victoria Mateos

“Our hypothesis was that the alternating scheme would minimize the emergence of resistant clones and that this combination would be superior in toxicity and efficacy with a less probability of cell tumor escape,” Mateos said during a presentation.

Patients in both treatment arms received 1.3 mg/m² bortezomib (Velcade, Millennium Pharmaceuticals) twice weekly for one 6-week cycle and then once weekly for eight 4-week cycles, followed by 9 mg/m² oral melphalan (Alkeran, GlaxoSmithKline) and 60 mg/m² prednisone daily on days 1 through 4 of each cycle. Patients received this combination alternately (n=120) or sequentially (n=121) with 25 mg lenalidomide (Revlimid, Celgene) on days 1 through 21 plus weekly 40 mg dexamethasone.

Researchers conducted an interim evaluation of the dosing schedules after nine cycles.

Results showed 78% of patients in the alternating treatment arm achieved at least a very good partial response compared with 54% of patients in the sequential treatment arm (P=.002). The difference between the rates for complete response also was statistically significant (41% vs. 26%).

The superiority of the alternating administration did not come at the cost of greater toxicity, researchers said.

Patients assigned to alternating dosing demonstrated fewer occurrences of grade 3 to grade 4 neutropenia (16% vs. 23%) and thrombocytopenia (16% vs. 20%) than patients assigned to sequential dosing.

Grade 3 to grade 4 non-hematologic infections occurred in 5% of patients in the sequential arm and 4% of patients in the alternating arm.

Four patients in the sequential arm experienced disease progression by this time point, whereas no patients assigned to alternating dosing had disease progression.

Eighteen-month OS was 93% in the alternating arm and 83% in the sequential arm, a difference that was not statistically different.

Patients who achieved complete response demonstrated a significantly longer 18-month time to progression in the sequential (100% vs. 71%; P=.006) and alternating arms (100% vs. 79%; P=.006).

“Regimens of therapy including alkylators, protease inhibitors and immunomodulatory drugs, not all at once but in a sequential or an alternating approach, are effective and well tolerated in elderly patients with multiple myeloma,” Mateos said. “After the first nine induction cycles, the alternating scheme appears superior, especially in terms of complete remission rate as compared with the sequential scheme, and most importantly, with no more toxicity.”

For more information:

Mateos MV. Abstract #403. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.

Disclosure: The researchers report honoraria and research funding from, as well as consultant, board of directors or advisory committee roles with, Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Novartis and Onyx. They also report the off-label use of lenalidomide plus dexamethasone.