Response Adapted Lenalidomide Based Therapy For Newly Diagnosed (ND) Standard Risk Older Adults With Multiple Myeloma (MM): An International Collaboration

Older MM patients continue to have poor outcomes. Lenalidomide (L) and low dose dexamethasone (D) was found to result in better overall survival than L and high dose D in ND MM (Rajkumar et al. Lancet Oncol 2010). In an attempt to decrease toxicity from therapy in this vulnerable patient population, we have initiated two phase II clinical trials evaluating a response adapted therapy using single agent L with sequential addition of corticosteroids. The trials had similar design and were conducted in one site in the United States (US) and multiple sites in South Korea (SK).

Eligible patients had symptomatic standard risk MM (b2microglobulin (b2m)≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to undergo high-dose melphalan. Patients received L on D1-21 every 28 days for 2 cycles based on renal function. If patients had a minimal response (MR) or better (25% reduction in serum M spike) after 2 cycles, they continued on single agent L until progressive disease. If patients had stable disease (SD) after 2 cycles, prednisone 100 mg PO D1-5 (P) was added to their L. In the event of progressive disease on single agent L or on LP, therapy was changed to L (at the tolerated dose) with dexamethasone 40 mg PO weekly (D). Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG and the primary end point was the 1 year progression free survival (PFS)of LD.

Between 2/2010 and 6/2013, 61 patients were enrolled (34 in SK and 27 in the US). The median age was 73 (range 48-85) and 58% were males. Compared to US, patients in SK had a younger age, lower weight and body surface area and a higher proportion of ISS 2. There were no differences in baseline performance status, hematologic parameters, creatinine clearance or baseline b2m. The overall response rate (≥PR) to single agent L was 48% (59% & 38% for US and SK) and the clinical benefit rate (≥MR) 64% (74% & 56% for the US and SK respectively). After a median follow up of 13.2 months, P was added for 16 patients (26%) and 7 (44%) had ≥PR. D was added for 14 patients (23%) and 10 patients (71%) had ≥PR. The 1 year dexamethasone free survival was 75% (84% & 67% in the US and SK respectively). To date, 3 patients progressed after the addition of D and the 1 year LD PFS was 90% (95% CI 78-96%). There were no statistical differences in grade 3/4 hematologic adverse events (table). Lenalidomide dose reduction was more frequent in the US (59% vs. 26%) however discontinuation from therapy for causes other than progressive disease or death was more frequent in SK (41% vs. 18%).

In This elderly patient population, response adapted (sequential) therapy results in outcomes comparable to LD in younger patients with MM with 78% of patients not requiring the addition of D. Social and ethnic causes of differential tolerance to therapy should be studied further.

Baz:Celgene: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Off Label Use: lenalidomide in newly diagnosed myeloma. Alsina:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Shain:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Kwak:celgene: Research Funding.