Lenalidomide (LEN) Therapy In Combination with Dexamethasone (DEX) Is Associated with a Low Incidence of Viral Infections

Multiple myeloma (MM) is associated with compromised immune function, involving both humoral and cellular mechanisms, and infections are a common problem. The risk of opportunistic infection is higher in relapsed/refractory (RR) MM due to the cumulative immunosuppression associated with prior therapies. Opportunistic viral infections, such as herpes zoster, occur in 5–13% of MM patients (pts) versus < 1% in the general population. LEN improves immune function by enhancing antigen-specific CD8⁺ T-cell proliferation, cytokine production and cytotoxicity, and natural killer cell activity. LEN+DEX has shown a predictable safety profile in pts with RRMM, but is associated with higher rates of grade (G) 3/4 neutropenia versus DEX alone. Although G3/4 neutropenia is 30–41%, the rate of G3/4 febrile neutropenia is low (3.4%; Dimopoulos M, et al. N Eng J Med 2007;357:2123-32; Weber D, et al. N Eng J Med 2007;357:2133-42). The occurrence of viral infections in this setting has not been formally evaluated.

This subanalysis is based on pooled data for pts treated with LEN+DEX from two pivotal, large, phase 3 registration studies (MM-009 and MM-010). The median duration of follow-up in all surviving pts as of data cutoff on July 2008 for MM009 and March 2008 for MM010 was 48 months. In these two studies, pts were randomized to receive either LEN 25 mg or placebo (PBO) on days 1–21 and oral DEX 40 mg on days 1–4, 9–12, and 17–20 for the first 4 cycles, after which DEX was administered on days 1–4 only of each 28-day cycle. Neutropenia was managed with dose adjustments and G-CSF per protocol. Protocol did not specify antiviral prophylaxis during the study. Pts diagnosed with relevant viral infection were included in this analysis and categorized as follows: herpes simplex infections (viral conjunctivitis not otherwise specified [NOS], herpes simplex, herpes viral infection NOS, herpes stomatitis), herpes zoster infections (herpes zoster, herpes zoster ophthalmic), and other viral infections (viral infection NOS). The same adverse events (AEs) but within a different time period or with a change in severity were counted as separate events. Viral infection events include the categories of herpes simplex, herpes zoster, and other viral infections.

Of 351 pts treated with PBO+DEX, 37 pts (11%) had 45 viral infection events; 4/45 (9%) were G3/4. Of 353 pts treated with LEN+DEX, 42 pts (12%) had viral infection events with 26 (7.4%) having herpes simplex, 20 (5.7%) herpes zoster, and 6 (1.7%) other viral infections. Among these 42 pts, 77 viral infection events were reported; 7/77 (9%) were G3/4. When events were adjusted for pt-months, overall incidence of viral infection was significantly lower with LEN+DEX versus PBO+DEX (0.9 vs 2.0 events per 100 pt-months; P < 0.01). The median time to both first viral infection event and first G3/4 viral infection event was 5 months. The median duration of G3/4 infection was 14 days. Four pts (1%) experienced 5 serious AEs with a median duration of 11 days. The occurrence of viral infection events remained constant over time with LEN+DEX, and did not increase during the duration of therapy.

LEN+DEX therapy is associated with a low incidence of viral infection and the incidence remained constant over the duration of therapy. The incidence of viral infections on LEN+DEX is significantly lower, despite a large number of pts who crossed over from PBO+DEX to the LEN+DEX arm. These data support the predictable safety profile of LEN+DEX, thereby supporting lenalidomide continuous therapy in pts with RRMM.

Baz:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Consultancy. Hussein:Celgene Corporation: Employment. Swern:Celgene Corporation: Employment. Dimopoulos:Celgene Corporation: Honoraria.