Over two-thirds of newly diagnosed multiple myeloma are over 65 years. The treatment goals for the non-transplant-eligible patients should be to prolong survival by achieving the best response, while ensuring quality of life. New upfront treatment combinations based on first generation of novel proteasome inhibitors and immunomodulatory drugs plus alkylating agents, the historical platform, have significantly improved outcomes in the past 10 years. Other non-alkylator induction regimens, essentially lenalidomide plus low-dose dexamethasone are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Data indicate that prolonged treatment extends the progression-free survival. In summary, this group requires individualized and dose-modified regimens to improve tolerability and efficacy, while maintaining their quality of life.