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Over the past 20 years, the treatment for multiple myeloma (MM) has evolved significantly. These pharmaceutical developments allow physicians to combine existing chemotherapy with newly approved novel and targeted medications to create various treatment regimens for MM. These novel drug combinations, immunomodulatory drugs (Thalidomide, lenalidomide and Pomalidomide) and proteasome inhibitors (Bortezomib and carfilzomib), are used upfront for induction therapy as well as for maintenance and treatment of subsequent relapses. However, the emergence of resistant myeloma clones to these drugs is usually inevitable. We describe 2 cases here that demonstrate beneficial response to old traditional chemotherapy combinations after patients become resistant to all novel drugs available. Therefore, our main message is that while novel drugs should be used in frontline combinations to treat MM patients, these novel drugs should not be the last word, and often going back to the old traditional chemotherapy may illicit response and possibly prolong survival.