Current and Novel Alkylators in Multiple Myeloma

A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors’ knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market.

Current and Novel Alkylators in Multiple Myeloma

A large number of novel treatments for myeloma have been developed and approved, however alkylating drugs continue to be part of standard regimens, additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors knowledge of the field to review the history, current use and novel concepts around traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of standard-of-care in myeloma, and new alkylators are coming to the market.

DNA Damaging Agents in Chemical Biology and Cancer

Despite their toxicity, DNA alkylating drugs remain a cornerstone of anticancer therapy. The classical thinking was that rapidly dividing tumour cells left more of its DNA in an exposed single-stranded state, making these rapidly dividing cells more susceptible to alkylating drugs. As our understanding of DNA repair pathways has matured it is becoming clear that compromised DNA repair – a hallmark of cancer – plays a role as well in defining the therapeutic window of these toxic drugs. Hence, although new alkylating motifs are unlikely to progress through the clinic, the legacy of these medicines is that we now understand the therapeutic potential of targeting DNA damage repair pathways. Here we look at the history of alkylating agents as anticancer drugs, while also summarizing the different mechanistic approaches to covalent DNA modification. We also provide several case studies on how insights into compromised DNA repair pathways are paving the way for potent and less toxic targeted medicines against the DNA damage response.