Despite enormous advances, management of multiple myeloma (MM) remains 
challenging. Multiple factors impact the decision to treat or which regimen to 
use at MM relapse/progression. Recent major randomized controlled trials (RCTs) 
showed widely varying progression-free survivals (PFS), ranging from a median of 
4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation 
proteasome inhibitors (carfilzomib and ixazomib), next-generation 
immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and 
daratumumab) were approved for relapsed and refractory MM. Daratumumab, 
targeting CD38, has multiple mechanisms of action including modulation of the 
immunosuppressive bone marrow micro-environment. In addition to the remarkable 
single agent activity in refractory MM, daratumumab produced deep responses and 
superior PFS in MM when combined with lenalidomide/dexamethasone, or 
bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and 
MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded 
superior response rates and PFS when combined with lenalidomide/dexamethasone. 
New combinations of these next generation novel agents and/or antibodies are 
undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, 
showed single agent activity in MM with t(11;14), and is being studied in 
combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, 
yielded promising results in quad- or penta-refractory MM including patients 
resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is 
being tested in combination with lenalidomide/dexamethasone or 
pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell 
maturation antigen have yielded deep responses in RRMM. Finally, salvage 
autologous stem cell transplantation (ASCT) remains an important treatment in MM 
relapsing/progressing after a first ASCT. Herein, the clinical trial data of 
these agents are summarized, cautious interpretation of RCTs highlighted, and 
algorithm for salvage treatment of relapse/refractory MM proposed.