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Bendamustine is a bifunctional alkylating agent. A retrospective study of bendamustine monotherapy and
corticosteroid combination has resulted in 3% “very good” partial response, 33% partial response, 26% stable
disease, and 20% progressive disease, along with a median PFS of 7 months and OS of 17 months in
[125]
RRMM . The combination regimens of bendamustine with thalidomide, lenalidomide plus
dexamethasone, and bortezomib plus dexamethasone have also demonstrated good tolerability and
improved efficacy in early trials of RRMM [126,127] .

Histone deacetylase inhibitors (HDACi) target the effects of epigenetic modification and have demonstrated
positive outcomes in RRMM patients, especially when used in combination with PIs. In the phase III
PANORAMA-1 trial, RRMM patients received panobinostat plus bortezomib and dexamethasone versus
placebo plus bortezomib and dexamethasone. The results demonstrated a clinically significant improvement
[128]
with a median PFS of 11.99 months vs. 8.08 months . Similarly, the PANORAMA-2 trial tested
panobinostat combination therapy in bortezomib-refractory patients with a subsequent 34.5% ORR and 6
[129]
months median response duration . Another HDACi vorinostat was tested in the VANTAGE 095 trial
involving heavily pretreated RRMM refractory to bortezomib and immunomodulators. A combination of
vorinostat and bortezomib resulted in an ORR of 17%, median response duration of 6.3 months, PFS of 3.1
months, and OS of 11.2 months . Furthermore, the phase III VANTAGE 088 trial compared the outcome
[130]
of vorinostat plus bortezomib with the bortezomib group alone. The study’s results included a PFS of 7.63
months vs 6.83 months and an ORR of 56.2% vs 40.6% .
[131]
Salvage ASCT
Salvage ASCT is an important therapeutic choice for RRMM. Several retrospective studies have
demonstrated post-reinduction salvage ASCT success in MM patients who relapsed after first ASCT or
RVD-alone treatment . Although most patients with RRMM were not candidates for salvage ASCT due to
[132]
age and comorbidities, those who underwent salvage ASCT exhibited a PFS of 7 to 22 months. The foremost
factor predicting improved PFS and OS after salvage ASCT is the duration of remission after initial
ASCT .
[121]
Selinexor
Selinexor is an oral, slowly reversible, first-in-class, potent selective inhibitor of nuclear export compound
that specifically blocks exportin 1 (XPO1). The Food and Drug Administration has approved selinexor for
RRMM patients who have had 4 previous therapies and disease refractoriness to 2 PIs, 2 IMiD agents, and
[133]
anti-CD38 mAb . The Selinexor trials are summarized in Table 5.
Immunotherapies for multiple myeloma
Advances in cellular immunotherapy - CAR (chimeric antigen receptor) T-cell therapy, B cell maturation
antigen (BCMA)-targeted therapies, and bispecific T cell engager (BiTE) and tri-specific T cell engager
[121]
(TiTE) - have good prospects in MM therapy . In CAR T-cell therapy, T cells are modified to express
CARs genetically through introducing fusion proteins that have an antigen recognition region and a co-
stimulation domain. CAR T-cells targeting BCMA, CD138, CS1 glycoprotein antigen (SLAMF7), and light
[134]
chains are in active development for RRMM treatment . BCMA is a type of surface receptor, which
belongs to the tumor necrosis factor superfamily. It is expressed in advanced B cell differentiation stages,
and predominantly in plasma cells. Several BCMA-targeted therapeutics, including antibody-drug
conjugates (e.g., belantamab mafodotin GSK2857916), CAR-T cells, BiTEs, and TiTE have also resulted in
[135]
incredible clinical response in RRMM . Tables 6 and 7 summarize immunotherapy clinical trials for MM.