Multiple myeloma (MM) is a malignant disorder of antibody-producing clonal plasma cells. It is the second most common hematologic neoplasia worldwide . Despite recent advances in myeloma treatment (high-dose chemotherapy followed by autologous stem cell transplantation, novel immunomodulatory drugs, and proteasome inhibitors); MM remains largely incurable with chemotherapy . This is mostly due to the persistence of minimal residual disease (MRD), which leads to high relapse rates . Furthermore, the prognosis of MM patients who become refractory to recently developed novel agents is very poor .
Myeloma is associated with profound immune dysfunction affecting the innate and adaptive immune system. Myeloma cells play also an important role in maintaining immunosuppression . In MM, there is reduced expression of HLA molecules, reduced tumor antigen peptides expression, enhanced expression of inhibitory ligands such as programmed cell death ligand 1(PD-L1) and PD-L2, and recruitment of counter-regulatory cells such as T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) .
The importance of host antitumor immunity is evidenced by long-term molecular CR observed post allogeneic stem cell transplantation  due to a graft-versus-myeloma effect exerted by donor-derived T lymphocytes . An overdue era of immune therapy in MM has begun .
So far, the only established immuno therapeutic approach for MM is allogeneic stem cell transplantation. However, it is associated with high morbidity and mortality and remains an option for only a fraction of patients .
MM immunotherapy can be divided into several categories:
Monoclonal antibodies targeting surface molecules present on myeloma cells;
Monoclonal antibodies targeting checkpoint inhibitors on immune cells;
In MM, several surface molecules have been explored in preclinical and clinical studies as potential targets of monoclonal antibodies. They include SLAMF7 (signaling lymphocyte activating-molecule family member 7), CD38, CD40, CD138, CD56, CD54 (also known as intercellular adhesion molecule 1), IL-6, PD1, CD74, CD162, B2-macroglobulin and GM-2 ganglioside. In 2015, FDA approved daratumumab (anti-CD38) and elotuzumab (anti- SLAMF7) for treatment of myeloma .
Monoclonal antibodies targeting CD38: CD38 is a type II transmembrane glycoprotein, expressed at high and uniform levels in most, if not all, plasma cells in all stages of the disease. It is not expressed on primitive hematopoietic precursors (CD34+CD38-), suggesting that hematopoietic recovery would occur following CD38-targeted cytotoxic agents . Both Daratumumab and isatuximab are anti-CD38 monoclonal
antibodies that trigger antibody-dependent cellular cytotoxicity
(ADCC), complement-dependent cytotoxicity and antibodydependent
phagocytosis, as well as inhibition of the enzymatic
activity of CD38. Moreover, even in the absence of Fc-receptorexpressing
effector cells, both monoclonal antibodies can induce
direct apoptosis and lysosome-mediated cell death in MM cells
harboring p53 mutations. However, CD38 levels alone may not
be the sole determinant of sensitivity to daratumumab, because
CD38-negative Tregs were also reduced in responsive patients
Daratumumab was approved for use in patients who have
failed at least 3 prior lines of therapy . Isatuximab shows
single-agent activity in relapsed / refractory myeloma (RRMM)
. Daratumumab was administered for prolonged periods at
moderate to high doses with little or no toxicity, despite the fact
that the CD38 molecule is also expressed at lower levels, on a
fraction of hematopoietic cells, cerebellar Purkinje cells, liver
and lung smooth muscle cells, and insulin-secreting cells of
pancreas . SAR650984 is another anti-CD38 antibody which
is under investigation in clinical trials .
Monoclonal antibodies targeting SLAMF-7: SLAMF7 is a
cell surface glycoprotein receptor highly expressed on MM cells
mediating family member 7 adhesion to BM stromal cells. It is
selectively expressed on plasma and natural killer (NK) cells
and lacks expression on other tissues. Elotuzumab is a fully
humanized monoclonal antibody directed against SLAMF-7. It
triggers ADCC and enhances NK cell function against MMCs .
Elotuzumab was approved in combination with revlimid and
dexamethasone for treatment of myeloma who received 1-3
prior therapies .
Compared with chemotherapeutic agents, monoclonal
antibody therapies appear to be associated with fewer side
effects and have distinct mechanisms of action that make them
more suitable and effective when combined with other antimyeloma
therapies, especially in patients with chemotherapyresistant
Monoclonal antibodies targeting checkpoint inhibitors
on immune cells: The engagement of T cell with its target is
regulated by a complex balance of costimulatory and coinhibitory
bidirectional signals (checkpoints)  which allow the cells to
turn on and off as needed. Checkpoint inhibitors take the brakes
off the immune system . Anti-PD-1 is a checkpoint inhibitor
that blocks the inhibitory interaction of PD-1 on T or NK cells
with its ligand PD-L1 on tumor cells or tumor-promoting
accessory cells . Blockade of PD-1/PD-L1 inhibits accessory
cell (plasmacytoid dendritic cells, pDC or MDSCs)-induced MM
proliferation and survival while triggering host T- and NK-cell
anti-MM cytotoxicity .
Recently, the anti-PD-1, pembrolizumab, in combination with
Rd (PRd), showed 38% response rate in lenalidomide refractory patients with an acceptable toxicity profile. The overall response
rate was 50% in a phase ½ study combining pembrolizumab
with pomalidomide in patients with a median number of 3
prior therapies. Seventy-five percent of patients were double
refractory to IMIDs and PIs . These studies demonstrate a
role for checkpoint inhibition in MM treatment paradigm and
underscore the need for IMIDs immunomodulation to achieve
this response .
Cancer vaccine aims to increase the precursor frequency
of antigen-specific T cells or antibodies through in vivo
priming . Vaccination against cancer-specific antigens
represents a promising strategy to modulate patient antitumor
immune response, particularly in the settings of early-stage
or minimal residual disease . Vaccines, in combination
with immunomodulatory agents, may serve to achieve and/
or maintain MRD hoping to prolong PFS (and possibly OS) .
Several vaccination approaches have been used for myeloma:
idiotype vaccines, GM-CSF-based cellular vaccines and dendritic
cells (DC)-based vaccines .
Idiotype refers to the unique immunological properties
of any individual immunoglobulin . The Id is expressed
and presented in an HLA-restricted manner on the surface of
malignant plasma cells . The secreted idiotype was up taken
and presented by dendritic cells and may act as T cell antigens
. However, idiotype vaccines were weakly immunogenic and
failed to elicit a measurable clinical benefit even when combined
with strong adjuvants such as granulocyte-monocyte colonystimulating
factor (GM-CSF), IL-12, alum or keyhole limpet
GM-CSF-based vaccine consists of 2 allogeneic cell lines:
H929 and U266, coupled to a GM-CSF-secreting by stander
cell line, K562/GM. This vaccine formulation has been tested
in patients with a near complete remission i.e. patients having
absent an M-spike and persistence of detectable immuno fixation
for 6months. This study suggested that the generation of tumorspecific
immunity in a low disease burden state can significantly
delay relapse .
Idiotype-loaded DCs have been used as vaccines in MM
patients, mostly in the setting of clinical remission after auto
transplant . Decreased regulatory-T cell function and minimal
disease state post transplant suggest that this is an optimal
setting for vaccination . Cancer testis antigens (C/T) are
physiologically expressed in testis and placenta trophoblast
only and have a potential role in cell cycle and apoptosis. C/T
antigens are up regulated in MM . C/T antigens are considered
ideal antigens to target and are the best studied examples within this category. They fulfill several parameters, including
their low expression on normal tissues and their expression
in more aggressive disease and in advanced stage disease .
However; their manipulation requires profiling of the C/T
antigen expression pattern in every MM individual patient .
An alternative approach is fusion of DCs with patient-derived
tumor cell lysates or apoptotic tumor cells. It optimizes antigen
presentation and immune priming against the entire antigenic
repertoire of each unique patients’ tumor. Presentation of
antigens from myeloma cell lines by dendritic cells is greatly
enhanced by coating myeloma cells with a specific antibody such
as anti-CD138 or use of myeloma cells lysed by repetitive freezethaw
IMiDs (thalidomide, lenalidomide and pomalidomide) are
incorporated into therapies for relapsed / refractory myeloma
(RRMM) and newly diagnosed MM. Moreover, maintenance
therapy with lenalidomide in both transplant-eligible and
-ineligible patients has markedly improved patient outcome .
They targets the tumor microenvironment through caspase-8-
mediated apoptosis; abrogation of MMC binding to BM stromal
cells; modulation of cytokine secretion; up regulation of T,
NK, and NK-Tcells; and down regulation of T regulatory cells.
Recently, the E3 ubiquitin ligase cereblon has been identified
as the molecular target of lenalidomide. Predicated on their
immuno stimulatory effects, IMiDs may enhance activities of
monoclonal antibodies, checkpoint inhibitors, and vaccines .
ACT aims to enhance T-cell antitumor activity through ex
vivo manipulations . Myeloma is an ideal disease to treat with
adoptive T cell therapy . This can be achieved through T cells
engineered to express large numbers of affinity-enhanced TCRs,
activated marrow infiltrating T cells and more recently with
cytotoxic T cells endowed with tumor-reactive chimeric antigen
receptors (CAR). Among these strategies, CAR-based therapies
are perhaps the most appealing, as CART cells recognize their
target antigens in an MHC-independent manner .
CAR T-cell therapy is the adoptive transfer of cytotoxic
T cells that are genetically engineered to express CAR.
CAR expressed on the cell surface redirect the cytotoxic T
cells toward the original target of the antibody in a non-
HLA-restricted manner . CAR T cells provide a new
and currently uncovered spectrum of effector mechanisms
against myeloma . There is a fully loaded pipeline of
novel CARs targeting myeloma antigens, including CD38 
and CD44v6 as well as SLAMF7-CARs [12,13].
CD38-CART cells are powerful immunotherapeutic
tools since they appeared capable in vitro of eliminating
primary CD38+ MM cells from patients who had become
resistant to various chemotherapies. This suggests that CD38-CAR therapy could be a viable choice for patients with
few or no further chemotherapy options. Further studies are
warranted to diminish the undesired effects of CD38-CART
cells against normal CD38+ cells .
B-cell maturation antigen (BCMA)-CART cells
BCMA is a target for immunotherapy because it is uniformly
expressed on myeloma cells. BCMA has no known expression
on normal solid tissue and only very restricted expression on
normal hematopoietic cells (normal plasma cells, some memory
B cells, and pDC). The observed toxicity was cytokine release
syndrome with fever, hypotension and hematologic toxicity.
The latter was quite significant in some patients, but within the
range that can be explained by the lymphodepleting conditioning
regimen and inflammation mediated by BCMA-CART cells in the
bone marrow. B-cell depletion is not anticipated when targeting
BCMA, as the majority of normal B cells are BCMA negative. The
persistence of BCMA-CAR T cells after administration to patients
in this trial was relatively short (3 months) .
The opportunity for using CAR is for dramatic tumor cell
reduction, even in high-risk, refractory MM . It can be used
also in the setting of fulminant relapsed disease when there is a
need for a rapid reduction in disease burden that would justify
the associated toxicity . Moreover, use of lenalidomide and/
or checkpoint inhibitors post-CAR-T cell therapy may allow for
persistence of cancer immune surveillance by avoiding T-cell
exhaustion . Its efficacy could be improved if combined
with immune checkpoint inhibitors and/or with survivin
and/or MCL-1 inhibitors which are effective modifiers of cell
adhesion-mediated immune resistance induced by the tumor
It is likely that the most effective immunotherapeutic
approach for MM will include strategies for expanding the
repertoire, function, and persistence of myeloma-directed T
cells as well as enhancing the sensitivity of MM cells to immune