Table 5.

Vantages and Disadvantage of monoclonal antibodies, Bispecific antibodies, Antibody drug conjugated and CAR-T cells.

Target	Therapeutic format	Advantage	Disadvantage
CD38	Naked monoclonal antibody	High clinical activity in triplets and quadruplets (dara-based regimens are novel standard of care for elderly patients).	Reduction of CD38+ activated T-cells. Perturbation of T-cell compartment.
		The target is generally unaffected by disease stage
	Bispecific antibody	No lymphodepletion regimen required No delay in treatment because they are “off the shell” products	Neurotoxicity, cytokine release syndrome (CRS) Short half-life and they need continuous infusion
SLAMF7	Naked monoclonal antibody (elotuzumab)	The target is slightly reduced during disease progression. However, SLAMF7 expression is retained in MM patients with relapsed/refractory disease, and after intensive prior therapy.	Lack of relevant clinical efficacy of elotuzumab as single agent or in triplets given frontline; it requires to be part of combination regimens
	Bispecific antibody	T-cell mediated cytolysis independent of major histocompatibility complex.	Short half-life and they need continuous infusion Multiple dosing is expected to elicit a durable response, with intermittent infusions (usually every 3 weeks)
	CAR-T cells	A virus-free CAR gene transfer using advanced Sleeping Beauty (SB) transposon technology. SB transposition in CAR-T engineering is attractive due to the high rate of stable CAR gene transfer enabled by optimized hyperactive SB100X transposase and transposon combinations, encoded by mRNA and minicircle DNA, respectively, as preferred vector embodiments (CARAMBA PROJECT). The allogenic anti-SLAMF7-CAR T cell (UCARTCS1) is the first ‘off-the-shelf’ CAR T-cell product in MM	Restrictive eligibility criteria (adequate heart, liver, and kidney function) SB technology requires lower biosafety level translating to lower infrastructure costs for manufacturing and quality control and high modularity
BCMA	Antibody drug conjugated	Off-the-shelf products, immediately available for patients with aggressive disease	Toxicity due to linker-payloads constructs (keratopathy for ADCs using anti mitotic agents). Potential lower response rate as single agents. Multiple dosing is expected to elicit a durable response, with intermittent infusions (usually every 3 weeks)
		Action independent from autologous T-cell fitness and host immune function (ideal for elderly patients).
	Bispecific antibody	Off-the-shelf products, immediately available for patients with aggressive disease Limited CRS (AMG420), extended half-life from dosing once a week (AMG701, CC-93269) to every 3 weeks (TNB-383B). Subcutaneous administration is intended to allow higher doses than intravenous administration without increasing adverse events and limited CRS (PF-06863135).	Cytokine release syndrome (CRS) Immune effector cells associated neurotoxicity syndrome (ICANS) Higher doses required for antigen target modulation AMG420: continuous I.V. infusion limits the patients’ compliance and quality of life, increased risk of catheter-related infections, neurological toxicity. PF-06863135: polyneuropathy Short half-life and they need continuous infusion
			Mechanisms of resistance: antigen loss or downregulation; immune response against BsAbs constructs; interference with sBCMA
	CAR-T cells	Usually only one infusion is needed The most potent single agent available in the RRMM setting CRS and neuropathy are usually grade 1–2 and manageable	Logistical challenges: lag time because of manufacturing Lymphodepleting conditioning chemotherapy required Cytopenias (sometimes severe and persistent) Limited persistence given the dependence on autologous T-cell fitness and host immune function Short-term remission duration Requirement of defined T-cell subset compositions and humanized targeting domains to reduce immunogenicity and promote engraftment and in vivo expansion High costs Exhaustion of manufacturing capacities of centralized and highly specialized GMP production facilities