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Hanley N Abramson Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, 48201, USACorrespondence: Hanley N AbramsonWayne State University, Department of Pharmaceutical Sciences, 259 Mack Ave, Detroit, Mi, 48201, USATel +1 248 420 5335Email ac2531@wayne.eduAbstract: Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) – the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease’s five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.Keywords: multiple myeloma, monoclonal antibodies, antibody-drug conjugates, bi-specific antibodies, chimeric antigen receptor T-cells, cytokine release syndrome

Therapeutic measures designed to treat multiple myeloma (MM) have undergone a fundamental shift over the past two decades as a number of small molecules that attack this cancer by different mechanisms, including proteasome blockade, immunomodulation, and histone deacetylase (HDAC) inhibition, have been introduced. The insertion of monoclonal antibodies (mAbs) into the mix began in 2015 with the U.S. Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, which target CD38 and SLAMF7, respectively. In 2020, they were joined by another anti-CD38 mAb, isatuximab, and the bispecific antibody-drug conjugate (ADC) belantamab mafodotin, which targets the B-cell maturation antigen (BCMA). This review focuses on additional mAbs currently under clinical study for MM. These include several BCMAxCD3-directed bispecifics (AMG 420, AMG 701, REGN5458, REGN5459, teclistamab, and TNB-383B), the ADCs indatuximab ravtansine and STRO-001, and checkpoint inhibitors, although the future status of the latter is in a state of flux due to toxicity issues that arose in trials in which these drugs, especially PD-1 or PD-L1 blockers, were combined with immunomodulators.

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

An application of aminoacetaldehyde dialkoxy acetal to introduce an amino fuctionality in the 6 and/or 11 position of the naphthacenetrione ring system, resulting in key intermediates to aminated anthracyclines, is described.

An efficient and simple preparation of α - substituted aminoanthraquinones using 2,2-dialkoxyethylamines is described.

An application of aminoacetaldehyde dialkoxy acetal to introduce an amino fuctionality in the 6 and/or 11 position of the naphthacenetrione ring system, resulting in key intermediates to aminated anthracyclines, is described.

A series of anthraquinonyl glucosaminosides (10a-e) were synthesized by Koenigs-Knorr glycosidation of the corresponding aglycones (11a-e) with bromo sugar 12 followed by saponification. These glycosides were intended to serve as models to study the role played by the hydroxyl substituents on the aglycone portion of the antitumor anthracycline antibiotics. Superoxide generation as measured in rat heart sarcosomes was found to increase with the addition of successive hydroxyl groups to the anthraquinone nucleus. The 1,8-dihydroxy pattern was determined to generate significantly less superoxide than the 1,4-dihydroxy pattern. Hydroxyl substitution was also observed to stabilize the complex formed between the anthraquinones and DNA and was required for antibacterial activity against a number of Gram-positive organisms.

The synthesis of a 3β‐thiocyanatocardenolide is described. The compound exhibited about 0.1 times the cardiotonic effect of digitoxigenin in the isolated frog heart preparation. At a dosage of 20 mg/kg in the intact rat, it elicited ECG changes similar to those seen with a 10‐mg/kg dose of digitoxigenin. Studies also revealed the new cardenolide to be a reversible inhibitor of sodium‐ and potassium‐activated adenosine triphosphatase.

A totally synthetic route to the antibacterial fungal metabolite nectriapyrone (1) has been achieved by condensation of methylmalonyl dichloride with ethyl trans-4-methyl-3-oxo-4-hexenoate followed by hydrolysis, decarboxylation, and methylation of the resulting 3-methyl-4-hydroxy-5-carbethoxy-6-(trans-1-methyl-1-propenyl)-2-pyrone. Exploration of an alternate scheme involving the dehydrogenation of 6-substituted-4-methoxy-5,6-dihydro-2-pyrones, prepared by Reformatsky reaction of ethyl γ-bromo-β-methoxycrotonate with various aldehydes, was abandoned since it did not appear to have general applicability to the preparation of nectriapyrone and its analogs.

The total synthesis of dl-4 xi-(4-carboxybutyl)-5-carbethoxy-cis-hexahydropyrrolo[3,4-d]imidazol-2-one (N-carbethoxyazabiotin) by a 16-step sequence, starting from 2-bromo-6-methoxyhexanoic acid, has been accomplished.

Bisnorazabiotin was synthesized in a six-step sequence from 1,5-dioxo-2-carbethoxypyrrolizidine. It is anticipated that the molecule will serve as a cofactor for biotin-requiring enzymes.

The sulfur atom in the vitamin biotin has previously been suggested to be essential in biotin's mechanism of action. In a series of investigations on structure-function relationships with biotin analogs not containing the sulfur atom, the biotin analogs, azabiotin, bisnorazabiotin, carbobiotin and isoazabiotin enhanced guanylate cyclase, an enzyme that has recently been demonstrated to be activated by biotin. These analogs increased guanylate cyclase activity two-fold in liver, cerebellum, heart, kidney and colon at 1 microM concentrations. The ED50 for stimulation of guanulate cyclase activity occurred at 0.1 microM for each of the biotin analogs. These data indicate that the sulfur atom is not essential in biotin's activation of guanylate cyclase since these analogs do not contain the sulfur atom. Studies on the ring structure of biotin revealed that even compounds with a single 5-membered ring (2-imidazolidone) could augment guanylate cyclase activity. The guanylate cyclase co-factor manganese was not essential for the enhancement of guanylate cyclase by these agents but a maximal activation of this enzyme by these analogs could not be obtained without manganese present.

Bisnorazabiotin was synthesized in a six-step sequence from 1,5-dioxo-2-carbethoxypyrrolizidine. It is anticipated that the molecule will serve as a cofactor for biotin-requiring enzymes.

The total synthesis of dl-3a,4,6a-cis-4-(4-carboxybutyl)-hexahydropyrrolo[3,4-d]imidazol-2-one hydrochloride (dl-azabiotin hydrochloride) was accomplished in a seven-step sequence from 2-ethoxycarbonylazepin-7-one.

A series of anthraquinonyl glucosaminosides (10a-e) were synthesized by Koenigs-Knorr glycosidation of the corresponding aglycones (11a-e) with bromo sugar 12 followed by saponification. These glycosides were intended to serve as models to study the role played by the hydroxyl substituents on the aglycone portion of the antitumor anthracycline antibiotics. Superoxide generation as measured in rat heart sarcosomes was found to increase with the addition of successive hydroxyl groups to the anthraquinone nucleus. The 1,8-dihydroxy pattern was determined to generate significantly less superoxide than the 1,4-dihydroxy pattern. Hydroxyl substitution was also observed to stabilize the complex formed between the anthraquinones and DNA and was required for antibacterial activity against a number of Gram-positive organisms.

Digoxigenin-3,12-dibromoacetate (DDB), an alkylating derivative of digoxigenin, was synthesized and tested as a cardiotonic steroid (CS) site directed affinity label for Na + +K + -ATPase (ATP phosphohydrolase EC 3.6.1.3). DDB inhibited rat brain Na + +K + -ATPase with an I 50 of 5 × 10 −6 M and readily displaced specifically bound 3 H-ouabain from its binding sites on Na + +K + -ATPase. If the enzyme was exposed to DDB prior to the addition of 3 H-ouabain its ability to bind 3 H-ouabain was decreased, consistent with the concept that DDB interacted irreversibly with the cardiotonic steroid binding sites of Na + +K + -ATPase. However, DDB proved to be an even more effective inhibitor of 3 H-ouabain binding under conditions where it was unlikely that it could interact with the CS binding sites of this enzyme, suggesting that DDB inhibited 3 H-ouabain binding by non-cardiotonic site directed actions. Similarly, the presence of excess strophanthidin did not protect this enzyme against irreversible inhibition by DDB. The data suggest that the presence of a bromoacetate group at the 12 position on cardiotonic steroids does not confer CS binding site directed alkylating properties on these drugs.

The total synthesis of dl-3a,4,6a-cis-4-(4-carboxybutyl)-hexahydropyrrolo[3,4-d]imidazol-2-one hydrochloride (dl-azabiotin hydrochloride) was accomplished in a seven-step sequence from 2-ethoxycarbonylazepin-7-one.

The cardiotoxicity and cytotoxicity for tumor cells of four new synthetic anthraquinonyl glucosaminosides were compared in vitro. The nonhydroxylated anthraquinone was not cardiotoxic, and its cytotoxic activity was the weakest of the compounds in the series. Increasing the number of hydroxyl groups on the anthraquinone moiety increased the inhibition of growth of L-1210 leukemia cells and pancreatic or colonic adenocarcinomas in a soft agar colony formation assay. However, cardiotoxicity was also increased in proportion to the number of hydroxyl groups present. The adenocarcinomas were slightly more sensitive than the leukemias to the inhibitory action of the dihydroxylated anthraquinonyl glucosaminosides on cell growth.

Nach Uberfuhrung von Digitoxin (I) in (II) auf bekanntem Weg erfolgt aus (II) in zwei Stufen die Darstellung der Verbindung (III).

The synthesis of a 3 β -thioacetylcardenolide is described. The thioacetate exhibited effects similar to those seen with digitoxigenin acetate on the isolated frog and guinea pig hearts at 1 × 10 − 7 dilution. In the intact rat heart, the lethal dose was 5 mg/kg for the thioacetate and 2.5 mg/kg for digitoxigenin acetate. The thioacetate inhibited sodium- and potassium-activated adenosine triphosphatase to the same extent as digitoxigenin, but it was somewhat less inhibitory than digitoxigenin acetate.