Multiple myeloma (MM) remains incurable despite the advances made with the discovery of many novel drugs and three- to four-drug combination regimen therapy consisting of alkylators, proteasome inhibitors (PI), immunomodulatory agents (IMiD), corticosteroids, histone deacetylase inhibitors (HDAC inhibitors), and monoclonal antibodies [1]. Treatment failure is seen mainly secondary to resistance to these therapeutic agents, with a death rate of 3.1 per 100,000 population per year, as seen in SEERS 2016–2020 ^[1][2][1,2].

In 2017, the efficacy of anti-BCMA CAR-T therapy was first published on relapsed/refractory multiple myeloma (RRMM) patients ^[3][4][8,9]. CAR-Ts, including idecabtagene vicleucel (ABECMA, March 2021) and ciltacabtagene autoleucel (Carvykti, February 2022), are genetically modified autologous T-cells received approval from Food and Drug Administration (FDA) for use in RRMM after four or more prior lines of therapy, including an ImiD, a PI, and an anti-CD38 monoclonal antibody ^[5][6][10,11]. Belantamab mafodotin is the first BCMA/ADC that received accelerated approval by the FDA to be used in adult RRMM; however, it was later withdrawn from the US market in November 2022 as the DREAMM-3 phase 3 trial did not meet its primary endpoint ^[7][12]. It is currently used in some circumstances as an expanded access program. On the other hand, teclistamab is the first bispecific antibody to attain accelerated approval by the FDA for adult RRMM who have received at least four prior lines of therapy including a PI, an IMiD, and an anti-CD38 monoclonal antibody ^[8][13]. To date, the BCMA-targeting agent has shown 70–100% overall responses in heavily treated RRMM ^[9][14]. However, patients can encounter life-threatening complications such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia(s), infections, hemophagocytic lymphohistocytosis, and other systemic toxicities.

2. Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Chimeric antigen receptor-T cells (CAR-T) are genetically modified T cells that express chimeric antigen receptors (CAR) that could beautologous vs. allogeneic, consisting of three domains: an extracellular (usually from a single-chain variable fragment of an antibody), an intracellular, and a co-stimulatory domain ^[9][14]. These cells bind to tumor antigens in a major histocompatibility complex (MHC)-independent manner, resulting in cytotoxic T-cell mediated tumor lysis ^[10][23]. To date, the FDA has approved two autologous CAR-T cells for adult RRMM patients who received four or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody ^[5][6][10,11]. The approval of idecabtagene vicleucel (ide-cel) was granted after a single-arm study (KarMMa, NCT03361748) on patients with RRMM; the multicenter multicohort phase II of this study (KarMMa-2) is ongoing (n = 31), which showed an overall response rate (ORR) of 87.1% with complete response/stringent complete response (CR/sCR) in 74.2%, very good partial response (VGPR) in 3%, and partial response (PR) in 1% patients after a median follow up (mFU) of 27.5 months ^[11][15]. An open-label phase III study (KarMMa-3, NCT03651128) assessed the difference in response in RRMM patients to ide-cel versus standard therapy. These patients previously received two to four regimens, including an IMiD, PI, and daratumumab. The ORR was recorded at 71% (CR in 39%) in ide-cel cohort, and 42% (CR in 5%) in the standard therapy cohort after a mFU of 18.6 months. The median progression-free survival (mPFS) was 13.3 and 4.4 months in the ide-cel and standard-therapy group, respectively ^[12][24]. The approval of the second CAR-T therapy ciltacabtagene autoleucel (cilta-cel) for RRMM came after the CARTITUDE-1 trial (NCT03548207), a phase Ib/II study (n = 97), in which eligible patients received ≥ 3 prior line of therapy (LOT) or were double refractory to a PI and IMiD. ≥CR was achieved in 78.3% of the cases after an mFU of 33.4 months. The median duration of response (mDOR) was 33.9 months, and the mPFS was 34.9 months ^[13][16]. In CARTITUDE-2 (NCT4133636), a phase II study, which is being conducted on three different cohorts, cohort A (n = 20) has patients with progressive MM after 1–3 prior LOT (including a PI and IMiD) with no previous exposure to BCMA, cohort B (n = 19) has patients with early progressive MM with one prior LOT without any exposure to BCMA, and cohort C (n = 20) has patients with progressive MM after exposure to BCMA-targeting agent. The ORR was recorded at 95% (≥CR in 85% and ≥VGPR in 95%), 100% (≥CR in 90% and ≥VGPR in 100%), and 60% (≥CR in 30% and ≥VGPR in 55%) in cohort A, B, and C, respectively ^[14][15][16][25,26,27]. Recently, a phase 1 clinical trial (NCT03287804) got published, in which dual targeting CAR was constructed to target two myeloma antigens and BCMA. In this study (n = 11), patients received a median of 5 prior LOT, with 81.8% being double-refractory and 18.2% penta-refractory. A total of 45.5% responded, with 9% showing VGPR, 27.3% PR, and 9% a minimal response. The mPFS was five months, and the median overall survival (mOS) was 375 days ^[17][28].

3. Bispecific Antibodies (BsAbs)

Bispecific antibodies (BsAbs) are molecules that bind simultaneously to the tumor binding domain (such as BCMA) of MM cells and CD3-positive T cells, resulting in perforin and granzymes-mediated MM cell lysis ^[18][29]. Even though multiple bispecific antibodies are being investigated in different clinical trials, only teclistamab got FDA approval for use in adult RRMM patients, who have received at least four lines of therapy, including a PI, IMiD, and anti-CD38 monocloncal antibody ^[8][13]. The approval came after the MajesTEC-1 trial (NCT03145181 and NCT04557098), which evaluated 165 RRMM patients with a median age of 64. Patients had a median of five prior LOT, with 78% of the included population being triple refractory. A total of 43% of the patients achieved ≥ CR after an mFU of 22 months. The mDOR, mPFS, and mOS were 24, 12.5, and 21.9 months, respectively ^[19][17]. Moreover, another BsAb named elranatamab received FDA breakthrough therapy designation based on the result of a multicentered phase II MagnetisMM-3 study (NCT04649359) ^[20][30]. In this study, 123 patients were enrolled; 96.7% were triple-refractory and 42.3% were penta-refractory. The ORR was recorded at 61%, with CR/sCR seen in 31.7%, VGPR in 23.6%, and PR in 5.7% of patients after an mFU of 12.8 months ^[21][31].

4. Antibody-Drug Conjugates (ADCs)

Antibody–drug conjugates (ADCs) are monoclonal antibodies (mAbs) bound to a toxin through a protein-based linker, causing targeted death of malignant MM cells and mildly affecting the healthy cells ^[9][14]. Belantamab mafodotin (blenrep) (GSK2857916) is an ADC investigated in the DREAMM-2 trial (NCT03525678) on heavily treated RRMM patients. In the 2.5 mg/kg group (n = 97), the ORR was recorded at 32%, with 19% achieving ≥ VGPR. The mDOR, mPFS, and mOS were recorded at 12.5, 2.8, and 15.3 months, respectively. For the cohort who received blenrep at 3.4 mg/kg (n = 99), the ORR was recorded at 35%, with 24% of patients achieving ≥ VGPR. The mDOR, mPFS, and mOS were recorded at 6.2, 3.9, and 14 months, respectively ^[22][18]. Based on this study, the FDA approved blenrep for RRMM patients in August 2020 ^[23][32]. DREAMM-14 (NCT05064358) is currently investigating whether alternative dosing and/or schedule regimens improve overall benefit or risk profile ^[24][33]. In November 2022, the DREAMM-3 (NCT04162210) trial did not meet its primary endpoint of PFS, upon which it is being withdrawn from the US market for RRMM patients ^[7][12]. DREAMM-3 is an open-label randomized phase III study (n = 325) that compared blenrep against pomalidomide and low-dose dexamethasone (Pd) in RRMM cases. The mPFS was longer for blenrep at 11.2 months compared to 7 months for Pd, which resulted in its withdrawal ^[25][34]. However, there are many phase I/II/III clinical trials are ongoing on blenrep either as monotherapy or combination therapy in RRMM such as, DREAMM 4 (NCT03848845), DREAMM 5 (NCT04126200), DREAMM 6 (NCT03544281), DREAMM 7 (NCT04246047), DREAMM 8 (NCT04484623), DREAMM 9 (NCT04091126), DREAMM 12 (NCT04398745), and DREAMM 13 (NCT04398680), which may provide another avenue of approval ^[26][35].