Emerging treatments

Cereblon E3 ligase modulators (CELMoDs)

Cereblon modulators, such as iberdomide and CC-92480, bind to cereblon with a higher affinity than lenalidomide or pomalidomide and degrade Ikaros (IKZF1) and Aiolos (IKZF3) in pomalidomide-refractory patients.[180] Iberdomide is being evaluated as monotherapy in patients with relapsed or refractory multiple myeloma (RRMM), and in combination with standard treatments in patients with newly diagnosed MM or RRMM.[181][182] Trials are also under way evaluating iberdomide as maintenance therapy in patients with MM post-transplant.[183][184] CC-92480 is being evaluated in combination with dexamethasone in patients with RRMM, and in combination with standard treatments in patients with newly diagnosed MM or RRMM.[185][186]

Belantamab mafodotin plus bortezomib plus dexamethasone (for relapsed or refractory MM)

In one phase 3 study of patients with RRMM after at least one line of therapy, median progression-free survival with belantamab mafodotin (an antibody-drug conjugate targeting B-cell maturation antigen) combined with bortezomib and dexamethasone was 36.6 months versus 13.4 months for daratumumab plus bortezomib plus dexamethasone.[187]

Belantamab mafodotin plus pomalidomide plus dexamethasone (for relapsed or refractory MM)

In one phase 3 study of lenalidomide-exposed patients with RRMM after at least one line of therapy, the 12-month estimated progression-free survival with belantamab mafodotin (an antibody-drug conjugate targeting B-cell maturation antigen) combined with pomalidomide plus dexamethasone was 71% versus 51% for pomalidomide plus bortezomib plus dexamethasone.[188]

Ixazomib plus pomalidomide plus dexamethasone (for refractory MM)

In one phase 1/2 study of patients with lenalidomide- and proteasome inhibitor-refractory MM, an oral triplet regimen comprising ixazomib plus pomalidomide plus dexamethasone demonstrated an overall response rate of 51.7%.[189] Median duration of response was 16.8 months, median progression-free survival 4.4 months, and median overall survival 34.3 months.[189]

Next-generation proteasome inhibitors

These include marizomib (also known as NPI-0052, an inhibitor of all three sub-units of the 20S proteasome [beta5, beta1, and beta2]) and oprozomib.[190][191][192]​ In one phase 1 dose escalation clinical trial, patients with RRMM responded to single-agent marizomib with minimal adverse effects.[193] Marizomib has received orphan drug designation for MM by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

B-cell maturation antigen (BCMA)-directed therapies

BCMA is a cell surface protein that is expressed on select B-cells and mature plasma cells. Binding of BCMA to its ligands APRIL and BAFF promotes B-cell proliferation and differentiation.[194] BCMA-directed bispecific antibodies/T-cell engagers (BITEs) include PF-06863135 and CC-93269. BCMA-directed antibody-drug conjugates include AMG-224 and SEA-BCMA.[195]​​[196][197][198][199]

Myeloid cell leukaemia-1 (MCL-1) inhibitors

Induced myeloid leukaemia cell differentiation protein Mcl-1, encoded by the gene MCL-1, is a member of the B-cell lymphoma 2 (BCL-2) family of multi-domain proteins that regulates apoptosis.[200] MCL-1 promotes the survival of MM cells.[201] MCL-1 inhibitors that are being evaluated in patients with MM include MIK665 (also referred as S64315), AMG 397, AZD5991, and AMG 176.

BCL-2 inhibitors

BCL-2 is a member of the BCL-2 family of pro-apoptotic and anti-apoptotic proteins that function to regulate apoptosis.[202] Trials of venetoclax (an oral BCL-2 inhibitor) in patients with RRMM were temporarily suspended following reports of an increased risk of death among patients receiving venetoclax (combined with bortezomib and dexamethasone [VD]) compared with the control group.[203] Overall survival analysis of the trial indicated that patients who benefited most from venetoclax plus VD were those with either t(11;14) or tumour cells with high BCL-2 expression.[204]

BRAF and MEK inhibitors

The use of combined therapy with a BRAF inhibitor (e.g., encorafenib, vemurafenib) and a MEK inhibitor (e.g., cobimetinib, binimetinib) has been reported in patients with BRAF V600 mutation-positive RRMM.[205][206][207] Research is ongoing.

Autologous stem cell transplantation followed by allogeneic transplantation

Autologous stem cell transplantation followed by non-myeloablative allogeneic transplantation improved survival compared with double autologous transplantation during a median 45-month follow-up.[208] Non-myeloablative regimens that preserve graft-versus-myeloma allogeneic immunity may help to reduce toxicity.[100][209] Allogeneic transplantation should only be conducted in the setting of specialised centres or clinical trials.  

Melphalan flufenamide

In February 2021, the FDA granted accelerated approval for melphalan flufenamide in combination with dexamethasone for use in adults with RRMM who have received four or more lines of prior therapy and with disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody. Accelerated approval was based on the results of a single-arm phase 2 study reporting an overall response rate of 29%.[210] A confirmatory phase 3 study showed no improvement in overall survival with melphalan flufenamide (plus dexamethasone) compared with pomalidomide (plus dexamethasone) in adults with RRMM, but its primary end point of improvement in progression-free survival was met.[211] In February 2024, the FDA announced its final decision to withdraw approval of melphalan flufenamide in the US due to the results of the confirmatory phase 3 study, and its safety and efficacy profile.[212]​ Melphalan flufenamide is approved in other countries (including Europe) for patients with RRMM (specific indications may differ).

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