Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse

Round 1

Reviewer 1 Report

This is a comprehensive review which presents the scenario of clinical interventions in patients with relapsed or refractory MM. To improve the manuscript, this reviewer recommends the following points:

In the first part (Overview of Available Therapies in RRMM), the author should:

1. Add a paragraph on the role of immune system in the activity of IMIDs

2. Add a paragraph on the mechanism of drugs, which are then described in the clinical scenario portion (e.g. selinexor)

3. Add a paragraph on BiTes and CAR-T therapy 

In the second portion (clinical scenario), additional more recent references should be added in the section on second transplant (e.g. Dhakal et al, Leukemia, 2021)

 

Author Response

Point 1: Add a paragraph on the role of immune system in the activity of IMIDs

 

Response 1: the following paragraph has been added to address the interplay of the immune system in the activity of IMiDs (line 102-116) with references added to reference section

 

In addition, immune dysregulation is a hallmark of MM by way of abnormal Th1/Th2 ratios, aberrant T cell function achieved via TGF-β secretion by MM cells, and immune suppression via disruption of Treg/Th17 balance [21].  IMiDs induce T cell proliferation and co-stimulation through INF-γ, IL-10, and IL-2 production. Dendritic cell (DC) activation through IMiD-enhanced DC-antigen presentation increases activation of CD4⁺/CD8⁺ T cells which promotes immune surveillance and an anti-myeloma profile [11]. Myeloma-induced exhaustion and senescence of T cells is seen in the bone marrow milieu. Lenalidomide maintenance has been shown to reduce programmed cell death protein 1 (PD-1) expression on CD8⁺ T cells which may be an additional mechanism by which IMiDs may reverse such senescence and exhaustion [22]. Lenalidomide’s ability to increase IFN- γ promotes a phenotypic shift to a Th1 profile that results in amelioration of the defective anti-tumor Th1 population seen in MM [23]. Myeloid-derived suppressor cells, Tregs, central memory CD8⁺ T cells, and effector memory CD8⁺ T cells were all increased following Lenalidomide treatment – suggesting immunomodulation on many different lymphoid compartments [24].

 

 

11. Corral, L.G., et al., Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol, 1999. 163(1): p. 380-6.
12. D'Souza, C., H.M. Prince, and P.J. Neeson, Understanding the Role of T-Cells in the Antimyeloma Effect of Immunomodulatory Drugs. Front Immunol, 2021. 12: p. 632399.
13. Danhof, S., et al., Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance. Haematologica, 2018. 103(3): p. e126-e129.
14. Luptakova, K., et al., Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother, 2013. 62(1): p. 39-49.
15. Busch, A., et al., Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients. Clin Exp Immunol, 2014. 177(2): p. 439-53.

 

 

 

Point 2: Add a paragraph on the mechanism of drugs, which are then described in the clinical scenario portion (e.g. selinexor)

 

Response 2: The following content has been added addressing the mechanisms of action of Selinexor (line 220-239) with references added to references section

 

2.6. Selinexor:

Selinexor, is a first-in-class oral selective inhibitor of nuclear export (SINE), currently FDA approved in combination with Bortezomib and Dexamethasone for patients having received 1 prior therapy [62]. Selinexor reversibly inhibits the nuclear export function of Exportin-1 (XPO1), a protein that is responsible for shuttling over 200 macromolecules out of the nucleus [63].  Selinexor binds the leucine-rich nuclear export signal (NES) found in the karyopherin XPO1. Also known as Chromosomal Maintenance 1 (CRM1), XPO1 inhibition blocks the exporting of oncogene mRNAs such as c-myc resulting in a reduction of oncoproteins [64].  Additional anti-myeloma effects of Selinexor occur through reactivation of tumor suppressor proteins (TSPs) such as p53, sensitization of the glucocorticoid receptor to Dexamethasone, inhibition of the mTOR pathway, and retention of inhibitor of NF-κB (lκB) [65-67].  Retention of lκB inhibits NF-κB signaling – a known pathway involved in myeloma cell survival.  Kashyap et al. documented the synergy of SINE compounds with proteasome inhibitors through inhibition of the phosphorylation of IκB and NF-κB subunits thereby protecting IkB from proteasome degradation.  This results in NF-κB suppression and a subsequent increase in the cytotoxicity of myeloma cells seen both in vitro and in vivo [68].  There is relative sparing of non-malignant cells by tumor suppressor protein (TSP)-induced apoptosis as TSPs induce apoptosis in cells with significant DNA damage. This first-in-class SINE compound offers several new mechanisms against MM and may elucidate additional means of synergy among myeloma treatments.

 

62. FDA. Selinexor. 12/18/2020; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-refractory-or-relapsed-multiple-myeloma.
63. Mo, C.C., et al., Selinexor for the treatment of patients with previously treated multiple myeloma. Expert Rev Hematol, 2021. 14(8): p. 697-706.
64. Xu, D., N.V. Grishin, and Y.M. Chook, NESdb: a database of NES-containing CRM1 cargoes. Mol Biol Cell, 2012. 23(18): p. 3673-6.
65. Argueta, C., et al., Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death. Oncotarget, 2018. 9(39): p. 25529-25544.
66. Tai, Y.T., et al., CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia, 2014. 28(1): p. 155-65.
67. Gravina, G.L., et al., Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol, 2014. 7: p. 85.
68. Kashyap, T., et al., Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-kappaB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death. Oncotarget, 2016. 7(48): p. 78883-78895.

 

 

Point 3: Add a paragraph on BiTes and CAR-T therapy 

 

Response 3:  The following content has been added addressing the mechanisms of action of BITEs and CAR-T therapy (line 242-274) with references added to references section

 

2.7. CAR-T/BITE Therapy:

The molecular mechanisms by which CAR-T and BITE therapies are effective in treating myeloma is largely based on the interaction of the malignant plasma cell with autologous T-cells.  Multiple cell surface proteins expressed on plasma cells are targets for drug development with the most notable being B-cell maturation antigen (BCMA), a transmembrane, non-tyrosine kinase, glycoprotein.  BCMA is an ideal target to inhibit as it is not only preferentially expressed on plasma cells with minimal expression in stem cells or non-hematopoietic tissue but is also needed for survival of bone marrow plasma cells [69].  Furthermore, overexpression and activation of BCMA is associated with progression of myeloma in preclinical models and humans via canonical and non-canonical NF-kB pathways in charge of cell survival, growth, and metastasis [69]. 

 

BCMA CAR constructs contain an extra-cellular component derived from immunoglobulin heavy and light chain variable domains that link to form a single chain variable fragment (scFv) capable of recognizing BCMA [70].  A hinge or spacer domain is then linked to an intracellular CD3-zeta signaling chain of the T-cell receptor which provides the first signal for activation of the T cell [70].  Additionally, to promote CAR-T cell survival and proliferation, additional costimulatory domains are incorporated into the construct, which in the case of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), the costimulatory domain is 4-1bb [70].  Subsequent tumor killing is mediated by activated CAR-T cell mediated tumor killing by (1) granzyme and perforin mediated cytotoxicity (2) cytokine release to sensitize tumor stroma for target cell death, and (3) Fas/FasL mediated activation of caspase mediated cellular apoptosis [71]

 

BITE therapies are recombinant proteins which contain two separate linked single-chain variable fragments (scFv) which can simultaneously bind to a tumor cell and an immune effector cell to generate an immune synapse between the two [72]. In the case of BCMA directed BITEs the scFv recognizes BCMA on the plasma cell and CD3 on the T-cell [72].  Downstream effects of T cell activation are like what is seen with CAR-T cell therapy in that tumor killing is mediated by granzyme/perforin, cytokine release, and caspase mediated apoptosis.  The added benefit of BITEs involves upregulation of multiple T-cell compartments, both CD4+ and CD8+, leading not only to myeloma cell lysis but also differentiation of naïve T cells into memory T cells as well [72].

 

69. Shah, N., et al., B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia, 2020. 34(4): p. 985-1005.
70. Rodriguez-Lobato, L.G., et al., CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions. Front Oncol, 2020. 10: p. 1243.
71. Benmebarek, M.R., et al., Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. Int J Mol Sci, 2019. 20(6).
72. Cho, S.F., et al., Bispecific antibodies in multiple myeloma treatment: A journey in progress. Front Oncol, 2022. 12: p. 1032775.

 

Point 4: In the second portion (clinical scenario), additional more recent references should be added in the section on second transplant (e.g. Dhakal et al, Leukemia, 2021)

 

Response 4: The following paragraph has been added in the section on second transplant (Line 689-695) with the recommended reference added to the reference section.

 

More recently, an updated retrospective analysis of CIBMTR data was published by Dhakal and colleagues of 975 patients undergoing second ASCT between 2010 and 2015 [121].  Findings of NRM, PFS, and OS remained consistent as compared to prior analysis [121].  NRM at day 100, 1 year, and 3 years was 1%, 1%, and 2%, respectively [121].  PFS at 1 and 3 years was 50% and 13%, respectively; OS at 1 and 3 years was 94% and 68%, respectively; with significant improvement in PFS/OS in patients relapsing > 3 years as compared to < 3 years [121].

 

121. Dhakal, B., et al., Salvage second transplantation in relapsed multiple myeloma. Leukemia, 2021. 35(4): p. 1214-1217.

Reviewer 2 Report

The presented review is addressing a very interesting topic. Looking into the available therapies in the Relapsed/Refractory Multiple Myeloma. Nice presentation of the pharmacologic mechanisms underlying active therapies and of the future emerging therapeutical options. The future is about new strategies that are related to patients survival and response, quality of life and cost. Data are clear and comprehensive.

Author Response

We appreciate Reviewer #2's thoughtful analysis and comments of our review article.  Per our review of their comments, no specific changes were recommended.

Reviewer 3 Report

The authors described the current situation of myeloma comprehensively. 

Minor　point

Line 396, BLC2→BCL2

Author Response

We appreciate Reviewer #3's thoughtful analysis and comments of our review article.  Per our review of their comments, we have corrected the typo in Line 396 and uploaded it with tracked changes in the revised manuscript.