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Educational theme | Monoclonal antibodies for the treatment of multiple myeloma
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Monoclonal antibodies (mAbs) have broadened the treatment scope of numerous pathologies, including cancer. As the next educational theme, the Multiple Myeloma (MM) Hub will be evaluating the ongoing potential of mAb-based therapies for the treatment of MM.
The use of mAbs in the MM setting is a relatively recent phenomenon, second to other hematological malignancies such as non-Hodgkin lymphoma and chronic lymphocytic leukemia, and is largely confined to patients with relapsed or refractory (RR) disease. Nonetheless, in addition to next-generation proteasome inhibitors (PIs) and novel immunomodulatory drugs (IMiDs®), mAbs have significantly improved the clinical outlook of patients with RRMM.
To supplement this educational theme, the MM Hub hereby presents a summary of a recent review published in Journal of Oncology, which provides an overview of mAb-based treatments for MM.1 This article also provides links to relevant articles and expert video interviews previously covered by the MM Hub.
mAb-based therapeutics1
There are a number of ways in which mAbs exert clinical activity, the basis of which include direct cytotoxic effects, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, complement-dependent cellular cytotoxicity (CDC), and disruption of cell–cell interactions. When considering therapeutic intervention with mAbs, target identification is of utmost importance. Ideal targets are those abundantly expressed or released by MM cells and may contribute directly to the pathogenesis of MM but should be inconsequential to physiological processes. Broadly speaking, target antigens include growth factors, signaling molecules, cell surface proteins, and adhesion molecules.
Current target antigens and therapeutics
Therapeutic mAbs have already demonstrated promising clinical outcomes in patients with MM, as summarized in Table 1.
Table 1. mAbs currently employed for the treatment of MM1
|
ADCC, antibody dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; BMSC, bone marrow stem cell; CDC, complement-dependent cellular cytotoxicity; FcR, Fc receptor; mAb, monoclonal antibody; MM, multiple myeloma; MoA, mechanism of action; NK, natural killer; Treg, T regulatory cells |
||
|
Target antigen |
mAb |
MoA |
|---|---|---|
|
CD38 |
Daratumumab |
– ADCC – ADCP – CDC – Direct apoptosis via FcR-mediated crosslinking – Increases CD8+/CD4+:Treg ratios
|
|
SLAMF7 |
Elotzumab |
– NK cell-associated ADCC – NK cell activation – Inhibition of MM cell–BMSC interaction |
CD38
Despite widespread expression, the transmembrane glycoprotein CD38 has proven an indispensable therapeutic target in MM. Preclinical evaluation of the humanized anti-CD38 mAb daratumumab (dara) revealed potent anti-MM activity in vitro. Dara has also been shown to enhance the overall immune response against MM cells via modulation of several immune components.
RRMM
Encouragingly, in vitro data translated to clinic, and single-agent dara received accelerated FDA approval in November 2015 for the treatment of patients with RRMM.2 Dara has since been successfully employed as a monotherapy and in combination with other novel agents (Table 2).
The phase III POLLUX (NCT02076009) study is currently investigating the clinical benefit of incorporating dara into a lenalidomide plus dexamethasone (Rd) regimen; results from the long-term follow up can be found here. Given the favorable patient outcomes demonstrated by dara in patients with MM, efforts are now underway to optimize the clinical potential. The MM Hub recently presented the results from an age-based subgroup analysis of the POLLUX and CASTOR studies, investigating the impact of age on the outcomes observed with different dara dosing schedules. The analysis showed that patients over the age of 65 benefitted most from the addition of dara to both Rd and bortezomib plus dexamethasone (Vd) regimens, compared to younger patients.
Dara in combination with the second-generation PI, carfilzomib, and dexamethasone is also being investigated in patients with RRMM in the CANDOR trial. The trial recently met the primary endpoint, with the primary analysis reported at the 61st American Society of Hematology (ASH) meeting. This combination appears to show particular promise in patients who are refractory to lenalidomide. Watch María Victoria Mateos discuss the CANDOR study below.
CANDOR study: should Dara-Kd become the new SOC for len refractory patients with RRMM?
Table 2. Summary of clinical trials investigating daratumumab for the treatment of RRMM1,3,4
|
dara, daratumumab; MM, multiple myeloma; MTD, maximum tolerated dose; NA, not available; NCT, national clinical trial; ORR, overall response rate; OS, overall survival; Pd, pomalidomide + dexamethasone; PFS, progression-free survival; Rd, lenalidomide + dexamethasone; Vd, bortezomib + dexamethasone *Updated analysis — median follow-up: 19.4 months (range, 0–27.7).4 †Primary analysis — median follow-up: 7.4 months.3 |
|||||||
|
Trial |
NCT number |
Phase |
Regimen |
ORR, % |
One-year OS, % |
Median PFS, months |
PFS, years (%) |
|---|---|---|---|---|---|---|---|
|
GEN501 |
I/II |
Dara |
36 |
77 |
5.6 |
— |
|
|
SIRIUS |
II |
Dara |
17 |
65 |
3.7 |
— |
|
|
EQUULEUS |
Ib |
Dara-Pd |
60 |
89 |
8.8
|
1 (42) |
|
|
CASTOR |
III
|
Dara-Vd vs Vd
|
83 vs 63
|
NA |
— |
1* (61 vs 27) 1.5† (48 vs 8) |
|
|
POLLUX |
III |
Dara-Rd vs Rd |
93 vs 76 |
NA |
— |
1 (83 vs 60) 2 (68 vs 41) |
|
NDMM
The phase III ALCYONE study (NCT02195479) uncovered that the addition of dara to a bortezomib, melphalan, and prednisone (VMP) regimen reduced the risk of disease progression by 50% in patients with newly diagnosed MM (NDMM) ineligible for transplant. The application of dara was henceforth extended to patients with NDMM when dara plus VMP was approved by the FDA in May 2018. It later gained European approval in September 2018 for the same indication.
Two major studies are currently evaluating the addition of dara to existing frontline triplet regimens for the treatment of NDMM. The CASSIOPEIA (NCT02541383) study aimed to determine the impact of adding dara to the bortezomib, thalidomide, and dexamethasone (VTd) regimen in patients with NDMM who were eligible for stem cell transplant. Results from Part 1 of the CASSIOPEIA trial revealed the benefit of dara plus VTd over VTd alone, and the quadruplet combination was approved by the FDA in September 2019 and the EMA in January 2020. Similarly, the GRIFFIN (NCT02874742) study is evaluating transplant-eligible patients with NDMM but with the combination of dara plus bortezomib, lenalidomide, and dexamethasone (VRd). Dara plus VRd improves stringent complete response rates and measurable residual disease (MRD) negativity vs VRd alone and stands as a promising treatment for patients with NDMM.5 Read the updated efficacy and safety results of the GRIFFIN trial here.
Highlights from ASH 2019 for transplant eligible patients with NDMM
SLAMF7
SLAMF7, otherwise known as CS1, is a cell surface glycoprotein, abundantly expressed by MM cells. The anti-SLAMF7 mAb, elotuzumab, has exhibited favorable clinical activity and safety profiles when combined with IMiDs or PIs in patients with RRMM.
A phase II study revealed that elotzumab enhanced the efficacy of Rd, inducing superior patient outcomes compared to Rd alone. Results from the phase III ELOQUENT-2 trial consolidated the addition of elotuzumab to Rd (EloRd), and these studies encouraged the FDA approval in 2015 of EloRd for the treatment of patients with RRMM following two or three prior therapies.6 EloRd is now an established first salvage regimen; read an article on the real-life experiences of EloRd here.
Elotzumab has made a promising addition to alternative regimens, receiving FDA approval for administration with pomalidomide plus dexamethasone (Pd) for the treatment of heavily pre-treated patients with RRMM in 2018. EloPd was later recommended by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) for patients with RRMM in 2019. Table 3 presents a summary of clinical trials investigating elotuzumab.
Table 3. Summary of clinical trials investigating elotuzumab in combination regimens in patients with RRMM1
|
Elo, elotuzumab; MTD, maximum tolerated dose; NA, not available; ORR, overall response rate; OS, overall survival; Pd, pomalidomide + dexamethasone; PFS, progression-free survival; Rd, lenalidomide + dexamethasone; RRMM, relapsed/refractory multiple myeloma; Vd, bortezomib + dexamethasone |
|||||
|
Trial |
Phase |
Regimen |
ORR, % |
Median PFS, months |
One-year OS, % |
|---|---|---|---|---|---|
|
Richardson et al., 20157 |
II |
Elo-Rd |
84 |
NA |
NA |
|
ELOQUENT-2 |
III |
Elo-Rd vs Rd |
79 vs 66 |
19.4 vs 14.9 |
NA |
|
Dimopoulos et al., 2018 |
II |
Elo-Pd vs Pd |
53 vs 26 |
10.3 vs 4.7 |
NA |
|
Jakubowiak et al., 2016 |
II |
Elo-Vd vs Vd |
66 vs 63 |
9.7 vs 6.9 |
85 vs 74 |
|
Jakubowiak et al., 2012 |
I |
Elo-Vd |
48 |
9.5 |
NA |
|
Lonial et al., 2012 |
I |
Elo-Rd |
82 |
NA |
NA |
CD20
CD20 has proven a particularly valuable therapeutic target in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia, and the anti-CD20 mAb, rituximab, is now used routinely to treat the conditions. The transmembrane phosphoprotein is copiously expressed across B-cell lineages, but demonstrates a significant decline following differentiation into plasma cells. Consequently, the clinical activity of rituximab is limited in MM. Furthermore, the increased expression profile of complement-inhibitory proteins exhibited by MM cells reduces the CDC-mediated effects of rituximab in MM.
Novel therapeutics1
Potential targets for mAb intervention are being uncovered frequently. Meanwhile, efforts are being made to refine mAb therapeutics against already established target antigens, such as CD38. Novel mAb-based therapeutics are illustrated in Table 4 and discussed further below.
Table 4. mAbs novel to the MM setting
|
ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; BMSC, bone marrow stem cell; CDC, complement-dependent cellular cytotoxicity; IL-6, interleukin 6, IL-6R, IL-6 receptor, mAb, monoclonal antibody; MoA, mechanism of action; PD-1, programmed death receptor-1; PD-L1, programmed death ligand-1 *Isatuximab triggers CDC in less than half of MM patients with high levels of CD38 in MM cells. |
||
|
Target antigen |
mAb |
MoA |
|---|---|---|
|
CD38 |
Isatuximab |
– Direct apoptosis – ADCC – ADCP – CDC* |
|
IL-6 |
Siltuximab |
– Complexes with IL-6 preventing binding to soluble and membrane-bound IL-6Rs – Inhibition of lymphocyte proliferation |
|
PD-1 |
Pembrolizumab Nivolumab |
– Reinstatement of immune-mediated tumor destruction |
Isatuximab (isa)
Isa, like dara, targets the CD38 receptor, but binds specifically to an epitope unique to human CD38. In concordance with other mAbs, addition of isa to existing treatment regimens has generated positive clinical outcomes. Results from a phase Ib study revealed the potential of isatuximab in combination with Rd for patients who had received ≥ 1 line of prior therapy, significantly improving overall response rates. Additionally, isatuximab plus Pd demonstrated significant clinical activity and favorable tolerability in a phase Ib study. The MM Hub presented a summary of the results from this study as presented at the 23rd Congress of the European Hematology Association (EHA) in 2018. Furthermore, the phase III ICARIA-MM trial (NCT02990338) reported clinical activity of isatuximab in combination with Pd vs Pd alone, and the regimen was granted FDA approval and EMA approval for the treatment of RRMM.
ICARIA MM: efficacy and safety of isatuximab, pomalidomide and dexamethasone in patients with RRMM
Siltuximab
As a crucial mediator of MM cell growth and survival, interleukin-6 (IL-6) is an attractive target for therapeutic intervention. Siltuximab is a chimeric anti-IL-6 mAb that has exhibited anti-MM activity in patients with dexamethasone-refractory disease. However, results from clinical studies in MM have reported conflicting results. One study suggested that, although siltuximab was not efficacious when used as a single agent, the combination of siltuximab with dexamethasone improved response rates in patients with dexamethasone-refractory MM. However, another showed that siltuximab failed to improve progression-free survival or overall survival as part of an alternative combination regimen with bortezomib. Siltuximab has also been evaluated for the treatment of smoldering MM, with the aim to delay progression to active disease, and also in combination with Vd to treat active MM. The clinical benefit of siltuximab is yet to be defined in MM but trial data suggest that IL-6 may not be as valuable a target as initially believed.
Pembrolizumab
The programmed death receptor-1 (PD-1)–programmed death-ligand 1 (PD-L1) axis is imperative for physiological immune regulation but has shown to be dysregulated in certain cancers. Inhibition of these immune checkpoint proteins reinstates immune-mediated tumor destruction, and anti-PD-1/PD-L1 mAbs have revolutionized the treatment setting of various cancers, including classical Hodgkin lymphoma. However, the lack of immune dysfunction in MM has led to contrasting conclusions, and trials that have continued to explore immune checkpoint inhibitors in the MM setting have reported limited success.
The KEYNOTE trials are some of the most prominent studies investigating the use of pembrolizumab, a humanized anti PD-1 mAb, as a treatment option for patients with RRMM and NDMM. The MM Hub was happy to provide an extensive summary of the key outcomes from across the KEYNOTE trials. The KEYNOTE trials were placed on clinical hold by the FDA due to increased risk of death amongst patients receiving pembrolizumab — for further information see the ‘What happened with pembrolizumab in MM clinical trials?’ article on the MM Hub.
Investigational mAbs
Considering the magnitude of factors contributing to malignancy in MM, the treatment scope of mAbs is vast. Target antigens are generally involved in MM cell growth, cellular adhesion, angiogenesis, apoptosis, and MM cell–microenvironmental cell contact. Table 5 presents novel targets, and their retrospective investigational mAbs, currently under investigation.
Table 5. Investigational humanized mAbs for the treatment of MM
|
luc, lucatumumab; mAb, monoclonal antibody; MTD, maximum tolerated dose; ORR, overall response rate; PR, partial response; Rd, lenalidomide + dexamethasone; taba, tabalumab, Vd, bortezomib + dexamethasone |
||
|
Target antigen |
mAb |
Clinical trials |
|---|---|---|
|
CD40 |
Dacetuzumab, lucatumumab |
Luc; 4% attained prolonged PR |
|
CD74 |
Milatuzumab |
No objective responses |
|
BAFF |
Tabalumab |
Vd + Taba; ORR, 44% |
|
GRP78 |
PAT-SM6 |
MTD not determined |
|
IGF-1R |
AVE1642 |
No objective responses |
|
ICAM-1 |
BI-505 |
No objective responses |
|
CD26 |
YS110 (huCD26mAb) |
Best responses, 50% |
Conclusion
A vast shift in the treatment approach to MM has been observed over the past few decades. mAbs have undoubtably contributed to this shift and the subsequent improvement in patient outcomes. mAb-based treatment represents a promising monotherapy, while also augmenting the clinical benefit of existing frontline combination regimens in the MM setting. mAbs may help to overcome resistance to certain therapies and improve patient outlook.
This introductory article has merely scratched the surface of the potential of mAb-based therapy in MM. mAbs are being extensively investigated, and are being exploited in novel therapeutic technologies including bispecific T-cell engagers, antibody–drug conjugates, and chimeric antigen receptor T cells. With continually increasing knowledge of the pathogenesis of MM, novel targets for mAb exploitation are being proposed on a regular basis.
The MM Hub will be generating a series of articles on mAbs for the management of MM. Make sure you check back for the next in the series!
Nishida H, Yamada T. Monoclonal antibody therapies in multiple myeloma: A challenge to develop novel targets. Journal of Oncology. 2019;2019:6084012. DOI: 10.1155/2019/6084012
FDA. Daratumumab (DARZALEX). https://www.fda.gov/drugs/resources-information-approved-drugs/daratumumab-darzalex. Published Nov 22, 2016. Accessed May 01, 2020.
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. New England Journal of Medicine. 2016;375(8):754-766. DOI: 10.1056/NEJMoa1606038
Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: Updated analysis of CASTOR. Haematologica. 2018;103(12):2079-2087. DOI: 10.3324/haematol.2018.194118
Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Blood. 2020. DOI: 10.1182/blood.2020005288
Gormley NJ, Ko CW, Deisseroth A, et al. FDA drug approval: Elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res. 2017;23(22):6759-6763. DOI: 10.1158/1078-0432
Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015;2(12):e516-527. DOI: 10.1016/S2352-3026(15)00197-0
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