Abstract

BACKGROUND

POM is an immunomodulatory agent with direct tumoricidal and immune-stimulatory activities. DARA also has direct tumoricidal activity and can stimulate immune-mediated tumor cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP).

Results from a clinical study demonstrated that POM + DARA has activity in pts with RRMM (Chari et al. Blood 2017). In the MM-014 trial, cohort B was designed to investigate the treatment (Tx) sequence of POM + LoDEX + DARA in pts relapsing after or refractory to LEN-based therapy as their last prior regimen. Resistance to LEN has been linked to reduced levels of cereblon in myeloma cells (Zhu et al. Blood 2011) after LEN-based Tx. However, the immune system may remain active. Here we report on the immune profile of peripheral immune cells from pts enrolled in cohort B of the MM-014 trial, since both DARA and POM exert their effects through cellular immunity.

METHODS

Adult pts with documented RRMM, 1 or 2 prior lines of Tx, and progressive disease after ≥ 2 cycles of first- or second-line LEN-based Tx were eligible. In 28-day cycles, pts received POM 4 mg/d on D1-21 + LoDEX 40 mg/d (20 mg/d if > 75 yrs) on D1, 8, 15, and 22 and DARA 16 mg/kg on DEX dosing days for cycles 1 and 2, then D1 and 15 for cycles 3-6, and D1 for cycle 7+. Immune profiling was performed by flow cytometry using multiple markers on peripheral blood at various time points: at screening, cycle 1 day 1 (C1D1), C1D8, C1D15, C2D1, C2D15, C3D1, and C5D1. The marker panels included T and B cells (CD3, CD4, CD8, and CD19), T regulatory (Treg) cells (CD25, CD127), monocytes (CD14), NK (natural killer) cells (CD16 and CD56), and a cell proliferation marker (Ki-67). CD38+ subpopulations of T, Treg, and NK cells were measured to test whether DARA has specific effects on these subsets of cells. The immune checkpoint and exhaustion markers (PD-1, ICOS, LAG-3, TIM-3) as well as activation and memory markers (CD45RA and CD45RO) were also investigated. The MM-014 trial is ongoing, with a planned total enrollment of 100 pts.

RESULTS

In cohort B, 70% of pts were refractory to and 30% relapsed on LEN, respectively. Median duration of prior LEN Tx was 23.9 mos; 43.6%, 17.9%, and 38.5% of pts were on 25 mg, 15 mg, and < 10 mg of LEN as their last dose, respectively. The current analyses are based on immune profiling of samples from 40 pts. POM + LoDEX + DARA induced broad changes in immune cell profiles at C2D15 compared with baseline levels. The proportion and absolute count of monocytes increased by 76.2% and 43.7%, respectively. Similarly, the proportions of CD3+, CD3+/CD4+, and CD3+/CD8+ T cells increased by 28.6%, 5.2%, and 61.2% and the proportion of proliferating CD3+, CD3+/CD4+, and CD3+/CD8+ T cells increased by 2.5-, 1.6-, and 3.3-fold, respectively. The NK cell count decreased from baseline by 91.3% at C2D15, as evidenced by the elimination of CD38+ NK cells with DARA Tx. Interestingly, however, of the total number of NK cells, the proportion of proliferating NK cells increased by 5.1-fold at the same time point. The regulatory T-cell populations were less affected, except for a small subset of CD38+ Treg cells that was eliminated.

CONCLUSIONS

The results of immune profiling of peripheral immune cells provide evidence for several possible mechanisms that support POM + LoDEX + DARA for the Tx of RRMM. Our data showed that this Tx increased total T cells, especially cytotoxic T cells. Monocytes were also significantly increased, which may enhance the ADCP effect of DARA. CD38 NK-cell proliferation was also increased, but the long-term impact of this finding remains to be determined since the total number of NK cells decreased. The number of Treg cells was little affected, except for a small subset of CD38+ Treg cells that was eliminated. Further analyses of other immune cell markers, including checkpoint markers, and the correlation of immune status to clinical outcomes will be performed. Together, these data support the hypothesis that the triplet of POM + LoDEX + DARA has significant immunostimulatory effects on cellular immune responses in RRMM. This observation of immune stimulation is of particular interest in this population, as all pts in the MM-014 trial must have had Tx failure with a LEN-based therapy immediately prior to entering the trial. Immune stimulation may be a mechanism of POM + LoDEX + DARA to overcome resistance to LEN-based therapy.

Disclosures

Qian: Celgene Corporation: Employment, Equity Ownership. Newhall: Celgene Corporation: Employment, Equity Ownership. Tometsko: Celgene: Employment. Bjorklund: Celgene Corporation: Employment. Bahlis: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Schiller: bluebird bio: Research Funding; mateon therapeutics: Research Funding. Sebag: Celgene, Janssen: Consultancy. Berdeja: Amgen: Research Funding; Constellation: Research Funding; Takeda: Research Funding; Bluebird: Research Funding; Curis: Research Funding; BMS: Research Funding; Janssen: Research Funding; Teva: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding. Ganguly: Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau. Matous: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talamo: Penn State Hershey Cancer Institute: Employment. Bar: Celgene Corporation: Consultancy. Fonseca: Celgene Corporation: Research Funding, Speakers Bureau. Reece: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Mouro: Celgene Corporation: Employment, Equity Ownership. Agarwal: Celgene Corporation: Employment. Zafar: Celgene Corporation: Employment. Thakurta: Celgene Corporation: Employment, Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.