Project Details
Project Description
Multiple myeloma (MM) is a common incurable plasma-cell (PC) malignancy. Current
treatment combines conventional cytotoxics with novel agents, including the thalidomide analogues (IMiDs). IMiDs modulate tumour immunogenicity while also stimulating host immunity. Evidence suggests a capacity for sustained periods of immune control of MM during the ‘plateau-phase’ of disease remissions. This equilibrium between host immunity and quiescent MM is prolonged by consolidation and/or maintenance IMiD therapy (Kalff et al, Lancet Haematol 2014). However, progressive immunoparesis and drug resistance ultimately lead to refractory relapse. Combinatorial strategies exploiting the capacity of IMiDs to augment anti-MM immunity are required. Immuno-oncology (IO) is rapidly advancing in MM, with the monoclonal antibodies (mAb)daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) showing efficacy in pivotal clinical trials (Lonial et al, NEJM 2015; Lokhorst et al, NEJM 2015). Whereas single-agent IO treatment has limited efficacy, immunomodulatory combinations dramatically augment activity. Thus there is a pressing requirement for biomarker studies to guide partnerships between IO agents in MM. We have developed MDX1097, a mAb directed against ‘kappa myeloma antigen’ (KMA), a tumour-specific cell surface conformational antigen that (unlike CD38, SLAMF7 or CD138) is exclusively expressed on MM cells, including ‘stem-like’ CD138-ve/CD45+ve populations. IMiDs up-regulate KMA, augmenting antibody dependent cell cytotoxicity (ADCC) vs. MDX1097-treated cells. Phase I/II evaluation demonstrated favorable tolerability and pharmacokinetics, with both paraprotein and FDG-PET responses observed following single infusions in patients with stable disease (SD). We propose to capitalize on early access to MDX1097, performing an investigator-initiated study in combination with lenalidomide (Revlimid, R; LEN) for patients in early relapse. Our study will be annotated by biomarker studies, including immunological readouts, genomic profiling and real-time disease monitoring utilizing cell-free (plasma) tumour DNA (ctDNA). This study will accelerate access for Victorian patients to a promising new IO therapy, while building the rationale for further MDX1097 combination studies.
treatment combines conventional cytotoxics with novel agents, including the thalidomide analogues (IMiDs). IMiDs modulate tumour immunogenicity while also stimulating host immunity. Evidence suggests a capacity for sustained periods of immune control of MM during the ‘plateau-phase’ of disease remissions. This equilibrium between host immunity and quiescent MM is prolonged by consolidation and/or maintenance IMiD therapy (Kalff et al, Lancet Haematol 2014). However, progressive immunoparesis and drug resistance ultimately lead to refractory relapse. Combinatorial strategies exploiting the capacity of IMiDs to augment anti-MM immunity are required. Immuno-oncology (IO) is rapidly advancing in MM, with the monoclonal antibodies (mAb)daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) showing efficacy in pivotal clinical trials (Lonial et al, NEJM 2015; Lokhorst et al, NEJM 2015). Whereas single-agent IO treatment has limited efficacy, immunomodulatory combinations dramatically augment activity. Thus there is a pressing requirement for biomarker studies to guide partnerships between IO agents in MM. We have developed MDX1097, a mAb directed against ‘kappa myeloma antigen’ (KMA), a tumour-specific cell surface conformational antigen that (unlike CD38, SLAMF7 or CD138) is exclusively expressed on MM cells, including ‘stem-like’ CD138-ve/CD45+ve populations. IMiDs up-regulate KMA, augmenting antibody dependent cell cytotoxicity (ADCC) vs. MDX1097-treated cells. Phase I/II evaluation demonstrated favorable tolerability and pharmacokinetics, with both paraprotein and FDG-PET responses observed following single infusions in patients with stable disease (SD). We propose to capitalize on early access to MDX1097, performing an investigator-initiated study in combination with lenalidomide (Revlimid, R; LEN) for patients in early relapse. Our study will be annotated by biomarker studies, including immunological readouts, genomic profiling and real-time disease monitoring utilizing cell-free (plasma) tumour DNA (ctDNA). This study will accelerate access for Victorian patients to a promising new IO therapy, while building the rationale for further MDX1097 combination studies.
| Short title | MDX1097 in myeloma |
|---|---|
| Status | Finished |
| Effective start/end date | 15/12/16 → 31/12/18 |