Enhanced Global Disease Assessment with Advanced Imaging and Targeted Myeloma Lesion Biopsy Highlights Spatial Heterogeneity and Detects Residual Disease in Multiple Myeloma

Background: Multiple myeloma (MM) is a biologically complex disease with marked heterogeneity; limitations remain in our standard myeloma disease assessment at diagnosis and in response to therapy. In this study, we aimed to prospectively investigate the utilization of advanced imaging and targeted focal lesion (FL) biopsies to augment global disease evaluation, detect residual tumor burden, and explore the diverse histologic and molecular landscape of this multifocal neoplasm. Herein, we present our final analysis of this clinical trial.

Methods: Adult patients with newly diagnosed clinical MM (NDMM) and bone or extramedullary (EM) FL were eligible to participate in this prospective study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI), standard bone marrow (BM) biopsy and aspiration, and targeted FL biopsy were performed at enrollment and after four 28-day cycles of induction therapy with carfilzomib (36 mg/m2 intravenously twice weekly), lenalidomide (25 mg orally days 1-21), and dexamethasone (40 mg orally weekly) (KRd), with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was also measured after each cycle of treatment. Patients were followed for 12 months after end of treatment or until data cutoff on February 23^rd, 2022.

Results: 27 patients were enrolled in this study between June 2018 and August 2021, with 25 evaluable for global response assessment. Median age was 61 years (range, 42-76 years) and 14.8% of patients were of Black or African American race. 85.2% of patients had Revised International Staging System (R-ISS) stage II or III disease. 51.9% of patients were identified as having EM disease arising out of bone or soft tissue and 44.4% of patients had high risk cytogenetics inclusive of chromosome 1 abnormalities. In sum, 70.4% of our cohort had at least 1 high risk feature at diagnosis (Table 1). 80% of patients had myeloma FL identified on advanced imaging that were missed on conventional skeletal survey. Of the 7 patients with cytogenetic and fluorescence in situ hybridization (FISH) testing performed on initial FL biopsy, 6 (85.7%) had findings discrepant from those seen on cytogenetic testing from standard BM samples. 9 patients had cytogenetic and FISH studies on repeat myeloma FL biopsy after KRd induction with 2 showing residual FISH abnormalities that were not detected on standard BM obtained for response assessment. Clinical response rates after 4 cycles of KRd were high in our study population with 88% of patients achieving a very good partial response (VGPR) or better and 20% with a stringent complete response (sCR) with minimal residual disease (MRD) negativity by flow cytometry. However, of the 22 patients with ≥VGPR by IMWG response assessment, 18 had residual disease on advanced imaging with WB-MRI (10 patients), PET/CT (7 patients), or MRI total spine (1 patient), including 3 of the 5 patients with sCR (Figure 1). 2 patients experienced disease progression during the study period with median progression free survival not reached by the patient cohort. Both patients with progression had a VGPR by conventional response assessment, though with residual FL on advanced imaging post-KRd induction.

Conclusions: While tumor spatial differences in MM have been observed retrospectively, prospective data on this important component of myelomagenesis is limited. In our cohort of high risk NDMM, we demonstrated spatial heterogeneity both at diagnosis and after KRd induction. Despite the deep clinical responses observed by IMWG response assessment, 81.8% of patients with ≥VGPR had ongoing abnormalities on advanced imaging which could potentially serve as disease reservoirs for future progression and development of treatment resistance. A novel assessment method in MM, inclusive of advanced imaging and targeted FL biopsies, may overcome the limitations of our standard response assessment with resultant improved knowledge of the varied intra-tumor disease biology as well as development of more refined treatment approaches. A potential limitation of our study is the smaller sample size with underrepresentation of minority populations. Data on whole exome sequencing of paired BM and FL biopsies will be reported separately.