Advanced Imaging and Targeted Myeloma Lesion Biopsies to Enhance Global Response Assessment and Evaluate Spatial Heterogeneity in Multiple Myeloma
Authors: Browning Sabrina L. , Parker Terri L. , Bar Noffar , Anderson Tara , Dhodapkar Madhav V. , Seropian Stuart , Lee Alfred Ian , Prebet Thomas , Halene Stephanie , Xu Mina L. , Gorshein Elan , Talsania Ashita , Kidwai Wajih Zaheer , Witt David H. , Chang Victor , Lischuk Andrew , Wei Wei , Haims Andrew , Neparidze Natalia 
Published: February 2021

Background: Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm with significant genetic and biologic complexity. Limitations remain in our standard assessment of response to therapy, as random bone marrow biopsy may misrepresent the varied histologic and molecular features of this multifocal disease. Advanced imaging is crucial in evaluating bone and extramedullary (EM) lesions. We aim to refine global response assessment in MM, with incorporation of advanced imaging-guided lesion biopsies, to improve knowledge of residual tumor burden critical to patient outcomes.
Methods: Patients ≥18 years of age with standard or high risk newly diagnosed clinical MM were eligible to participate in this study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI) based on access, standard bone marrow biopsy and aspiration, and targeted lesion biopsy occurred at enrollment and after 4 cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). Carfilzomib was administered intravenously at a dose of 36 mg/m2 twice weekly, lenalidomide orally 25 mg daily days 1-21, and dexamethasone orally 40 mg weekly, with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was assessed after each cycle of treatment.
Results: An interim analysis was completed on 17 patients enrolled between June 2018 and March 2020, with 14 evaluable for global treatment response. Median age was 61 years (range, 43-76 years) and 82.4% of patients were male. 76.5% had Revised International Staging System (R-ISS) stage II or III disease and 58.8% had EM disease arising from bone (EM-B, 41.2%) or independently in soft tissue (EM-S, 17.6%). 70.6% of patients had at least one high risk feature at the time of diagnosis (Table 1). Of the 16 patients with conventional skeletal survey (CSS) at study entry, 68.8% had at least 1 myeloma-defining lesion on advanced imaging that was missed on CSS. Four patients had adequate sample from initial lesion biopsy for cytogenetics and fluorescence in situ hybridization (FISH), 3 of whom demonstrated discordant FISH results when compared to standard bone marrow samples. Clinical response rates after 4 cycles of CRd were notable with 85.7% of patients achieving ≥ very good partial response (VGPR) and 3 patients with stringent complete response (sCR) and minimal residual disease (MRD) negativity by flow cytometry with a sensitivity of 10-5. However, of the 12 patients with ≥ VGPR by conventional response assessment, 9 had residual disease on advanced imaging with PET/CT (2 patients), WB-MRI (6 patients), or total spine MRI (1 patient) (Figure 1). Repeat myeloma lesion biopsy was limited to 6 patients with targetable lesions after induction therapy, with diagnostic yield impacted by the presence of sclerotic tissue and insufficient marrow elements in some of the lesions sampled (Table 2). 85.7% of patients continued CRd or proceeded to high dose therapy and autologous stem cell rescue, with no patients transitioning directly to maintenance treatment after 4 cycles of CRd. At a median follow-up of 8 months, 14.3% (2/14) of patients have had progression of disease. Both individuals had residual lesions on imaging at end of treatment, despite one with flow MRD-negative sCR and normal FISH by standard assessment. There were no grade 4 serious adverse events or deaths.
Conclusions: In our cohort of high risk newly diagnosed MM, CRd induction was potent and well-tolerated. While deep clinical responses were observed by conventional clinical assessment, two thirds of patients had persistent abnormalities on advanced imaging with concern that these sites could give rise to progressive MM. Our patients demonstrated spatial heterogeneity, highlighting the limitations of standard bone marrow evaluation. Use of advanced imaging and targeted lesion biopsies in response assessment enhances our understanding of tumor growth pattern in MM and consideration could be given to integrating these into clinical care when available. Current limitations of this study include a small number of patients with lesions amendable to repeat biopsy and their incomplete diagnostic yield. Ongoing investigation includes whole exome sequencing of paired bone marrow and focal lesion biopsies and application of a WB-MRI lesion scoring system to further augment this novel response assessment method.

Disclosures
Anderson: Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Dhodapkar:Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Kite: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Prebet:Jazz Pharmaceuticals: Consultancy, Research Funding. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Haims:Pfizer: Consultancy. Neparidze:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

OffLabel Disclosure:
Carfilzomib has been shown to have significant anti-myeloma activity in relapsed myeloma. Phase I/II studies as well as one phase III study also showed favorable outcomes with carfilzomib-based regimens in newly diagnosed multiple myeloma, including in patients with high risk disease. We utilized an induction regimen with carfilzomib, lenalidomide, and dexamethasone given that patients enrolled in this study were required to have bone or soft tissue disease on advanced imaging, indicating a likely high risk feature with potentially aggressive disease biology. It has been shown that the combination of carfilzomib, lenalidomide, and dexamethasone is a safe regimen for patients with multiple myeloma. This combination is approved in the relapsed/refractory setting and included in NCCN guidelines for newly diagnosed multiple myeloma.