PET-CT for Assessment of Multiple Myeloma Disease Burden and Metabolic Response before and after Carfilzomib-Based Induction, Consolidation and Carfilzomib Maintenance Therapy: Data from the UK NCRI Cardamon Study
Authors: Bygrave Ceri A , Subesinghe Manil , Wilson William , Popat Rakesh , Ramasamy Karthik , Pang Gavin , Jenner Richard , Kamora Sumaiya , Dadaga Tushhar , Pike Lucy , Streetly Matthew , Camilleri Marquita , Owen Roger G , Cavenagh James , Sive Jonathan , Chapman Michael , Phillips Elizabeth H , Chavda Selina J , Cuadrado Maria del Mar , Benjamin Reuben , Eccersley Lydia , Moore Sally , Banerjee Lalita , Clifton-Hadley Laura , Barrington Sally F , Yong Kwee 
Published: November 2021

Abstract
Background:
FDG PET-CT can assess bone, bone marrow and extramedullary disease (EMD) in multiple myeloma (MM), can identify disease missed through patchy marrow infiltration and complement established markers of adverse prognosis. The evolving definition of 'PET-CT high-risk disease' includes the presence of EMD and paramedullary involvement which are associated with inferior outcome. Other potential factors include SUV max &gt;4.2 at baseline, &lt; complete metabolic response (CMR) after autograft and &gt;3 FDG avid focal lesions (FL).
Methods:
In the CARDAMON study, newly diagnosed MM patients eligible for ASCT received KCd (Carfilzomib, cyclophosphamide and dexamethasone) induction and either KCd consolidation or ASCT, then K maintenance for 18 cycles. In a consenting subgroup of patients, FDG PET-CT was performed at baseline, 14-28 days after completing consolidation or 100 days post-ASCT, and after 6 months maintenance. PET-CT scans were independently reviewed by 2 readers with PET positive lesions defined as uptake within focal lesions (FL) and/or diffuse marrow uptake &gt; liver. A CMR required a Deauville score (DS) of 1-3 in FL and bone marrow.
Results:
Of 31 patients registered to the sub-study, 28 had available PET data and are included in this analysis, 61% male, median age 60 years (range 36-69). 14 patients had standard risk disease, 10 had isolated 1p-/1q+ and 4 had genetically HR disease (t(4;14), t(14;16), t(14;20) or del17p &gt; 50% cells). Revised International Staging System (R-ISS) was I in 5/28, R-ISS II or III in 20/28 (unknown in 3/28).
Baseline PET was positive (PP) in 21/28 patients (77.8%), negative (NP) in 6/28 (22.2%) and 1 patient had a baseline scan that was not evaluable. Of the PP group, 3 had diffuse disease only, 13 had focal disease only and 5 had both focal and diffuse disease. The focal and diffuse pattern was most frequently seen in PP patients with genetic HR disease.
Median SUV max of FL in PP patients was 5.78 (range 2.19-12.93). 9/21 PP patients had &gt;3 FL with uptake &gt; liver at baseline and 19/21 had bone marrow DS &gt;3. Patients with &gt;3 FL had significantly worse PFS than those with ≤3 (HR = 5.41 (95% CI 1.05-27.9), p=0.04). There was a trend for higher presenting bone marrow trephine plasma cell involvement in PP patients at baseline (median PP 50% [range 15-85]), median NP 20% [range 1-70]) (p=0.07). PET-CT was positive at baseline in 4/5 R-ISS I patients and 15/21 R-ISS II/III. Three out of 4 patients with HR disease and evaluable scans had positive baseline PET-CTs; 1 with focal disease only and 2 with focal and diffuse disease.
Of 16 patients who underwent 2 nd PET, 12 showed CMR and 1 partial metabolic response (PMR). Four patients withdrew before assessment, 3 for progressive disease and 1 death, and 3 patients had no FDG avid lesions at baseline and post-induction. Further analysis of patients with CMR showed 1 CR and minimal residual disease negative, (MRD-ve), 7 VGPR (4 MRD+ve, 3 MRD-ve) and 4 PR (2 MRD+ve, 2 MRD-ve). The 1 patient with PMR had a VGPR (MRD-ve).
A further 11 patients underwent PET 6 months post maintenance of whom 5 remained in CMR and 5 were PET negative at baseline and response. Serological responses in the patients in CMR were 1 sCR (MRD-ve), 1 CR (MRD-ve) and 3 VGPR (1 MRD+ve, 2 MRD-ve).
With a median follow-up of 2.3 years, median progression free survival (PFS) for patients in the sub-study has not yet been reached, compared to a median PFS for the whole cohort of 3.3 years (95% CI 2.8-N/A). Median overall survival (OS) is awaited, for both groups. In the PP group, 2-year PFS was 65.6% (95% CI 41.0-82.0) vs 100% (95% CI N/A) for NP group, however due to small numbers and limited follow-up this difference was not significant (p=0.2).
Conclusions:
In the CARDAMON PET sub-study over 75% of patients had a positive baseline PET. This group had heavier marrow burden, with predominant focal disease. Patients with focal disease and &gt;3 FL with uptake &gt;liver had a significantly worse PFS. Follow-up PET scans for those available for response assessment showed high rates of CMR (12/13, 92%) with variable depth of serological response and MRD. Overall, K maintenance sustained PET negativity at 6 months in 10/11 patients who underwent a 3rd scan. PET is a valuable addition to disease response measures; further work will clarify the role of increased monitoring and therapeutic adaptation in PET defined high-risk groups.

Disclosures
Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Ramasamy: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene (BMS): Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Pfizer oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Streetly: BMS-Celgene: Consultancy; Sanofi: Consultancy; EUSA Pharma: Consultancy. Eccersley: Wolters-Kluwer: Honoraria. Clifton-Hadley: Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Bristol-Myers Squibb Pharmaceuticals Ltd..: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.. Barrington: Bristol Myers Squibb international corporation: Research Funding; Pfizer Inc: Research Funding; Amgen Ltd: Research Funding; Takeda Speakers Bureau: Honoraria. Yong: Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Autolus: Research Funding; Takeda: Honoraria; GSK: Honoraria; Amgen: Honoraria; BMS: Research Funding.