Prospective Evaluation of 460 Patients from Total Therapy II -- Identification of Characteristic on Baseline MRI Examinations of Prognostic Significance - Importance of Focal Lesions (FL) in Multiple Myeloma (MM)
Ronald Walker, MD, Bart Barlogie MD, PhD, Joth Jacobson, MS, John Shaughnessy, PhD, Joshua Epstein, PhD, Edgardo Angtuaco, MD, Elias Anaissie, MD, Choo-Kee Lee, MD, Raymond Thertulien, MD, PhD, Frits van Rhee, MD, PhD, Maurizio Zangari, MD, PhD, Ernest Ferris, MD, Guido Tricot, MD, PhD

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MM frequently presents with focal plasmacytoma lesions (FL) superimposed on diffuse infiltration of the marrow which can be recognized on MRI (T1-weighted and STIR images). These MRI-FL have previously been shown to contain malignant plasma cells morphologically and by flow cytometry, cytogenetics and FISH, and gene expression profiling. These lesions can be associated with or develop into osteolytic lesions (OL), as recognized on standard X-rays, typically progressing when treatment is ineffective. To evaluate the significance of diffuse and FL patterns on MRI in MM patients enrolled in TT II (intensive remission induction, tandem autotransplants with melphalan 200 mg/m², consolidation chemotherapy for 1 year and interferon maintenance, up-front randomization to +/- thalidomide), 460 MRI baseline examinations, of an eventual accrual target of 660, of the axial skeleton were prospectively evaluated in terms of signal characteristics on T1-weighted and short-tau inversion recovery (STIR) sequences for the presence of hyper-, iso- or hypointense background; homogeneous versus heterogeneous overall signal, and number of FL present (FL being a sharply circumscribed region thought to be myeloma measuring ≥5 mm in diameter). The only statistically significant (p≤0.01) prognostic characteristic of baseline MRI was the number of FL in the spine and pelvis, revealing significantly superior event-free survival (EFS) and overall survival (OS) with < 5 FL. Four-year estimates of EFS were 68% for < 5 FL, 54% for 5–20 FL, and 37% for FL ≥ 21 (p=0.0002). Similarly, 4 yr OS was 78% with < 5 FL compared to 62% for 5-20 FL and 35% for FL ≥ 21 (p=0.001). Examination with Cox multivariate regression for potential associations with standard prognostic factors (SPF) such as β₂M ≥ 4.0, CRP ≥ 4.0, LDH ≥ 190, cytogenetic abnormalities (CA), albumin < 3.5, platelets < 150K, HGB < 10, and creatinine ≥ 2 revealed superior significance of number of FL ≥ 5 in OS (HR 1.9, CI 1.2, 3.1, p=0.008) and EFS (HR 1.9, CI 1.3, 2.8, p=0.002), and of any CA in OS (HR 2.9, CI 1.7, 4.8, p<0.001) and EFS (HR 2.7, CI 1.8, 4.0, p<0.001). Interestingly, while a variety of CA were present (T01p, Del08, Del13, Del17, and Del20), all patients with Del20 had FL ≥ 5, whereas no patients with FL < 5 had Del20 (p<0.001). Follow-up of OS in 296 patients and EFS in 280 at a one-year landmark following enrollment demonstrate this correlation with number of FL to continue (OS p=0.0009, EFS p=0.0001). We conclude that the presence of MRI defined FL ≥ 5, present in 43% at baseline, often without associated OL, identifies a MM entity with distinct biological and clinical characteristics, including inferior survival. These patients are at high-risk, and should be targeted for novel treatments as well as detailed biological investigation.
Keywords: Myeloma, MRI, Prognosis, Focal Lesion

• Introduction
• Aims of Study
• Methods
• Results
• Conclusion

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