Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

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Abstract

In FY22, in collaboration with Dr. Kazandjian and Dr. Landgren, we evaluated the effects of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma. High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, seen at the NIH Clinical Center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). The primary outcome was to determine the rates of minimal residual disease (MRD)-negative complete response (CR). Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. A total of 54 patients (median age, 59 years, range, 40-79 years) were enrolled, with a median follow-up time of 31.9 months (range, 6.7-102.9 months). Serial bone marrow MRD monitoring and PET/CT imaging were performed at CR or at cycle 8 completion, whichever occurred first, and after cycles 20 and 32. After maintenance therapy, patients were observed with routine and myeloma laboratory examinations every 3 months and annually with PET/CT and bone marrow biopsy with MRD assessment indefinitely. Bone marrow MRD involvement was assessed by histopathological, immunohistochemical and flow cytometric evaluation of clonal plasma cell burden. The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). Importantly, MRD negativity was achieved irrespective of age, sex, race/ethnicity, cytogenetic risk, or high-risk criteria. The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection. There were no grade 4 events. Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease.