Clinical and Correlative Pilot Study of Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (crd – R) in High Risk Smoldering Multiple Myeloma Patients

Abstract Background Multiple myeloma (MM) consistently has a precursor state. High risk smoldering myeloma (SMM) or “early myeloma” has a 72-76% risk of progression at 5 years. In this phase II single arm pilot study, we report the results based on the completed enrollment of high risk (Mayo clinic or PETHEMA models) SMM patients treated with CRd (carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) followed by 2 years of Ln extended dosing. Methods This phase II single arm study treats high risk (Mayo clinic or PETHEMA models) SMM patients ≥18 years old with 8 cycles of CRd therapy. Dosing schedule consists of 28-day cycles of CFZ 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, 16; LEN 25 mg PO daily on days 1-21; and DEX 20/10 mg IV/PO on days 1, 2, 8, 9, 15, 16, 22, 23. After 8 cycles of induction, patients with SD or better response receive LEN extension at 10 mg daily on days 1-21 for 2 years. The primary endpoint is response rate with the secondary endpoints of progression free survival, duration of response, and correlative assays focusing on minimal residual disease (MRD). Patients are evaluated for clinical biomarkers, FDG-PET CT, and MRD studies (flow cytometry and VDJ sequencing of bone marrow aspirates) at regular intervals. Flow cytometry utilizes an 8-color flow panel and analyzes ≥3 x 106 events (sensitivity detection rate of 1 x 10-5). Results Twelve patients (42% males; median age 58, range 48-65) meeting eligibility criteria have been enrolled onto study and are evaluable for toxicity and response. Eleven patients met high risk SMM criteria by PETHEMA model alone, and one patient met criteria for both PETHEMA and Mayo Clinic models. Mean baseline serum M-protein was 2.1 g/dL (1.1-3.3). Best responses (n=12) after a median of 6 cycles of CRd-R delivered (range 2-14 cycles) are 5-sCR/2-CR/2-nCR (75%) and 3-VGPR (25%). Among the 7/12 (58%) that reached CR/sCR, median time to CR/sCR was 5 cycles. Nine patients have completed 4 cycles of CRd therapy with all 9/9 (100%) reaching at least VGPR or better response. Non-hematologic toxicities ≥ grade 3 include: rash 2(17%), CHF 1(8%), dyspnea 1(8%), LFT elevation 1(8%), creatinine increase 1(8%), and hyperglycemia 1(8%). Hematologic toxicities include lymphopenia 4(33%), thrombocytopenia 1(8%), leukopenia 1(8%), neutropenia 1(8%), and anemia 1(8%). All patients have thus far maintained their best responses and none have progressed to clinical symptomatic multiple myeloma. Overall the treatment regimen has been well tolerated with manageable toxicities; one patient discontinued after 6 cycles due to CHF. Among 7 CR/sCR patients, 6/7 (86%) are MRD negative based on high-quality 8-color flow cytometry (sensitivity detection rate of 1 x 10-5) of bone marrow aspirates. In addition, one nCR patient does not demonstrate evidence of abnormally immunophenotypic plasma cells using multi-parameter flow cytometry (post 8 cycles of CRd). Conclusions Among patients completing 4 cycles of CRd therapy, 100% have achieved a VGPR or better. High risk SMM or “early myeloma” may represent a key interventional time point before the development of debilitating complications including onset of end-organ damage. The enrollment for this pilot study has been completed; an expansion cohort for additional 16 patients just opened for enrollment. Updated results will be presented at the meeting. Larger clinical studies are needed to replicate and expand on these promising results. Disclosures: Off Label Use: The abstract discussess off-label use of carfilzomib and lenalidomide.