Abstract
Abstract
Background: High-dose melphalan (MEL)-based autotransplants (AT) have significantly improved complete response rates (CR) and survival in MM. We previously reported on DTPACE (Dexamethasone, Thalidomide, cis-Platin, Adriamycin, Cyclophosphamide, Etoposide) as a highly effective salvage regimen, although EFS and OS were short in the presence of cytogenetic abnormalities (CA) and elevated LDH. Hypothesizing that the 2–3mo recovery after MEL-AT permitted MM re-growth, we explored whether non-stem cell-toxic rapidly cycled dose-intensified DTPACE (HD-DTPACE) induced more sustained responses in AR-MM.
Patients and Methods: 23 patients (median age, 58yr; range, 43–74) had high-risk features comprising CA, elevated LDH or high-risk gene expression profiles; 21 (91%) had progressed after AT(1, 4 pts; 2, 14 pts; 3, 3 pts); all had failed ≥1 line of salvage. HD-DTPACE comprised iv D 200mg/d and po T 200mg/d for 4–6d, and 4-day continuous infusions of P 15mg/m2/d, A 15mg/m2/d, C 600mg/m2/d and E 60mg/m2/d, which is an increase in D from 40mg to 200mg and 50% dose escalation of PACE.
Results: 23 patients received 39 cycles of HD-DTPACE (1, 15 pts; 2, 3 pts; 3, 4 pts; 4, 1 pt); 18 (78%) responded (CR, 3; near-CR, 8, PR, 7). Focal lesions (FL) were present on PET-CT scans in 15 patients before therapy; after 1 cycle, the median FL decreased from 39 (range, 2–103) to 9 (range, 1–44); in 6 of 12 patients, extramedullary MM resolved. Thirteen patients subsequently received MEL- or BEAM-based AT; 7 received further consolidation and/or maintenance therapy. The tolerability of HD-DTPACE was underscored by its out-patient administration in 17 patients, only 3 of whom required subsequent admission. The median days to ANC> 500/ml and platelets>20.000/ml after the 1st cycle was 16 (range, 9–23) and 18 (range, 10–56). Prior to HD-DTPACE, 4 patients had compromised bone marrow reserve reflected by a platelet count <100,000/ml; however, only 1 required a PBSC boost. The median intervals between cycle 1–2, 2–3 and 3–4 were 41 days (range: 22–165), 39 days (range: 36–93), and 77 days respectively; 3 of 8 patients undergoing repeated cycles of HD-DTPACE had inter-cycle intervals of 22, 29 and 31 days, respectively, with excellent hematopoietic recovery. Consistent with the absence of hematopoietic stem cell injury, there was no evidence of cumulative thrombocytopenia. Non-hematological toxicities included colitis in 4 patients, although oral mucositis was virtually absent. Sepsis, CMV reactivation and DVT occurred in one patient each. Three patients died after HD-DTPACE (progressive disease n=2; cause unknown, n=1). While follow-up is short (median 4mo; range, 1–11), of the 33 patients, 11 remain event-free and 18 alive.
Conclusion: HD-DTPACE is an effective, well-tolerated salvage regimen for AR-MM and could be cycled rapidly in heavily pre-treated patients. Rapid cycling of HD-DTPACE within 28 days will be evaluated up-front in patients with poor prognosis MM (CA, high LDH, high-risk genetics), whose 6-yr EFS and OS in our Total Therapy II trial was only 21% and 32%, respectively. Such approach has substantially advanced the outcome patients with aggressive, high-LDH lymphoma.