Total Marrow Irradiation (TMI): A New Ablative Regimen as Part of Tandem (T) Autologous Peripheral Blood Progenitor Cell Transplant (AT) for Patients (pts) with Multiple Myeloma (MM).

Background: Radiation therapy has been used primarily for palliation in pts with MM. Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle AT was found to be too toxic, and therefore inferior, in comparison to MEL. TMI, a form of image-guided targeted TBI using intensity modulated helical tomotherapy, when given as the sole ablative regimen during the second cycle of TAT, may improve the efficacy of MEL without unacceptable toxicities. Patients and Methods: We designed a phase I-II TAT study in pts with Durie-Salmon stages I–III MM in response or with stable disease (SD), who were ≤ 70 years old. Pts received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT was administered (cycle 2). The dose of TMI started at 1000 cGy, and was to be escalated by an increment of 200 cGy per cohort, up to 200 cGy twice daily x 5 days. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day x 4 days and thalidomide (Thal) 50–200 mg daily on a 28-day cycle, administered for 6 cycles for pts in complete response (CR), or for a minimum of 12 cycles for pts not in CR. Results: The median age was 53.5 years (35–66). Twenty three pts (13 female, 10 male) with stages I (1), II (6), III (16) MM received MEL at a median time of 10 mos (7–18) from diagnosis; 22 pts received TMI (1000 cGy through 1800 cGy); 1 pt did not receive TMI due to post-MEL toxicities. The median time between MEL and TMI was 63.5 days (range, 44–119). Granulocyte recovery to >1000/microliter following Mel was 14 days (13–15) versus 15 days after TMI (range; 13–19). Platelet recovery to >20,000/microliter was identical: 13 days (range: 0–16 versus 0–17). Reversible grade 3 non-hematologic toxicities by TMI dose levels included febrile neutropenia (levels 1 and 2: 1 pt each); none (level 3); fatigue (level 4: 1 pt). Dose limiting toxicities (DLT) at level 5 (1800 cGy) were reversible, and included grade 3 radiation pneumonitis/congestive heart failure necessitating administration of oxygen, steroids, and oral cardiac medications, and abdominal pain/enteritis requiring parenteral feeding (n: 1), and grade 3 hypotension requiring pressor support (n: 1), defining the maximum tolerated dose (MTD) at 1600 cGy (200 cGy twice daily x 4 days). The estimated median radiation dose to normal organs was 14–64% of the targeted bone marrow dose in the 6 pts each treated at doses 1600 and 1800 cGy. Late toxicities included reversible enteritis in the pt previously experiencing the same symptom as DLT after receiving 1800 cGy of TMI, and lower extremity deep venous thrombosis (DVT) during maintenance therapy in 2 pts. We observed neither primary nor secondary engraftment failure. Best responses included CR (n: 12), very good partial response (VGPR, n: 4) PR or stable disease (n: 6). At a median follow-up of 22 months (range, 10–39+ months) 5 pts progressed (at 7.5, 8, 16, 21, and 22 months) and 8 pts continue on maintenance. Conclusion: We defined the MTD of TMI as 1600 cGy. Delayed toxicities are limited so far, but underline the need for careful long-term monitoring and DVT prophylaxis during Thal-based maintenance. Phase II of this trial at the MTD of 1600 cGy of TMI is ongoing.