Escalated Dose-Rates of Total Marrow Irradiation (TMI) Combined with Treosulfan and Fludarabine-Based Conditioning Chemotherapy Regimen for Chemosensitive Advanced Multiple Myeloma (MM) Patients Undergoing a Matched Allogeneic Stem-Cell Transplantation: First Results of a Phase I/II Prospective Monocentric Study (TrRaMM TMI)

Background

In an effort to reduce transplantation-related morbidity and mortality in patients (pts) undergoing total body irradiation as part of myeloablative conditioning regimen for hematological malignancies candidated to allogeneic transplant, data have been emerging in support of Helical Tomotherapy to deliver radiation doses to target organs, as bone marrow and lymph nodes, sparing normal organs. We report the first results of feasibility and efficacy of myeloablative Treosulfan-based conditioning chemotherapy combined with dose-escalating (8-10-12 Gy) TMI in pts affected by chemosensitive advanced MM (TrRaMM-TMI: Eudract N° 2013-002479-16).

Patients and methods

Ten pts (7 females and 3 males with a median age of 60 years), affected by chemosensitive advanced MM have been treated from December 2012 to December 2015. Most of them have received previous therapies with Bortezomib (90%) and IMIDs (80%) and all pts experienced relapse after autologous transplant; active disease was present in the 30% of the pts at the time of the transplant. The pts' median score of HCT-comorbidity index was 2. All pts received a myeloablative Treosulfan-based chemotherapy (Treosulfan 14g/mq/day on days -6 to -4; Fludarabine 30mg/mq/day on days -6 to-2), combined with TMI delivery on day -2 and -1 if 8Gy and on day -3, -2 and -1 if 10 Gy or 12 Gy, using Helical Tomotherapy. Each pt had a personalized immobilization device and before any fraction the correct set-up was controlled by a mega-voltage CT scan. Three pts have been submitted as pilot cases to TMI 8 Gy, and four and three pts respectively in the two protocol cohorts of TMI 10 Gy and 12 Gy. Peripheral-blood has been the stem cell source for all the pts: three from a matched sibling donor and seven from a matched unrelated donor (10/10 HLA match in six cases and one 9/10 HLA match). A median of 5x10e6 Cd34+/kg and of 319x10e6 Cd3+/Kg have been infused and graft versus host disease (GVHD) prophylaxis with sirolimus and mycophenolate mofetil has been administered; antithymocyte globulin on days -4 to -2 and rituximab on day -1 were added in the unrelated transplant setting.

Results

All pts received the planned TMI dose in each cohort; engraftment occurred in all pts and no secondary graft failure was observed. No grade 3 and 4 extra-hematological toxicities were observed, and lower grade toxicities, especially gastrointestinal, were completely reversible. No more than 10% of viral reactivations have been demonstrated and one case only of severe sepsis occurred, promptly resolved. No invasive fungal infections occured. No transplant related mortality (TRM) was registered and the two deaths were due to progressive disease. Immune reconstitution after transplant described a T-cell CD8+ and CD4+ repertoire recovery with a median number of 350/microL and of 100/microL on day +90 respectively; NK cells recovery was rapid with a median of 140/microL on day +90, while B cells were still missing on day +90. With a median follow-up time of 22 months on surviving pts, a 2-year PFS of 64% and a 2-year OS of 77% have been described. The day +100 cumulative incidence of grade II-IV acute GVHD was 40%; if grade >III 10%; chronic GVHD 1-year cumulative incidence was 42%; if moderate and severe 31%. 2-year relapse incidence was 36%.

Conclusions

The first data coming out from the present experience show that TMI addition to Treosulfan-based chemotherapy has not demonstrated an addition of at least short-term toxicities, confirming the combination feasibility, so that TMI 14 Gy delivery is in the plan for the third cohort of the study. Moreover the efficacy outcomes in terms of survival and acceptable TRM, suggest that myeloablative conditioning is feasible in the context of MM and especially promising even in pts with advanced and heavily pretreated disease.