A Dose Escalation Study of Total Marrow Irradiation and Autologous Stem-Cell Transplantation for Relapsed Multiple Myeloma Patients

Background: Local irradiation results in long-term control and even cure of solitary plasmacytomas, but traditional total body irradiation (TBI) elicits excessive normal tissue toxicity limiting dose escalation for multiple myeloma patients. Intensity modulated radiation, a more targeted form of irradiation to the entire marrow (total marrow irradiation or TMI), delivers up to 70% less radiation to adjacent normal tissues compared to standard TBI approaches. We postulate that TMI will allow delivery of higher doses of radiation to the marrow which might improve outcome of patients with myeloma. Objectives: Primary outcomes are to determine safety and maximum tolerated dose (MTD) of TMI. A secondary outcome was time to next treatment (TTNT). Methods: This is an ongoing dose-escalation study of TMI as sole conditioning for salvage autologous hematopoietic stem-cell transplant (TMI-SCT) in radiation-naïve myeloma patients failing a first-line melphalan-aHSCT (Mel-SCT). Measurable myeloma and stored CD34+cells (≥2.5 × 106/kg) were study prerequisite. TMI doses were given twice daily starting with 14 Gy, then one fraction of 2 Gy was added to successive cohorts of three patients. Acute and long-term toxicity were graded using Bearman scale and LENT-SOMA respectively. Results: Fourteen patients were transplanted between January-2010 and May-2017. Three patients received 14 Gy, 16 Gy, 18 Gy and 20 Gy. One patient received 22 Gy and one patient scheduled for 22 Gy received 19.8 Gy because of early mucositis. Median age at TMI was 59.5 years and median time between Mel-SCT and TMI-SCT was 2.9 years. Increase in TMI dose was associated with mucositis worsening (P < .01), but not with narcotics usage, or fever. Xerostomia was the most common long-term toxicity observed, and it was graded LENT-SOMA ≥ 2 in 63.6%, 38.5% and 25% of the patients at D100, 6 months and 12 months post-TMI respectively. There was no difference in length of hospitalization, neutrophil engraftment, and incidence of acute toxicity between TMI-SCT and Mel-SCT. There was no difference in myeloma response after Mel-SCT compared to after TMI-SCT (Table 1).Table 1Response StatusCRVGPRPRSDPDTotalStatus after Mel-SCT554--14Status before TMI-SCT-164314Status after TMI-SCT3461-14Median TTNT was 1.6 year after second-line TMI-SCT and 2.0 years after first-line Mel-SCT (P = .21). Open table in a new tab Median TTNT was 1.6 year after second-line TMI-SCT and 2.0 years after first-line Mel-SCT (P = .21). Conclusion: When compared to a well-established conditioning, TMI was safe and disease control was encouraging. MTD was not reached. Further increase in TMI dose and longer follow-up are needed for better investigation.

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