T-Cell Depleted Allogeneic HCT for Patients with Relapsed, High-Risk Multiple Myeloma Permits Long-Lasting Remissions in the Absence of Graft-Versus-Host Disease and Provides a Platform for Adoptive Immunotherapeutic Approaches

Introduction: We planned to reduce early transplant related mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HSCT)  and reduce acute or chronic GvHD related to non-myeloablative allo HSCT while maintaining the graft-versus-myeloma effect for patients with high-risk multiple myeloma.

Methods: 34 pts using allo T-cell depleted (TCD) HSCT from HLA compatible (matched related = 12, matched unrelated = 13, and mismatched unrelated = 9) donors. All 34 pts had relapsed myeloma within 15 mos following auto HSCT, and 26/34 pts also had high-risk cytogenetics at diagnosis [t(4;14), t(14;16), del17p by FISH and/or del13q by karyotyping] are reported. All pts had to achieve at least a partial response from salvage chemotherapy (n=26) salvage auto HSCT (n =8). Pts underwent allo TCD HSCT with busulfan (0.8mg/kg x 10 doses), melphalan (70mg/m² x 2 days), fludarabine (25mg/m² x 5 days) and rabbit ATG (2.5mg/kg x 2 days). T-cell depletion was performed by positive CD34 selection (Isolex) followed by rosetting with sheep erythrocytes for the initial 13pts (2008-09) and by CD34+ enrichment by the Miltenyi Device in 21pts thereafter, achieving < 10⁴CD3+/kg for all grafts. None of these pts received immuno suppressive therapy post TCD HSCT. Pts were also eligible to receive low doses of donor lymphocyte infusions (DLI) (5x10e⁵ – 1x10e⁶ CD3+/kg) no earlier than 5mos post allo HSCT.

Results:34 pts with a median follow up of 33.6mos (range: 9.6 – 67.1 mos) of survivors are reported, median age 56 years (range 32 – 69). TRM and acute GvHD (grade II-IV) at 12mos is 9% (95% CI: 2% – 23%) and 6% (95% CI: 1% – 17%). Chronic GvHD was not observed in any pt. OS and PFS with their 95% CI are shown in Table 1. Factors associated with worse outcome were disease status and number of previous treatments prior to TCD HSCT.

Table 1.	All patients	3-4 lines of Rx	5-6 lines	> 6 lines
N=	34	13	14	7
CR/nCR	3	3	0	0
VGPR	16	7	7	2
PR	15	3	7	5
PFS @ 1yr (95%CI) PFS @ 2yr (95%CI)	0.49 (0.34 – 0.69) 0.27 (0.14 – 0.49)	0.57 (0.36 - 0.90) 0.46 (0.24 - 0.86)	0.60 (0.38 -  0.95) 0.26 (0.10 -  0.68)	0.0 0.0
OS  @ 1yr (95%CI) OS  @ 2yr (95%CI)	0.66 (0.51 - 0.85) 0.52 (0.36 - 0.73)	0.71 (0.51 - 0.99) 0.71 (0.51 - 0.99)	0.75 (0.54 - 0.99) 0.64 (0.41 - 0.99)	0.43 (0.18 - 0.99) 0.0

15/34 pts are alive, 10/15 pts are in complete remission (CR), 4 pts are have been in continued CR for 46, 55, 64 and 67mos post allo TCD HSCT. 5/15 pts alive have progressed and 4/5 pts are currently responding to salvage chemotherapy and/or DLI. 14/19pts pts died of disease progression, 3/19 died of infectious complications and 2 pts died of complications associated with acute GvHD.

Conclusion:  Long-lasting disease control can be achieved with TCD HSCT in pts with multiply relapsed MM including those with high-risk cytogenetics. TRM and GvHD are low in these heavily pretreated pts. Outcome of TCD HSCT is influenced by numbers of regimens administered and disease status prior to allo BMT.