Abstract
Pts with high-risk cytogenetics and/or relapsed multiple myeloma (MM) post autologous transplant have a particularly limited prognosis. Conventional allogeneic hematopoietic stem cell transplantation (allo HSCT) has been associated with unacceptably high rates of mortality and non-myeloablative allo HSCT has resulted in high rates of acute and chronic graft-versus-host disease (GvHD) and progression.
We report results of a phase II clinical trial of 34 pts, using T-cell depleted allo HSCT (allo 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]. All pts had to achieve at least a partial response from preceding salvage chemotherapy (n=26) or second 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 with 10/10 HLA matched donors were also eligible to receive low doses of donor lymphocyte infusions (DLI) (5x10e5 – 1x10e6 CD3+/kg) no earlier than 5mos post allo HSCT.
34 pts with a median follow up of 31.6mos (range: 7.6 – 65.1 mos) of survivors are reported, median age 56 years (range 32 – 69). All pts engrafted promptly (median d+10, range d+9 to +12).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. The overall survival (OS) and progression-free survival (PFS) with their 95% confidence intervals (CI) are shown in Table 1. Factors associated with worse outcome were disease status and number of previous treatments prior to TCD HSCT. (Table1; Figure 1)
Table 1
| All patients | 3-4 lines of Rx | 5-6 lines | Ø 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 |
| All patients | 3-4 lines of Rx | 5-6 lines | Ø 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 |
OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT
OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT
15/34 pts are alive, 10/15 pts are in complete remission (CR), 4 pts are have been in continued CR for 44, 53, 62 and 65mos 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.
Long-lasting disease control can be achieved with TCD HSCT in pts with multiply relapsed MM including those with high-risk cytogenetics in the absence of chronic GvHD. TRM and acute 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. Pts who failed to respond to standard chemotherapeutics pretransplant responded to reuse of this therapy post TCD HSCT.
Based on these results, we are aiming to perform TCD HSCT for pts with MM who have high-risk cytogenetics at an earlier time point before multiple relapses develop and to integrate post transplant immunotherapeutic or immunomodulatory strategies to further reduce risk of relapse in these high-risk pts.
No relevant conflicts of interest to declare.
