Introduction: Residual disease (RD) after autologous transplantation as well as following induction therapy in multiple myeloma (MM) patients ineligible for transplant is associated with inferior survival. The significance of RD quantified by multiparameter flow cytometry (MFC) in the setting of allogeneic hematopoietic stem cell transplantation (HCT) for MM has not been reported. Using MFC we assessed the likelihood of RD clearance after HCT and assess whether RD status before HCT and at 1 and 3 months after HCT was associated with survival.
Methods:We include 51 consecutive patients who underwent HCT for high-risk relapsed MM at our center between January 2014 and October 2016. All received CD34+ selected peripheral blood stem cell grafts. Donors included matched related (n=15), matched unrelated (n=20) and HLA 9/10 mismatched unrelated (n=16). The preparative regimen included busulfan (0.8mg/kg x 10 doses), melphalan (70mg/m2 x 2days), fludarabine (25mg/m2 x5days) and rabbit ATG (2.5mg/kg x 2 days).
RD was assessed using MFC at 3 time points (TP) including TP0: median of 28 days (14-64) before transplantation (n=51), TP1: median of 28 days (range 26-55 days) after HSCT (n=48) and TP2: median 97 days (range 90-180days) after HSCT (n=43). MFC RD analysis was performed on marrow aspirate samples using 8-color flow analysis with sensitivity of 0.01% of white cells in 2013-till December 2015 and 10-color flow analysis with sensitivity of 0.0005% subsequently.
Standard criteria were used to define categorical MM disease response. Overall survival (OS) was assessed using the Kaplan-Meier method and groups were compared using the log rank test. A landmark analysis was performed to assess the significance of MRD status at TP1 and TP2, with patients who relapsed or progressed within 30 days of the respective TP excluded from the landmark analysis.
Results:Themedian age was 55 years (range 35-67). All patients had undergone prior autograft. Twelve experienced disease progression or relapse and 21 died, including 7 deaths due to relapsed MM and 14 due to transplant related mortality. The median follow-up amongst survivors (n=30) was 524 days (97-1089 days). Categorical disease status at HCT included: CR (n=9), VGPR (n=12), PR (n=21) and SD/PD (n=9) and this was associated with RD status. Detected RD was noted in 2/9 (22%), 8/12 (67%), 18/21 (86%) and 6/9 (67%) patients in CR, VGPR, PR and SD/PD, respectively (p=0.01).
At TP0 34/51 had RD including all 13 with ≥5% marrow plasma cells. At TP1 31/48 were RD- (3 did not undergo RD assessment at TP1 due to TRM 49, 50 and 122 days after HCT). Of the 31 who were RD+ at TP0 and had assessment at TP1, 15 became RD- (48%). Sixteen of 17 who were RD- at TP0 remained RD- at TP1 and only 1 became RD+. Between TP1 and TP2 the concordance of MRD status among 43 patients who had assessment at both time points was 81% (RD+ at TP1 and TP2 n= 12, RD- at TP1 and TP2 n=23). Two became RD- at TP2 and 6 (14%) became MRD+, 4 of whom died due to MM.
Categorical disease status before HCT was associated with RD status at TP1 and TP2. At TP1, 3/20 (15%) evaluable patients who were in CR or VGPR before HCT were RD+, compared to 14/28 (50%) who were in PR/SD or PD (p=0.016). At TP2, 3/19 (16%) evaluable patients who were in CR/VGPR prior to HCT were RD+ compared to 15/24 (63%) who were in PR/SD or PD (p=0.004). (Table 1)
Conclusions: HCT resulted in the clearance of RD at TP1 in 48% of patients. Unlike autologous transplantation and pharmacologic therapy, HCT benefited MM patients irrespective of pre HCT RD status. Recurrence of RD by MFC was identified in 14% of patients between TP1 and TP2 suggesting this may be an optimal time to intervene with post transplant maintenance strategies. Improved RD sensitivity may be needed to better assess progression risk of MM post HCT.
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Asterisk with author names denotes non-ASH members.