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Tandem transplantation for multiple myeloma
Figure 4. Survival from disease relapse/progression after allogeneic hematopoietic cell transplantation for an overall 152 relapsed patients.
86) after allogeneic HCT. Seventeen patients completed the planned treatment (lenalidomide, n=7; bortezomib, n=10). Disease progression was the reason for early treat- ment discontinuation in 9 of the treated patients. One patient on lenalidomide stopped the treatment due to an acute GvHD flare which was successfully treated. Other causes included: patient choice (n=1), diarrhea not GvHD- related (n=1), severe headache (n=1), and liver function abnormalities (n=1). By univariate analysis, maintenance therapy was not associated with any clinical outcome. Median OS was 6.3 (95%CI: 3.6-not reached). There was no difference in terms of median PFS between those patients who received maintenance treatment (n=31) after allogeneic HCT (2.56 years; 95%CI: 0.88-4.22) and those (n=175) who achieved a response after allogeneic HCT but did not receive maintenance (2.59 years; 95%CI: 1.86- 3.50).
Survival after disease progression - One hundred and fifty- two patients (62%) experienced relapse or progression. Median survival after the first relapse/progression was 2.9 years (95%CI: 1.9-3.7) for the entire cohort (n=152) (Figure 4). Twenty-eight of the 152 received palliative best supportive care and died after a median of 2.1 months. One patient died during conditioning for a planned subse- quent allogeneic HCT. Data on salvage therapy were not available for 5 patients (3%). One hundred and nineteen patients received a total of 228 lines of treatment, with a median of two lines (range, 1-9) of therapy each. Treatments included lenalidomide (n=67), bortezomib
(n=54), thalidomide (n=36), alkylators/anthracyclines (n=27), pomalidomide (n=10), carfilzomib (n=9), daratu- mumab (n=1), and others (n=6). Twenty-seven (23%) of the 119 treated patients were unresponsive to salvage treatments and died after a median of 9.2 months (95%CI: 5.5-12.0), while the 83 patients who achieved at least a PR had a median survival of 7.8 (95%CI: 5.9-10.6) years. Disease responses for those 83 patients included: 29 CR (15 of these patients are still in CR, 4 are alive with PD, and 10 have since died), 13 VGPR (3 are still in VGPR, 2 are alive with PD, and 8 have since died), and 41 PR (9 cur- rently with stable disease, 10 alive with PD, while 22 have since died). Data on disease response after salvage treat- ments were not available for 9 patients. Eighteen patients received a median of 2 donor lymphocyte infusions (range, 1-4) (preceded by chemotherapy in 9 patients) after a median of 1.4 years post-allografting (range, 0.9-8.3). Four of these achieved a partial response, while the remaining 14 did not show a response. Patients who relapsed during the first 18 months after allogeneic HCT (n=82) had a worsened prognosis (median survival after relapse/progression: 1.1 years; 95%CI: 0.6-1.9) compared to those (n=70) who relapsed beyond 18 months after allogeneic HCT (median survival after relapse/progres- sion: 7.2 years; 95%CI: 4.3-10.6; P<0.0001).
Discussion
Advances in the understanding of MM biology have led to novel treatments that have dramatically prolonged PFS and OS. First-line autologous HCT has remained standard of care for eligible patients. Three randomized trials reported significantly superior median PFS, ranging between 25 and 32 months, as compared to conventional chemotherapy.35-37 PFS was further improved up to 43-50 months after “new drugs” were employed both in the induction and consolidation/maintenance phases.38-40 Whether double autologous transplants are superior to a single autograft remains to be determined.41-43 In our series, an overall median PFS of 1.9 years may appear modest. However, when applying retrospective risk stratification, median PFS was 6.5 years in standard-risk patients, 2.5 year in high-risk patients, and 0.7 years in ultra-high-risk patients. Extramedullary relapse without marrow relapse has been frequent after allografting.44-46 Sanctuary sites may be less accessible to graft-versus-myeloma effects than marrow. Of note, extra-medullary relapse occurred in 25% of current patients who did not have extramedullary involvement at diagnosis. Overall NRM was low (2% at
Table 4. Multivariate† risk factors in 211 patients. Relapse
Progression-free survival
Overall survival HR (95% CI) P
High risk
Ultra-high-risk Chemorefractory
Age ≥ 60 years at allo HCT
Unrelated donor
HR (95% CI)
1.74 (1.1–2.9)
4.99 (2.9–8.7) 5.35 (3.4–8.6) 1.16 (0.8–1.8)
1.54 (1.0–2.3)
P
0.03
<0.0001 <0.0001 0.48
0.04
HR (95% CI)
1.62 (1.1–2.5)
3.47 (2.1–5.7)
4.61 (3.0–7.1)
1.22 (0.8–1.8)
1.47 (1.0–2.1)
P
0.03
<0.0001
<0.0001
0.29
0.04
2.48 (1.4–4.3)
3.87 (2.1–7.2)
3.28 (2.1–5.2)
0.001
<0.0001 <0.0001
1.33 (0.9–2.0) 0.18
1.32 (0.9–2.0) 0.20
HR: Hazard Ratio; CI: Confidence Interval; allo HCT: allogeneic hematopoietic cell transplantation. †Includes variables significant at 0.05 level in univariate analysis for any end point.
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