Autologous Hematopoietic Cell Transplantation in Patients with High Risk Multiple Myeloma: Post- Transplant Responses Do Not Translate to Longer Survival
Authors: Sharma Manish , Hari Parmeswaran , Le-Rademacher Jennifer , Krishnan Amrita , Nieto Yago , Gasparetto Cristina , Huang Jiaxing , Scott Emma C. , D'Souza Anita 
Published: October 2019

Abstract
Background: Multiple myeloma remains an incurable disease with a heterogeneous clinical course, somewhat explained by the occurrence of high-risk prognostic markers. The International Myeloma Working Group defined high risk myeloma (HRM) as the presence of del17p13 or t(4;14) with ISS II/III. Conflicting data exist regarding t(14;16), hypodiploidy and chromosome 1 abnormalities (1q21 amplification, 1p deletion and others).
Methods: We analyzed the outcomes of 142 HRM patients with high risk FISH or cytogenetic findings reported to the CIBMTR from 2008-2012 treated with an upfront (within 12 months of diagnosis), melphalan-conditioned autologous hematopoietic cell transplant and compared them to 573 patients with no high-risk markers (NHRM). Patients that received more than 2 induction regimens were excluded in this analysis. The HRM cohort comprised del17p13 (n=27), t(4;14) (n=27), t(14;16) (n=5), chromosome 1 abnormalities (n=42), hypodiploidy (n=13) and ≥2 high-risk markers (n=31). Planned post-transplant therapy was collected. Outcomes of interest included progression-free survival (PFS) and overall survival (OS).
Results: The HRM and NHRM groups were similar to each other except for the following differences: HRM was associated with lower Karnofsky (KPS) (49% vs 36% with KPS<90, p 0.02) and higher stage at diagnosis (41% vs 28% with ISS/DSS III, p 0.008). More HRM patients received induction with bortezomib and immunomodulatory drug (imid) combinations (55% vs 43%, p <0.001) and had a lower complete response rate prior to transplant (12% vs 16%, p 0.04). More HRM patients had planned post-transplant combined bortezomib and imid therapy (27% vs 12%, p<0.0001). Median follow up in the 2 groups was 36 months for HRM and 44 months for NHRM. At 100 days post-transplant, similar numbers of patients had achieved complete and very good partial responses in the 2 groups (Table 1). At 3 years post-transplant, HRM patients had lower PFS (36% vs 50%, p <0.001) and OS (73% vs 85%, p <0.001) compared to NHRM. Univariate outcomes are shown in Table 2 divided by type of HRM. Table 3 shows the results of the multivariate analysis. The figure shows the Kaplan-Meier curves of probability of survival. Among the relapsed patients (HRM = 91, NHRM = 296), the 2 year survival was 48 (35-60)% for HRM and 70 (64-76)% for the NHRM groups, p-value 0.004.
Conclusions: Patients with HRM achieved similar day 100 response compared to NHRM but were unable to maintain this response over time despite being more likely to receive post-transplant therapy. HRM was associated with shorter PFS and further shortened post-relapse survival. Patients with chromosome 1 abnormalities or del 17p alone appeared to have similar outcomes to those with NHRM while those with t(4;14) and those with more than 1 high-risk marker had the least favorable outcomes. In addition to HRM, obtaining less than complete response prior to transplant and the lack of post-transplant therapy were associated with worse PFS and OS. Finally, African-American race and higher stage at diagnosis were also associated with lower OS in our study.
Table 1. Day 100 post-transplant response Variable HRM NHRM P-value Day 100 response 0.55 sCR/CR/nCR 40 (28) 176 (31) VGPR 43 (30) 174 (30) PR 39 (27) 129 (23) SD/NR 14 (10) 63 (11) Progression/relapse 5 (4) 13 (2) Missing 1 (<1) 18 (3)
Table 2. Outcomes at 3 years post-transplant. Values are expressed as probabilities with 95% confidence intervals. NHRM t(4;14) del 17p Chr 1 ≥ 2 HR p-value PFS 50 (46-55)% 30 (12-51)% 44 (25-64)% 40 (24-56)% 23 (9-41)% <0.001 OS 85 (81-88)% 58 (36-78)% 81 (60-95)% 87 (74-96)% 65 (47-82)% <0.001
Table 3. Multivariate analysis Outcome Hazard ratio (95% CI) p-value PFS HRM vs NHRM 1.7 (1.3-2.3) <0.0001 Pre-transplant CR PR SD Progression 1 2.1 (1.2-3.7) 2.0 (0.8-5.0) 4.5 (1.9-10.3) 0.0245 0.008 0.14 0.0003 Planned post-transplant therapy vs no therapy 0.6 (0.4-0.8) <0.0001 OS HRM vs NHRM 2.0 (1.4-3.0) 0.0001 African-American race vs Caucasian 1.7 (1.1-2.5) 0.007 ISS/DSS III Yes vs No 1.8 (1.2-2.5) 0.0008 Pre-transplant CR PR SD Progression 1 1.4 (1.0-1.9) 1.8 (1.0-3.0) 2.7 (1.5-4.8) 0.008 0.03 0.02 0.0004 Planned post-transplant therapy vs no therapy 0.5 (0.3-0.8) 0.0001
Figure 1. Figure 1.

Disclosures
Krishnan: Onyx: Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy, Speakers Bureau; Millenium: Speakers Bureau; Jazz: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.