Depth of Response and Outcomes in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation
Authors: Shah Gunjan L. , Seier Kenneth , Devlin Sean M , Chung David J. , Scordo Michael , Hultcrantz Malin , Korde Neha , Lendvai Nikoletta , Lesokhin Alexander M. , Mailankody Sham , Smith Eric L. , Landgren Ola , Landau Heather J. , Giralt Sergio 
Published: October 2019

Abstract
Background: For multiple myeloma (MM) patients, depth of response after induction therapy and after autologous hematopoietic stem cell transplantation (AHCT) has been shown to be important for progression free (PFS) and overall survival (OS) in some studies. Furthermore, the impact of minimal residual disease (MRD) on outcomes and treatment decisions has been widely discussed. We aimed to evaluate outcomes by depth of response after induction and AHCT.
Methods: MM patients who received their first AHCT within 1 year of starting induction were identified from the institutional registry. MRD was assessed by non-10 color flow cytometry. Response was defined by the International Myeloma Working Group criteria. Summary statistics were used to describe the population. Kaplan-Meier methodology estimated PFS and OS by response status pre-AHCT and at post-AHCT restaging.
Results: Between 2012 - 2014, 182 MM patients met our inclusion criteria, with 83% alive at last follow-up. The median age at AHCT was 60 years (range 29-76) with 57% male. By the International Staging System (ISS), 50% were stage I, 26% stage II, and 24% stage III. High risk cytogenetics were detected in 24%. Isotype was IgG in 55%, IgA 21%, Kappa Free Light Chain (KFLC) 11%, and lambda FLC (LFCL) 9%. First induction therapy included bortezomib in 90% and lenalidomide in 79%. Median time to AHCT was 5.5 months (range 2.8-11.7). The median follow-up from AHCT was 3.7 years (range 0.22 - 4.6 years), with 84% of patients receiving lenalidomide maintenance, and 9% receiving an additional autologous or allogenic transplant at relapse.
Response prior to the initial AHCT was a complete remission (CR) in 13.7% (MRD negative 6.6%, positive 4.4%, unknown 2.7%), very good partial remission (VGPR) 38%, partial remission (PR) 40%, stable disease (SD) 5%, and progressive disease (PD) 4%. At post-AHCT restaging, responses had improved to 42% CR (MRD negative 23%, positive 6%, unknown 13%), 35% VGPR, 19% PR, 2% SD, and 3% PD.
Median PFS from AHCT for the entire cohort was 3.2 years (95% CI 2.4 - 4 years) with 1-year and 3-year PFS 85% and 52%, respectively. Median OS was not reached (NR) (95% CI 4.4 years - NR) with 1-year and 3-year OS 97% and 88%, respectively (Figure 1).
PFS from AHCT was significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached (95% CI 1.7 - NR) compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.64 years (95% CI 1.09-3.64), 3.46 years (95% CI 2.4 - NR), and 2.44 years (1.68-3.56 years), respectively, p=0.048] (Figure 2A). From post-AHCT restaging, PFS was also significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.49 years (95% CI 0.86-3.49), 3.56 years (95% CI 2.5 - NR), and 2.4 years (1.6-3.33 years), respectively, p=0.026] (Figure 2B). However, there was no difference in PFS based on the post-AHCT restaging with median PFS in MRD negative CR, MRD positive/unknown CR, VGPR, and ≤ PR of 3.49 years (95% CI 2-NR), not reached (95% CI 1.4-NR), 2.96 years (95% CI 1.7-NR), and 2.86 years (95% CI 1.7 - NR) (p=0.78, Figure 2C), respectively.
OS from AHCT was not significantly different by pre-AHCT response, and the median was not reached in any group (p=0.33, Figure 3A). Finally, the median OS from post-AHCT restaging by pre-AHCT response or by post-AHCT response was also not reached in any group (p=0.32 and 0.31, respectively; Figure 3B & C).
Conclusion: For MM patients, AHCT deepened responses and increased the CR rate. We were unable to show a significant difference in outcomes at post AHCT restaging, which may be due to the effect of maintenance therapy, the small numbers of MRD negative patients, or the sensitivity of the MRD assay available during this time period, though potentially show that MRD positive patients do as well as MRD negative patients after AHCT. We plan to add additional patients treated in the more recent years who were assessed by more sensitive methods.

Disclosures
Shah: Janssen: Research Funding; Amgen: Research Funding. Korde:Amgen: Research Funding. Lesokhin:Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Squibb: Consultancy, Honoraria. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.