Tandem autologous stem cell transplantation in patients with persistent bone marrow minimal residual disease after first transplantation in multiple myeloma

Attainment of bone marrow (BM) minimal residual disease (MRD) negativity is associated with superior progression free (PFS) and overall survival (OS) in multiple myeloma (MM).1 Persistent disease during and after therapy signifies an increased risk of relapse.2 MRD risk adapted treatment approaches are presently the subject of several clinical trials, but changing treatments in patients with persistent MRD positivity is not widely embraced in clinical practice. We have reported that MRD positive disease after high dose chemotherapy and autologous stem cell transplant (ASCT) is associated with worse outcome and further treatment should be consolidated to induce deeper and durable responses.3 Clinical trials investigating consolidative therapy after ASCT have mixed results and the outcome of studies specifically designed for patients with persistent disease after ASCT are awaited.4, 5 Role of tandem ASCT is controversial, with more recent studies showing benefit in high-risk disease.4, 6 Herein, we seek to investigate the role of a planned tandem ASCT with either standard melphalan (Mel, 200 mg/m2 or 140 mg/m2) conditioning or BEAM (BCNU, 300 mg/m2; etoposide, 100 mg/m2; cytarabine, 100 mg/m2; and melphalan, 140 mg/m2) conditioning in newly diagnosed multiple myeloma (NDMM) patients with BM MRD positivity after upfront ASCT. Of 339 planned tandem ASCTs that were performed at our institution from 2013 until 2019, 168 patients had BM MRD positivity following first ASCT (ASCT1) and were included in this analysis. Clinical variables including patient characteristics, disease parameters, cytogenetic risk at diagnosis, pre-transplant work up, engraftment, and toxicities including death, BM MRD status, and disease response as defined according to the IMWG criteria7 before ASCT1, before second ASCT (ASCT2), and after ASCT2 were collected. High-risk cytogenetics was defined by detection of t (4;14), t (14;16), t (14;20), del 17p/monosomy 17, gain/amplification 1q by FISH or abnormal metaphase cytogenetics. Risk stratification by gene expression profiling (GEP) on BM aspirate at the time of diagnosis or presentation to our institution was performed as previously described.8 For this analysis, high-risk (HR) disease is defined as patients who have any one of the following criteria: high-risk GEP70, high-risk cytogenetics, or ≥3 focal lesions by PET.9 All patients were treated with induction chemotherapy that included a combination of immunomodulatory agents (IMiD) and proteasome inhibitor (PI) added to a backbone of multi-agent chemotherapy (PACE [Cisplatin, Adriamycin, Cyclophosphamide and Etoposide]) followed by tandem ASCT and maintenance therapy consisting of a combination of an IMiD, PI, and dexamethasone.10 Imaging studies with 18fluoro-deoxyglucose positron emission tomography (18F-FDG PET)9 and whole-body magnetic resonance imaging (MRI) and MRI with diffusion-weighted MRI with background suppression (DWIBS)11 were performed at diagnosis and repeated at follow-up. BM aspirate MRD assessment was performed using clinically validated 8-color flow cytometric analysis with a minimal sensitivity of 10−5 cells12, 13 and was performed within 100 days of ASCT1 and ASCT2.3 The median age at ASCT1 was 58 (interquartile range [IQR] 52–63) yrs with 40% (68/168) being female patients (Table S1). Black patients accounted for 16% (n = 26) of all patients. About 106 patients (63%) had HR disease. ASCT2 was performed at a median of 78.5 (IQR 27–232) days after ASCT1. All patients had melphalan conditioning before ASCT1; most patients had melphalan (150/168; 89.3%) conditioning prior to ASCT2, while 18 (10.7%) patients received BEAM conditioning. Among the patients who received BEAM conditioning, 56% (9/16) had high-risk FISH, 28% (5/18) complex metaphase cytogenetics, 67% (12/18) ≥3 PET FL at diagnosis, and 50% (2/4) had a high-risk GEP70. A median of 6.85 (IQR 5.62–8.90) million CD + 34 cells were infused with ASCT2. The median time to neutrophil and platelet engraftment were 11 (IQR 10–11) and 8 (IQR 6–10) days, respectively. In about three-quarters of the patients (77%), ASCT was performed entirely outpatient, with inpatient admission required in the rest of the patients at a median of 8.11 (range 1.6–14.8) days from day 0. During the first 100 days after ASCT, there was one death attributed to disease progression. There were no transplant-related deaths in this cohort. Most patients went into ASCT1 with a PR response (n = 89; 54%) to induction therapy. An ORR of 96% (159/168) was attained after ASCT1. VGPR, CR, and sCR rates were 48% (n = 80), 12% (n = 19), 1.2% (n = 2), respectively. Following ASCT2, there was deepening of response with ORR of 97% (n = 163). After ASCT2, the VGPR, CR, and sCR rates were 47% (n = 77), 19% (32), and 19% (31), respectively (Figure S1). About 51% (n = 81) of patients achieved BM MRD negativity following ASCT2. Deepening of responses and higher rates of ≥ VGPR were also noted in the HR subgroup (Figure S1), with 52.4% (54/103) attaining MRD negativity. In patients who received BEAM conditioning, there was a lower ORR (93.6% vs. 99%, p = .022) and MRD negativity rates (6.7% vs. 56%; p < .001). The 3-year PFS and OS were 72% (95% CI 65–80) and 92% (95% CI 87–96), respectively (Figure 1A,B). Looking specifically into the HR subgroup, the 3-year PFS and OS were 63% (95% CI 57%–69%) and 89% (95% CI 84%–93%), respectively (Figure S2a,b). Achievement of MRD negativity after ASCT2 was associated with an improvement in 3-year PFS (MRD-85% vs. MRD+ 62%; p = .007) without a statistically significant difference in the 3-year OS (MRD-97% vs. MRD + 91%; p = .38) (Figure 1C,D). Similar results were observed when HR patients were stratified by MRD status after ASCT2 (3-year PFS MRD- 73.7% vs. MRD+ 49.3%; p = .007, 3-year OS MRD- 91.4% vs. MRD+ 87.6%; p = NS) (Figure S2d,c). The clinical trials investigating tandem ASCT in the era of novel agents reported mixed results. The phase 3 BMT-CTN 0702 STAMINA trial reported no increment in PFS or OS with either a second ASCT or VRD consolidation following a single upfront ASCT in NDMM.14 In an update of the BMT-CTN 0702, the per protocol analysis showed a PFS benefit in the tandem ASCT arm that was primarily driven by high-risk MM (5- year PFS ASCT/ASCT: 43.7% vs. ASCT/RVD 37.3% vs. ASCT/maintenance 32%; p = .03) patients.6 Moreover, this study enrolled patients with mostly VGPR (47%) following induction therapy and did not report the IMWG disease response or MRD status following upfront ASCT. If there is a role of additional therapy, either a second ASCT or consolidation in patients who did not have ≥VGPR following the first ASCT remains to be answered. Despite being underpowered to study the effect of tandem ASCT in different risk group, the EMN02/HO95 study showed a significantly longer PFS (HR 0·74) and OS (HR 0·62) with double HSCT and a higher magnitude of benefit (HR for disease progression and death 0·24 and 0·30, respectively) was noted in subgroup with del 17p. Other reports also indicated an improvement in outcomes with tandem ASCT approach, particularly in advanced ISS stage, high-risk subgroup such as del 17p and those who failed to achieve a CR.4, 15 MRD positivity particularly confers poor outcome in the setting of HR disease.3, 16 Our study population is enriched in HR disease (63%) with BM MRD positivity in all patients after ASCT1. Overall, there was augmentation of disease responses including attainment of MRD negativity in about 50% of patients after ASCT2 that translated into improved PFS. The benefit was also evident in HR patients included in our analysis. We have previously reported a lower rate of sustained MRD negativity in HR patients, which could explain the lower PFS despite attaining MRD negativity after ASCT2.17 OS data remain immature due to short follow-up. There were no safety concerns with tandem ASCT (TRM of 0%). The lower ORR and MRD negativity rates following BEAM conditioning for ASCT2 should be interpreted with caution due to preferential use of this regimen in patients with high-risk features in this series. The recently reported MASTER trial establishes the feasibility of treatment-free period as guided by BM MRD status in the context of Dara-KRd induction, ASCT, and Dara-KRd consolidation.18 The subset of patients with HR and ultra-HR disease suffered clinical relapses due to fewer sustained MRD negativity in this population.18, 19 Management of patients with persistent MRD disease positivity after ASCT, particularly in HR patients, remains unclear, and question remains if treatment escalation should be adopted to improve outcome. In the PETHEMA/GEM2012MENOS65 trial, MRD conversion to negative state occurred in only 17% of patients and most of these occurred in the first year of maintenance therapy.16 There are several ongoing trials investigating intensification of treatment in the context of MRD positive disease after upfront ASCT in NDMM. The phase 3 AURIGA study randomizes patients with MRD positive disease after ASCT to daratumumab/lenalidomide vs lenalidomide alone maintenance with a primary outcome of MRD conversion at the end of 12 months of treatment. Other strategies include augmented daratumumab-based quadruple therapy consolidation (NCT04140162), chimeric antigen receptor T cell therapy (NCT04436029), belantamab mafodotin (NCT04876248, NCT05091372), and a tandem ASCT (NCT04934475) are also being investigated in persistent MRD positive disease after ASCT in MM. As we await these studies, this single-center retrospective study of upfront tandem ASCT is a clinically useful and safe option to attain MRD negativity, especially in HR disease. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Rates of overall responses (ORR) and ≥ very good partial responses (VGPR) post ASCT1 and ASCT2. Figure S2. Kaplan Meier curve showing progression survival (2a) and overall survival (2b) of high risk, MRD positive patients undergoing a planned tandem ASCT approach1c and 1d showed the progression free and overall survival of patients stratified by MRD status post ASCT2 in high-risk patients. Table S1. Baseline characteristics. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.