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Background: The results of international randomized clinical trials emphasize the expediency of maintenance therapy following auto-HSCT. However, these studies did not assess such important issues as the need for maintenance therapy in patients who have achieved complete remission (CR) or stringent CR following auto-HSCT. Probably, the results of studying MRD following auto-HSCT will allow receiving a substantiated answer to this question. Aims: To evaluate the efficacy of maintenance therapy following auto-HSCT depending on MRD in patients with multiple myeloma. Patients and methods: Over the period from January 2012 to April 2018, 70 MM patients (24 males and 46 females) aged 32 to 65 years (median=56) were enrolled into a prospective study. The disease stage according to the International Staging System (ISS) was I, II and III in 28, 19 and 23 patients, respectively. All patients received induction therapy with bortezomib; immunomodulatory drugs were used in 10 cases. After the induction therapy, a single and tandem auto-HSCT were performed in 57 and 13 patients, respectively. On Day 100 following auto-HSCT, bone marrow examination was carried out in order to determine MRD using six-color flow cytometry with a panel of antigens: CD38, CD138, CD45, CD56, CD117, CD19. MRD-negative status was diagnosed in case of detection of <20 clonal plasma cells among 2,000,000 white blood cells (<0.001%; detection limit 10-5). On Day 100 after the auto-HSCT, all patients achieved CR of the disease and were randomized to receive maintenance therapy with lenalidomide 15 mg/day from Day 1 to Day 21 of a 28-day course within a year or no such therapy. The follow-up period since the moment of MRD determination was 2-28 months (median 15). Survival curves were constructed using the Kaplan-Meier method. Statistical analysis was done using Statistica 10. Results: 37 patients were randomized to receive maintenance therapy with lenalidomide following auto-HSCT, including 23 patients in whom plasma cell immunophenotyping showed the lack of MRD and 14 patients in whom MRD-positive status was confirmed. Thirty-three patients were followed-up without further treatment after the auto-HSCT, including 24 cases with MRD-negative status and 9 cases with the presence of abnormal plasma cells in the bone marrow. The compared groups were comparable in respect of such parameters as age and the ISS stage. The differences between two-year PFS rates in MM patients with MRD-negative status following auto-HSCT who received (n=23) or didn't receive (n=24) the maintenance therapy, showed no statistical significance (p=0.3) and were 88% and 74%, respectively (Fig.1a). In patients with MRD-positive status following auto-HSCT who received lenalidomide, two-year PFS rate was significantly (p<0.05) higher and was 92% versus 45% in the group of patients who didn't receive the maintenance therapy (Fig.1b). Conclusion: Achievement of MRD-negative status following auto-HSCT was accompanied by high values of PFS regardless of the use or not use the maintenance therapy with lenalidomide (88% versus 74%, p=0.3). Prescription of the maintenance therapy to patients with MRD-positive status following auto-HSCT improves the PFS. Disclosures No relevant conflicts of interest to declare.

Background: Necessity of maintenance therapy (MT) in patients with multiple myeloma (MM) after auto-HSCT continues to be a matter of debate in the community. To ensure it's proper application, it is important to set clear criteria when it is an appropriate type of treatment. MRD status of the patient after auto-HSCT could be such a criteria, than can be used to stratify the risk of relapse and justify the MT. Aims: To assess the efficacy of MT in patients with MM achieving a complete response after auto-HSCT accounting on whether or not they have minimal residual disease. Patients and Methods: Fifty-two patients with MM (19 male and 33 female, 24 to 66 years old - median, 54 years) who had achieved a complete response after auto-HSCT were enrolled in a prospective randomized clinical study in the period from January 2014 to February 2016. Subjects were at the following stages of the disease (ISS): 11 at Stage I, 23 at Stage II, and 18 at Stage III. The remission induction protocol included: bortezomib-containing regimens (VCD, PAD) for all 52 patients, immunomodulatory agents for 8, and bendamustine for 2. Distribution of patients by type of anti-tumor responses (according to the International Myeloma Working Group classification criteria) after induction was as follows: complete response in 26 patients (50 %), very good partial response in 12 subjects (23 %), and partial response in 5 individuals (27 %). Single auto-HSCT was used in 36 subjects and tandem auto-HSCT in 16. At 100 days post auto-HSCT, the MRD status was assessed by means of bone marrow examination using six-color Flow Cytometry with a panel of antibodies to the following antigens: CD38, CD138, CD45, CD56, CD117, and CD19. Tests yielding less than 50 clonal plasma cells in 500,000 white blood cells (< 0.01 %, Limit of Detection: 10-4) were reported as an MRD-negative status. A stringent complete response after auto-HSCT had been achieved in 25 patients (48 %), while an MRD-positive status was detected in 27 subjects (52 %). At 100 days post auto-HSCT, MRD-negative patients were randomized into two arms: 14 subjects were given bortezomib MT (1.3 mg/m2 s.c., one dose every two weeks for one year), and 11 patients were not administered M"; one female patient was subsequently withdrawn from maintenance therapy due to drug toxicity. Some of the MRD-positive subjects (19) received bortezomib MT according to the aforementioned regimen, while the others (8 patients) did not receive MT. The follow-up period from the time of MRD detection ranged from 5 months to 27 months (median 14 months). Two deaths (unrelated to the underlying condition) were registered in the course of the trial. Relapse-free survival (RFS) rate was selected as the efficacy endpoint for MM patients. Survival curves were constructed using the Kaplan-Meier method and a log-rank test was used to compare the survival estimates between two groups. The compared groups were overall balanced for known prognostic factors. Statistical analysis was done using SAS 9.4. Results: MRD-positive patients were found to have a lower 2-year RFS rate compared with MRD-negative patients: 49 % vs 60 % (P=0.056); the presence of MRD increases the risk of relapse (Hazard Ratio: 1.7, 95 % CI: 1.3 − 3.4) (Fig. 1). MT administered in MRD-negative patients did not increase their RFS: the 2-year RFS rates were found to be approximately the same in the MT and no MT arms (P=0.46), and equal to 84 % (Fig. 2). MT used in MRD-positive patients did increase their RFS: the 2-year RFS rate was higher in patients treated with MT compared with the no MT treated: 43 % vs 35 % (P=0.076) (Fig. 3). Following completion of MT, 8 out of 19 MRD-positive patients (42 %) achieved a better antitumour response, i. e. a stringent complete response. Conclusion: The reported study demonstrated that assessment of the MRD status provides an effective criterion for risk stratification in patients who have received auto-HSCT and are considered for MT. Maintenance therapy appears to be most appropriate in patients found to be MRD-positive after auto-HSCT, while for MRD-negative patients carrying out MT is inappropriate because it does not result in significant effect, but is associated with toxic complications. This study was approved by the local ethics committee. Disclosures No relevant conflicts of interest to declare.

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