Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Autologous stem cell transplantation (ASCT) proceeded by induction with proteasome inhibitor, immunomodulatory agent, +/- CD38 monoclonal antibody and dexamethasone is the standard of care (SOC) for eligible patients with multiple myeloma. Despite novel drugs, the outcome of high-risk patients is poor. This phase 2 Nordic Myeloma Study Group (NMSG) trial, NCT03376672, investigates the response to ixazomib (I), lenalidomide (R) and dexamethasone (D) (IRD) induction followed by IRD consolidation and risk-based maintenance either with R alone in non-high-risk patients (NHR) or IR in high-risk patients (HR). Here we present the preplanned results for all patients after 2 years on maintenance. Aims: The primary endpoint is the minimal residual disease (MRD) <10-4 (positive or negative) by flowcytometry at any time during treatment compared to the historical Finnish Myeloma Group (FMG) trial (RVD+ASCT+R maintenance). The secondary endpoints include flow-MRD negativity <10-5, overall response rate (ORR), safety, progression-free survival (PFS), results between NHR and HR patients and overall survival (OS). MRD was assessed every 6 months in patients achieving CR. Methods: A written informed consent was obtained from all patients. Altogether 120 patients were included in the study which consisted of 4 IRD cycles as induction, ixazomib 4 mg on days (d) 1, 8, 15, lenalidomide 25 mg on d 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and single ASCT were performed according to the SOC. Three months post-ASCT patients received 2 IRD consolidation cycles followed by risk stratified maintenance. Patients with del17 (cut of 60%), t(4;14), t(14;16), t(14;20) or +1q were included in HR group and they received ixazomib 4 mg on d 1, 8, 15 and lenalidomide 10 mg on d 1-21/28. If well tolerated, lenalidomide was increased to 15 mg after 3 cycles. At inclusion 52.5% of patients belonged to NHR and 47.5% to HR group. Results: The ORR, at least PR, with induction, was 84%. Forty-three percent (51/120) of patients were MRD <10-4 at any time during protocol treatment versus 45% of historical control. At 2 years on maintenance 40/120 (33%) were ≥CR and 18/40 (45%) also flow-MRD neg <10-5. At 2 years on maintenance 82% of NHR and 74% of HR patients were progression-free (p= 0.395). In the high-risk group, patients with +1q with other HR aberration had the shortest median PFS, 24 (6-48) months. Sustained flow-MRD negativity <10-5 in at least two consecutive samples was detected in 12 patients in the HR group (21%) compared to 12 in the non-HR group (19%), p=0.778. Median PFS for patients with sustained flow-MRD negativity was not reached and was 38 (20-48) months for patients who lost the negativity and 29 (0-47) months for flow-MRD positive patients. OS at 3 year was 92% in NHR and 86% in HR group, p=0.573. Treatment related mortality was 1.7% Pneumonia was the most common grade 3 SAE. Two (1.7%) secondary malignancies were diagnosed: one lung and one pancreas cancer. Summary/Conclusion: The ORR was 84% for IRD induction and 43% had MRD <10-4 at any time during treatment. After 2 years of maintenance 33% of patients were in ≥ CR and 45% of those were also flow-MRD negative <10-5. There was no difference in sustained MRD negativity <10-5 or PFS between HR and NHR patients. The 3-year OS was comparable between NHR and HR groups, 92% vs 86%, respectively. Ixazomib plus lenalidomide maintenance seemed to overcome the worse prognosis for HR in regard to PFS and OS. Keywords: Multiple myeloma, Minimal residual disease (MRD), High risk
Background: Several authors have highlighted the importance of a deep response to chemotherapy in multiple myeloma (MM), especially in first line. Aims: The objective was to assess which patient/treatment/disease characteristics are prognostic for a deep response. Also, to assess whether the deep response is prognostic for overall survival (OS) independent of treatment, treatment line and patient/disease characteristics. Methods: A retrospective analysis was performed on 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics such as age, gender, ISS stage, albumin, creatine, and MM type, which were recorded at start of first line therapy. The following outcomes were considered; response, time to next line of treatment (TTNT) and OS. The following categories of response were differentiated: progressive disease (PD), no response (NR), partial response (PR), very good PR (VGPR) and equal or better than near complete response (>=nCR). To identify prognostic factors for response, univariate and multivariate multinomial regression were conducted with response as dependent and patient baseline characteristics and type of treatment as independent variables. To assess whether response is an independent predictor of OS, multivariate cox-proportional hazard models were run for the first four lines of treatment. Results: Patients in the dataset were on average 67 years old, 48% were male, 28%, 41% and 31% in ISS stages I, II and III, respectively. Multinomial regression showed that type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. In second line, first line response, type of treatment and age were significant prognostic factors for response in second line. Multivariate cox-regression showed that in first line patients with NR, PR, VGPR and >=nCR had significant lower hazard ratio's (HRs) 0.61 (0.43-0.85), 0.56 (0.41-0.78), 0.34 (0.22-0.51) and 0.36 (0.24-0.54) respectively compared to PD. Age, Albumin, Calcium and Beta-2-microglobulin levels were also significant prognostic factors for OS with HRs of 1.03 (1.01- 1.04), 0.98 (0.96-0.99), 1.41 (1.11-1.79) and 1.02 (1.01-1.03) respectively. The following categorical variables also were significant prognostic factors for first line OS; type of treatment, ISS-stage and MM type. For second line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.58 (0.46-0.73), 0.42 (0.3-0.58), 0.4 (0.27-0.6) compared to PD respectively. Age also had a significant HR of 1.02 (1.01-1.03). For third line OS multivariate cox-regression showed that patients with NR, PR, VGPR and >=nCR had significant lower HR's 0.67 (0.5-0.89), 0.37 (0.27-0.51), 0.32 (0.21-0.5), 0.18 (0.1-0.34) compared to PD respectively. Age also had a significant HR of 1.01 (1.00-1.02). For fourth line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.45 (0.31-0.64), 0.31 (0.19-0.52) and 0.39 (0.21-0.73) compared to PD respectively. Age was also identified as a significant prognostic factor. Summary and Conclusions: Type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. For second line response, the significant prognostic factors were response in first line, type of treatment and age. Moreover, multivariate cox-regressions shows that in the first four lines of treatment, response is an independent prognostic factor for OS. Future research should include genetic prognostic factors, which were not collected in our dataset and could therefore not be assessed.
The growth factor‐dependent myeloma cell line OH‐2, which has previously been shown to be responsive to interleukin (IL)‐6, tumour necrosis factor (TNF)‐α and lymphotoxin, was examined for response to other growth factors. Enhanced proliferation was found in the presence of IL‐10, IL‐15, IL‐2 and insulin growth factor (IGF)‐1. Proliferation was strongest in response to IL‐6, intermediate and roughly equipotent in response to IL‐15, IL‐10 and TNF‐α, and modest in response to IL‐2 and IGF‐1. IL‐15 was synergistic with TNF‐α, whereas combinations of IL‐15 and the other cytokines were merely additive. IL‐15‐induced proliferation could not be blocked by neutralizing antibody against gp 130, the common transducer chain of IL‐6 and related cytokines. IL‐15 and IL‐6 prevented apoptosis equally well, both better than TNF‐α, IL‐10, and IGF‐1. In four out of six samples of purified primary cells, IL‐15 and IL‐6 induced proliferation. Furthermore, IL‐15 mRNA was detected by RT‐PCR in most myeloma cell lines and freshly isolated purified patient samples. IL‐15 protein was detectable only in one out of about 20 tested cell supernatants from patients and myeloma cell lines. The OH‐2 cell line is multi‐responsive to cytokines and is a good system for the study of integration of cytokine signal transduction and growth control in myeloma. IL‐15 represents a novel modality of growth regulation in myeloma.
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
