We assessed the outcomes of pomalidomide and dexamethasone treatment in relapsed/refractory multiple myeloma (RRMM) patients with ≥1 prior line of therapy. We analyzed the data of all RRMM patients ...treated with pomalidomide and dexamethasone at nine Czech centers between 2013 and 2018. The source of the data was the Registry of Monoclonal Gammopathies of the Czech Republic. Primary endpoints included response rates based on International Myeloma Working Group criteria and survival measures, including progression-free survival (PFS) and overall survival (OS). Secondary endpoints were toxicities and previous treatment patterns, including refractory to lenalidomide, and their impact on final outcomes. The overall response rate was 51.8% and the clinical benefit rate (including patients with minimal response) was 67.1%, with 0.6% of complete responses, 8.5% of very good partial responses, and 42.1% of partial responses (PR). Overall, 16.5% of patients had a minimal response, and 32.3% had stable disease /progression. Median PFS was 8.8 months and the median OS was 14.2 months. In patients who achieved ≥PR, the median PFS and OS were significantly longer compared to non-responders (median PFS (12.1 vs. 4.5 months, p≤0.001 respectively), median OS (22.1 vs. 7.7 months, p≤0.001, respectively). The most frequent adverse events (AEs) were neutropenia (29.9%) and anemia (18.9%), non-hematological AEs included infections (14.6%) and fatigue (7.3%). Our analysis confirmed the effectiveness of pomalidomide and dexamethasone in a real-world setting. This therapy achieved reasonable outcomes comparable to the data from clinical trials even though this was an unbiased cohort of patients.
Background: Treatment of relapsed and refractory multiple myeloma (RRMM) has become a chalenge with the introduction of combined lenalidomide-based triplets. The addition of proteasome inhibitors ...(PI) or monoclonal antibodies (MoAb) significantly improved the therapeutic outcomes of previous RD regimen (lenalidomide, dexamethasone). The clinical trials with RD triplets confirmed the outstanding synergistic effects of lenalidomide with PIs or MoAbs. However, the outcomes between individual regimens are not easily comparable as the trials used different cohorts of patients. Moreover, the clinical trials often overestimate the outcomes due to selection bias. Aims: Our aim was to compare the outcomes of lenalidomide-based triplets in an unselected “real-world population”. Patients and methods: We performed a large registry based analysis of RRMM patients treated with daratumumab, lenalidomide and dexamethasone (DRD), carfilzomib, lenalidomide and dexamethasone (KRD), and ixazomib, lenalidomide and dexamethasone (IRD) from the Czech Registry of Monoclonal Gammopathies (RMG) treated within 1st-3rd relapse. We excluded patients treated in clinical trials as well as patients with follow-up shorter than 6 months. For the IRD combination we performed 2 separate analyses: from 2016-2018 (early IRD, e-IRD) and 2019 onwards (late IRD, l-IRD), as the first cohort was treated within a Named Patient Program and had no competitive RD triplet or clinical trial, whereas patients treated after 2019 were those who were generally not eligible for competing KRD or DRD regimens. Altogether we assessed 224 patients with DRD regimen, 143 with KRD, 104 with e-IRD and 67 with l-IRD regimen. Data were described by absolute and relative frequencies of categorical variables and median (min-max and 5 th-95 th percentile) for quantitative variables. Survival analysis for different endpoints - overall survival (OS), progression free survival (PFS), time to next treatment (TNT), and duration of therapy (DOT) - was conducted using the Kaplan-Meier method complemented by the 95% Greenwood confidence interval for estimates of probability survival. Statistical significance of differences in survival among subgroups was assessed using the log-rank test. All statistical tests were performed at a significance level of α = 0.05 (all tests two-sided). Results: There were slight but significant differences within the demographic data: Patients treated with DRD and KRD were younger than patients on both e-IRD and l-IRD (median 65.5 vs 64.4 vs 67.2 vs 69.9 years) and had better overal performance status (PS 0 or 1 in 87.9 vs 92.2 vs 83.5 vs 76.1%). They were also less pretreated (1 previous line in 73.2 vs 70.6 vs 62.5 vs 38.8%). Also, patients on DRD and KRD had slightly lower ISS stage versus e-IRD and l-IRD patients (ISS 1 in 48.4 vs 55.5 vs 42.2 vs 37.5%). Patients on KRD had slightly higher presence of extramedullary and/or paraskeletal disease (45.6% versus 32.5% and 35.0% vs 31.6% in DRD and e-IRD and l-IRD, respectively). The presence of high-risk cytogenetics was higher in KRD and l-IRD (42.7 vs 53.1%) than in the e-IRD and DRD group (32.3% and 24.6%). The overal response rates (ORR) in DRD, KRD, e-IRD and l-IRD were following: 91.4% vs 89.6% vs 79.6% vs 70.8%. The rates of very good partial response or better (VGPR+) were 67.3% vs 62.3% vs 40.8% vs 25%. Median PFS in DRD vs KRD vs e-IRD vs l-IRD was 23.64 vs 16.52 vs 19.97 vs 11.57 months. Due to short follow-up, the median OS was not assessable with an estimate around 40 months for all the cohorts. The toxicity was similar to the data reported from clinical trials with no new safety alerts. Conclusions: We conclude that lenalidomide based triplets (DRD, KRD and IRD) have significant efficacy in RRMM even in the routine clinical practice but as expected, they do not achieve the outcomes reported in clinical trials. DRD regimen seems to be the most efficient regimen even in “real-world” setting but the results are biased by the cohort heterogeneity. The outcome of a regimen in “real-world” depends significantly on other variables including competing regimens or clinical trials, and may have large individual differences as seen in the case of e-IRD (assessed at the time with no competing lenalidomide-based triplets) versus l-IRD (influenced by the choice between several effective modalities). Supported by MH CZ - DRO (FNOL, 00098892).
Full text
Available for:
IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible.
Patients and Methods
We ...analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real‐world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib‐cyclophosphamide‐dexamethasone) (47.5%) over VMP (bortezomib‐melphalan‐prednisone) (21.7%), BDd (bortezomib‐doxorubicin‐dexamethasone) (9.8%), and VTd (bortezomib‐thalidomide‐dexamethasone) (2.9%).
Results
The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); and 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd, and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 mo, (P = .275), respectively, and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2 mo (P = .004), respectively. The most common grade 3‐4 toxicities were anemia in 17.4% and infections in 18% of patients.
Conclusion
Our study confirmed that bortezomib‐based treatment is effective and safe in NDMM transplant ineligible patients, especially VMP, which was identified as superior between bortezomib‐based induction regimens not only in clinical trials, but also in real clinical practice.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Our aim was to correlate serum levels of selected markers of bone metabolism and bone marrow microenvironment to cytogenetic changes in patients with multiple myeloma (MM).
Methods
We ...assed cytogenetic changes in 308 patients and correlated them with the following levels of bone marrow metabolism: thymidine kinase (TK), β2‐microglobulin (b‐2‐m), Dickkopf‐1 protein (DKK‐1), C‐terminal telopeptide collagen‐I (ICTP), N‐terminal propeptide of type I procollagen (PINP), receptor for interleukin 6 (rIL‐6), vascular cell adhesive molecule‐1 (VCAM), soluble intercellular adhesion molecule‐1, osteoprotegerin (OPG), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), syndecan‐1 (SYN‐1) and Fas antigen.
Result
Individuals with delRB1 had lower levels of OPG (M = 7.39 vs. 5.46 pmol/L, p = .025) and VEGF (M = 304 vs. 196 pg/ml; p = .036). t(14;16) was associated with higher β2m levels (M = 7.59 vs. 4.13 mg/L; p = .022) and lower DKK‐1 levels (M = 4465 ng/L vs. 12,593). The presence of 1q21 gain was associated with higher levels of TK (M = 100.0 vs. 11.0 IU/L, p = .026) and lower levels of PINP (M = 49.3 vs. 67.4 mg/L, p = .030).
Conclusions
Our analysis has shown, some cytogenetic changes, especially delRB1, t(14;16) and 1q21gain, which affect the components of the cytokine network in multiple myeloma.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Waldenström's macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM ...patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease.
Aims
To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status.
Methods
Analyzed DNA was isolated from mononuclear fraction of bone marrow or peripheral blood cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions.
Results
We analyzed 23 patients with WM. All patients were MYD88L265P-positive (100 %), and 7 of them (30,4%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 6 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease: higher ISSWM score (low 0/intermediate 1/ high 6 risk), anemia (7/7), hyperviscosity syndrome (2/7) at time of diagnosis. CXCR4WHIM-WT patients were often asymptomatic (5/16) with lower ISSWM score (low 5/intermediate 5/ high 6 risk) but with common adenopathy (11/16). CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were refractory to initial therapy and needed 2nd line treatment, 3 patients had only partial response to first-line therapy, one patient died after 2nd cycle due to abdominal septic complication and only one patient reached VGPR). Progression-free survival in treated patients was 32 vs. 8 months in CXCR4 mutants.
Conclusion/summary
The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the diseases. CXCR4 mutations were found in nearly one third of WM patients. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. On the contrary CXCR4WHIM-WT patients have more indolent course of the disease.
This work was supported by grant IGA-LF-2018-004 and MH CR - RVO (FNOL, 00098892).
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
