Thalidomide Maintenance Research Articles

Autologous-allogeneic versus autologous tandem stem cell transplantation and maintenance therapy with thalidomide for multiple myeloma patients under 60 years of age: a prospective, phase II study.

The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma is controversial. Between 2008 and 2014 a total of 217 multiple myeloma patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multicenter clinical trial to compare alloTSCT to autologous tandem transplantation (autoTSCT) followed by 2 years of maintenance therapy with thalidomide (100 mg/day) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent a second transplant (132 allogeneic, 46 autologous). PFS at 4 years after the second transplant was 47% (95% CI: 38-55%) for alloTSCT and 35% (95% CI: 21-49%) for autoTSCT (P=0.26). This difference increased to 22% at 8 years (P=0.10). The cumulative incidences of non-relapse mortality and of relapse at 4 years were 13% (95% CI: 8-20%) and 2% (95% CI: 0.3-2%) (P=0.044) and 40% (95% CI: 33-50%) and 63% (95% CI: 50-79%) (P=0.04) for alloTSCT and autoTSCT, respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (P=0.002). Four-year overall survival was 66% (95% CI: 57-73%) for alloTSCT and 66% (95% CI: 50-78%) for autoTSCT (P=0.91) and 8-year overall survival was 52% and 50% (P=0.87), respectively. In conclusion, alloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly. This study was registered with ClinicalTrials.gov (NCT00777998).

Maintenance therapy with a combination of azacitidine, danazol, and thalidomide after intensive chemotherapy in patients with acute myeloid leukemia

ABSTRACTObjectiveThis study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in patients with acute myeloid leukemia (AML).Methodswe retrospectively analyzed the clinical data of 11 patients treated with AZA combined with DNZ and THD as maintenance therapy after IC at the Baiyun Hospital were between February 2017 and March 2021. The patients' clinical features, relapse-free survival (RFS), and overall survival (OS) were analyzed.ResultsEleven cases fulfilled the AML criteria per the 2016 World Health Organization classification. Of the 11 patients, five were females, and six were males, with a median age of 45 years (range, 23-65 years). Ten patients were in the first complete remission (CR1), and one patient was in the second complete remission (CR2). All patients received AZA combined with DNZ and THD maintenance therapy after IC. The median number of AZA cycles received was 7 (6-12). Until June 2022, the median follow-up period was 37 (14-63) months; one patient had a relapse, and three died. RFS at 1 year and 3 years was 100% and 71.1%, respectively, and OS at 3 years was 100%.ConclusionAZA combined with DNZ and THD maintenance therapy is effective for patients with AML who are ineligible for allogeneic hematopoietic stem cell transplantation. Further studies with large sample sizes and randomized are needed to verify these findings.

Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China.

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0-3.4; OS, 54.9 months vs. NR, p<0.001, HR=3.2, 95% CI 1.5-7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival.

Clinical Characteristics and Prognosis of Secondary Acute Lymphoblastic Leukemia in Patients with Multiple Myeloma during Long-Term Thalidomide Maintenance.

Background: Secondary primary malignancies (SPM) have attracted increasing attention with the application of autologous hematopoietic stem cell transplantation (ASCT) and novel agents in multiple myeloma (MM). Secondary acute lymphoblastic leukemia (sALL) has rarely been reported, and the clinical characteristics and prognosis of sALL have not been described in detail. Methods: We retrospectively enrolled 179 consecutive newly diagnosed multiple myeloma (NDMM) patients undergoing bortezomib-based induction regimens followed by upfront ASCT and maintenance therapy from December 2006 to April 2018 in our center. Results: The median follow-up interval was 69.1 months, and 12 patients (6.7%) developed sALL during maintenance therapy. The median time from the diagnosis of MM to the occurrence of sALL was 51.1 (31.7-91.5) months. All sALL patients received thalidomide as maintenance therapy before the onset of sALL, and the median duration of thalidomide maintenance was 39.5 (24-74) months. The cumulative incidence of sALL was 6.6% and 11.2% at 5 and 10 years after the diagnosis of MM, respectively. All sALL patients presented with a B-cell immunophenotype accompanied by myeloid antigen expression according to flow cytometry analysis, and the BCR/ABL fusion gene was all negative. Only one patient had evidence of active MM, and the other patients were in stable status at the time of the diagnosis of sALL. The prognosis of most sALL patients was very poor, and the median overall survival time was 11.9 (1.1-51.2) months since the diagnosis of sALL. Conclusions: sALL should be considered for MM patients who developed unexplained persistent cytopenia while on long-term thalidomide maintenance treatment, particularly if it has been more than 3 years. With the increasing availability of new drugs for MM, thalidomide may be recommended for no more than 3 years. Sequential allogeneic hematopoietic stem cell transplantation was considered as soon as possible after achieving remission in order to achieve a longer survival.

Is VTD the Best First Line Therapy for Multiple Myeloma in an Environment with Limited Resources? an Analysis of Outcomes and Costs

INTRODUCTIONAutologous hematopoietic stem cell transplantation (auto-HSCT) prolongs the progression free survival of patients with multiple myeloma (MM). Currently there are multiple treatment regimens for MM, however, in an environment of limited resources, it is essential to implement an adapted treatment plan to reduce costs and increase accessibility. We aim to compare the cost of auto HSCT and thalidomide maintenance with other treatment strategies. MATERIAL AND METHODS This was a retrospective observational study performed in a University Hospital in Mexico. Patients with MM treated between 2017 and 2019 with 4 cycles of VTD (Bortezomib, thalidomide, dexamethasone) followed by auto-HSCT and maintenance with thalidomide were included. The cost of auto- HSCT was analyzed as well as the VTD, KRD, VRD and Dara-VTD schemes. Progression-free and overall survival (PFS and OS) of the auto- HSCT group were compared with data published in the literature for the different treatment schedules. RESULTS 44 consecutive patients with MM were included, with a median age of 57 years (range, 39-70). Thirty patients were women (68.20%) and fourteen patients were men (31.80%). One half of all patients (50%) had Durie Salmon stage I disease, (22.72%) had stage II and (27.27%) had stage II, at the time of auto- HSCT: was complete response in 10 patients (22.70%) very good partial response in n=26 (59.10%) and a partial response in n=8 (18.20%). All patients proceeded to auto-transplant. Conditioning was melphalan 200 mg/m2 in n=35 (79.5%). OS at day +100 was 97.7% (43 patients) and progression-free survival was 76.7% at 60 months. Regarding the status of the MM at day +100 was in these 43 patients, with a median follow-up of 30 months (range: 3-60), currently 33 patients (76.7%) patients are in complete response, 1 (2.3%) in partial response), 4 (9.3%) in relapse and 5 (11.6%) died from non relapse mortality (acute myocardial infarction, stroke, heart failure) The median time to relapse was 33.5 (3-60) months. The cost of auto- HSCT was $5,800 USD. Table 1 compares the costs of 4 induction cycles with usual scheme CONCLUSIONS The response with VTD followed by auto-HSCT and maintenance with thalidomide are comparable in overall and progression-free survival with more expensive schemes such as KRd, VRd and Dara-VTd with lower cost. Key words: stem cell trasplantation, multiple myeloma, cost, limited resource Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma.

Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patient-specific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

MCT1 is a predictive marker for lenalidomide maintenance therapy in multiple myeloma

AbstractBiomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.

Comparison of MRD Detection in Autografts in Multiple Myeloma between Novel High-Sensitivity Euroflow-NGF and NGS

Background: Autologous stem cell transplantation (ASCT) remains the gold-standard treatment for multiple myeloma (MM). To date, we have reported the prognostic value of minimal residual disease (MRD) detection in autografts in an ASCT setting using EuroFlow next-generation flow (NGF) and next-generation sequencing (NGS) (Takamatsu et al., ASH 2018, 2020). The main problem with NGF is its lower sensitivity (2 × 10 -6) compared with that of NGS (<1 × 10 -6).Methods: We reanalyzed 11 autografts in which the MRD were negative on NGF but positive (n = 7) or negative (n = 4) on NGS (Takamatsu et al., ASH 2018, abstract #258) using 5-20 mL of autografts with NGF to increase the sensitivity of MRD detection. Additionally, we enrolled 9 patients with newly diagnosed MM, from whom 5-20 mL of apheresed autografts were cryopreserved. We included 20 patients with newly diagnosed MM. The median age at ASCT was 60 (range, 45-67) years, and the patients included 12 men and 8 women at International Staging System I (n = 3), II (n = 13), and III (n = 4), 6 of whom harbored high-risk chromosomal abnormalities, including t(4;14) (n = 3), t(14;16) (n = 1), del17p (n = 1), and t(4;14) and del 17p (n = 1). All patients received bortezomib-based chemotherapy for induction followed by melphalan at a dose of 200 mg/m 2 for conditioning before ASCT. Three patients received consolidation therapy with carfilzomib-lenalidomide-dexamethasone (n = 2) or bortezomib-lenalidomide-dexamethasone (n = 1), and 18 patients received lenalidomide (n = 16), thalidomide (n = 1), or thalidomide and lenalidomide (n = 1) maintenance. Frozen autografts (n = 20) were thawed for MRD assessment using NGF and NGS. The NGF method was based on a previous report (Flores-Montero et al., Leukemia 2017). NGS-based MRD assessment was performed using Adaptive's standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020). The NGF method was modified to increase the sensitivity of MRD detection by capturing up to 6 × 10 7 cells.Results: Frozen autografts were used in this study; therefore, we performed a sensitivity test using a dilution of frozen/thawed primary MM cells in an autograft with NGF. The sensitivity test revealed a strong correlation between 5 × 10 -7 and 1 × 10 -4 MRD levels (Figure 1A; r = 0.999, P <0.0001). Next, MRD in autografts (n = 20) was evaluated using NGF and NGS. The sensitivity of NGS was 1.7 × 10 -7-8.7 × 10 -5 (median, 7 × 10 -7) using 2-4 mL of autografts; the sensitivity of NGF was 1.6 × 10 -7-3.7 × 10 -6 (median, 3 × 10 -7) using up to 20 mL of autografts based on the detection of ≥10 abnormal cells. MRD levels in autografts using NGF and NGS were correlated (Figure 1B; r = 0.979, P <0.0001). There was no discrepancy in the MRD negativity between both methods except for two cases (MRD-negative on NGF/positive on NGS [n = 2]). All high-risk chromosomal abnormality cases (n = 6) revealed MRD levels <10 -5 butonly three patients achieved MRD levels <10 -6. The best responses included 16 cases of a stringent complete response and 4 of a very good partial response. Three patients with positive MRD in the autograft exhibited progression. With a median follow-up period of 41 months after ASCT, the 3-year progression-free survival (PFS) was 90%, and the 3-year overall survival was 95%. There was no significant difference in the PFS based on the MRD levels between NGF and NGS. MRD negative cases tended to show better PFS than MRD positive ones (Figure 1C; P = 0.077 by NGF; P = 0.111 by NGS).Conclusion: The modified EuroFlow-NGF method may be used to assess MRD in frozen/thawed autografts, and its sensitivity may increase up to 5 × 10 -7, which is comparable to that of NGS. [Display omitted] DisclosuresYamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Nakao: Novartis Pharma: Honoraria; Symbio: Consultancy; Kyowa Kirin: Honoraria; Alexion Pharma: Research Funding. Takamatsu: Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

P-175: Outcomes of autologous-allogeneic vs autologous tandem approach followed by thalidomide maintenance for transplant-eligible patients with newly diagnosed multiple myeloma: a prospective phase II-study

P-175: Outcomes of autologous-allogeneic vs autologous tandem approach followed by thalidomide maintenance for transplant-eligible patients with newly diagnosed multiple myeloma: a prospective phase II-study

Limited benefits of thalidomide and dexamethasone maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma patients: a prospective phase II multi-center study in Korea

Although the clinical outcome of newly diagnosed multiple myeloma has improved with maintenance therapy, maintenance with novel agents is not always available depending on medical expenses or drug accessibility. We intended to investigate the efficacy and toxicity of thalidomide/dexamethasone maintenance in Korean patients. In this multicenter phase 2 study, patients with newly diagnosed myeloma who underwent induction chemotherapy followed by autologous stem cell transplantation (ASCT) were enrolled to receive maintenance treatment of 100mg thalidomide daily for 28 days and 40mg dexamethasone daily for 4 days each cycle. Maintenance was given up to 12 cycles. The primary endpoint was a 1-year event free survival (EFS) rate. It was assumed that EFS at 1-year would be 91% with thalidomide and 1-year EFS below 82% would be of no effect. A total of 43 patients were consecutively enrolled (median age, 58 years [range, 34 – 65]; male, n = 31). With a median follow-up duration of 17.3 months (range, 1.1 – 32.2), EFS at 1 year was 65.1% (95% confidence interval [CI], 48.9 – 77.3). PFS and OS at 1 year was 85.6% (95% CI, 70.7 – 93.3) and 90.4 (95% CI, 76.3 – 96.3), respectively. In terms of side effects, 39 patients (90.7%) experienced adverse events (AEs) of any grade, and 14 patients (32.6%) experienced grade 3 or 4 adverse events. 15 patients (34.9%) failed to complete 12 cycles of maintenance, and the most common reason for premature termination was AEs (n = 6). In Korean patients the benefits of thalidomide maintenance does not seem to outweigh the toxicity of thalidomide, especially in high-risk MM. Considering the long clinical course of MM, preservation of quality of life and finances might be more beneficial for subsequent MM treatment.

Frailty Predicts Survival and Toxicity in Newly Diagnosed Multiple Myeloma Patients Ineligible for Autologous Stem Cell Transplantation; Report of the HOVON-87/Nmsg-18 Study Group

IntroductionWe previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS [1]. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome.MethodsFrailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared test was used to evaluate the association of frailty with discontinuation rate and toxicity.ResultsAll 637 eligible patients from the HOVON-87/NMSG-18 trial were included in the analysis. Median age was 73 years; 66% of patients were ≤ 75 years, 24% were 76-80 years and 10% were > 80 years. A CCI of 0, 1, 2 and ≥3 was found in 61, 20, 7 and 4% of patients respectively (8% unknown). The most common comorbidities were diabetes mellitus without end organ complications (12%) and myocardial infarction (6%). A WHO performance of 0, 1 and ≥ 2 was observed in 35, 47 and 16% respectively (3% unknown).Univariate analyses showed that older age (>80 years: HR 1.59 [95% CI 1.12-2.25]), a higher CCI (CCI ≥2: HR 1.41 [95% CI 1.01-1.95]); and a poor WHO performance (WHO ≥2: HR 2.05 [1.49-2.82]) were associated with an inferior OS. HR's were 1.07 [95% CI 0.82-1.40] and 1.27 [95% CI 0.98-1.65] for age 76-80 years and WHO performance respectively. For age and the CCI the IMWG frailty score classification was used. For the WHO, scores were assigned based on the HR: WHO 0; 0 points, WHO 1; 1 point and WHO ≥2; 2 points. Fit patients were defined as a proxy frailty score of 0, unfit as a score of 1 and frail as a score of ≥2, comparable to the IMWG frailty score.Using this modified IMWG frailty score, 135 patients were fit (21%), 199 were unfit (31%) and 259 were frail (41%) (7% unknown). The median OS was found to be significantly different in fit versus unfit versus frail patients; 58, 55 and 46 months respectively (p=0.004). In contrast no significant difference in median PFS was found; 26, 20 and 21 months respectively (p=0.30).The inferior OS for the frail might be partly explained by higher discontinuation rate of induction therapy; 50%, versus 43% in unfit, and 34% in fit patients (p=0.011), being mainly due to excessive toxicity (25, 23 and 16% respectively). The cumulative incidence of treatment discontinuation on protocol (induction plus maintenance), corrected for death and progressive disease which were considered as competing risks, is depicted in figure 1B. Discontinuation rate at 2 years for fit, unfit, and frail patients were 48%, 48%, and 59% respectively (p=0.06). There were significantly more grade ≥3 adverse events on protocol in frail and unfit patients (both 86%) as compared to fit patients (77%, p=0.039). Especially more grade ≥3 infections were found in frail (28% versus 18% in unfit and 13% in fit). In contrast, frailty was not associated with hematological toxicity.ConclusionWe here present a modified frailty score, using the WHO performance instead of the (i)ADL, combined with age and the CCI, that enables the identification of frail MM patients with an inferior OS, a higher discontinuation rate and a higher rate of grade ≥ 3 toxicity. This non-laborious modified frailty score can be easily implemented in clinical trials and allows to compare the outcome of frail patients in nte-NDMM trials, which will hopefully result in frailty-adapted therapy in clinical daily practice.Reference:1. Zweegman S, Holt vd B, Mellqvist U, et al. Blood 2016;127(9):1109-16 [Display omitted] DisclosuresMellqvist:Celgene: Honoraria; janssen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Sandoz: Other: participation advisory board; Amgen: Honoraria, Other: participation advisory board. Abildgaard:Takeda: Research Funding. Plesner:Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Van De Donk:Janssen, Celgene, Bristol-Myers Squibb, Amgen: Research Funding. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy. Waage:Celgene, Takeda: Honoraria. Zweegman:Celgene: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Takeda: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation.

Thalidomide and Dexamethasone Maintenance after Autologous Stem Cell Transplantation in Newly Diagnosed Korean Multiple Myeloma Patients: A Prospective Multi-Center Study in Asia

BackgroundMaintenance is a part of standard practice in multiple myeloma patients receiving induction followed by autologous stem cell transplantation (ASCT). Various regimens including thalidomide, lenalidomide and proteasome inhibitor are used as maintenance treatment. However, few prospective trials have been performed evaluating maintenance treatment in Asian myeloma patients. In this prospective multi-center trial, we evaluated the efficacy and toxicity of thalidomide-based maintenance therapy in Korean myeloma patients.MethodsWe conducted an open-label, prospective, multicenter phase II study. Patients with newly diagnosed multiple myeloma who underwent induction followed by ASCT were enrolled. Patients should not have refractoriness to previous thalidomide if the drug is included in induction regimen, and should have achieved at least partial response (PR) after ASCT. Patients received maintenance treatment of 100mg thalidomide daily for 28 days and 40mg dexamethasone for 4 days. The maintenance therapy was continued for one year unless there were disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was 1-year event-free-survival (EFS). Progression free survival (PFS), overall survival (OS), drug tolerability and safety were also evaluated.ResultsA total of 43 patients were enrolled. One-year EFS rate was 60.47% (95% confidence interval (CI), 44.34-73.26%). Progression-free survival (PFS) was 86.05% at 1-year and 72.09% at 2-year. Overall survival (OS) at 1-year and 2-year was 90.70% and 88.37%, respectively. Among 21 patients who did not acquire complete remission (CR) after ASCT, 4 patients reached CR after maintenance therapy. The maintenance treatment was discontinued in 15 patients (34.9%). The most common cause was adverse events (6 patients) followed by disease progression (4 patients). Rest of the patients terminated the treatment by patient's withdrawal (3 patients) and investigator's decision (2 patients). In each cycle, up to 23.3% of patients experienced dose reduction or delayed medication. Two leading causes of the schedule change were the adverse event and physician's decision. Grade 3 or 4 hematologic adverse events (AE) was upper respiratory infection (20 patients, 46.5%) followed by peripheral neuropathy (19 patients, 44.2%). Among the patients with neuropathy, 2 patients showed more than grade 3 symptom. Two patients showed serious adverse events (pneumonia and fulminant hepatitis). Thromboprophylaxis was performed in 37 patients using aspirin and one patient developed deep vein thrombosis during maintenance.ConclusionsThalidomide and dexamethasone maintenance for transplant eligible, newly diagnosed Korean multiple myeloma patients showed 1-year EFS and OS rate of 60.47% and 90.70% which is similar to the reports from western countries. Thalidomide and dexamethasone were tolerable as maintenance in Asian patients, although high hematologic toxicity draws concern. We concluded that thalidomide-based maintenance therapy is one of suitable option in Asian transplant eligible, newly diagnosed multiple myeloma patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Higher Expression of Nuclear Cereblon in Bone Marrow Biopsies of Patients with Multiple Myeloma Included in the HOVON-87/Nmsg-18 Trial May be Associated with Longer PFS and OS

IntroductionResponse to treatment in patients with multiple myeloma (MM) is variable. With increasing possibilities of treatment regimens, predictive factors for response are important. Immune modulating agents (IMiDs) require Cereblon (CRBN) for activity. Therefore, the aim of this study is to identify the genes of the CRBN pathway which predict the response to therapy with IMiDs. In this abstract the first results are presented.MethodsParaffin embedded bone marrow biopsies from patients included in HOVON-87/NMSG-18 trial obtained at inclusion were used for this study. In this trial elderly patients with MM were randomized between treatment with Melphalan-Prednisone (MP)-Thalidomide followed by thalidomide maintenance versus MP-Lenalidomide followed by lenalidomide maintenance (Zweegman et al. Blood 2016;127:1109-1116).Bone marrow biopsies were stained with a fully automated dual color, bright-field immunohistochemical (IHC) assay for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets IRF4 and c-MYC. CD138 was used to identify MM plasma cells in the bone marrow samples. For CRBN, both nuclear and cytoplasmic staining was evaluated. The distribution and intensity of the immunostaining was assessed using the H-score. The H-scores were calculated using the following formula: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] and range from 0-300 (0-600 for combined cytoplasmic-nuclear CRBN H-score). For the Cox regression analysis H-scores were corrected by dividing these by a factor 100: hazard rates were considered per 100 points increase of the H-score. 113 bone marrow samples were selected so far. Protein levels were compared between patients with complete response (CR) or very good partial response (VGPR) vs partial response (PR) and no change (NC). Statistical analysis was done using univariate Cox regression analysis for progression free survival (PFS) and overall survival (OS), and Mann-Whitney test for comparing response groups. Kaplan-Meier survival curves were generated to illustrate survival.ResultsSo far, bone marrow samples obtained at diagnosis from 34 patients were evaluated. Fourteen patients were treated in the Thalidomide arm vs 20 patients in the Lenalidomide arm. Median age was 72 years [range 60-84]. ISS stages I/II/III were 38%/47%/15% respectively. At the time of analysis, median follow up of the 16 patients still alive was 53 months [range 18-85 months]. Best response on protocol treatment was sCR in 12%, CR in 9%, VGPR in 35%, PR in 29% and NC in 15%.Comparing protein expression across the response groups showed a trend of higher levels of combined cytoplasmic and nuclear CRBN in patients who responded better (sCR/CR/VGPR; median H-score: 360 (90-544)) compared to patients with a worse response (PR/NC; median H-score: 273 (185-471)) Mann-Whitney p-value=0.09). In addition, a trend for increased Aiolos expression to be associated with poorer response was found (Mann-Whitney p=0.08; median H-score sCR/CR/VGPR: 251 (162-260) vs PR/NC: 254 (221-267)).Higher H-score of nuclear staining of CRBN was associated with a longer PFS and OS, with a hazard ratio (HR) of 0.47 for PFS (95% confidence interval (95% CI)=0.24-0.92, p=0.027) and a HR of 0.42 for OS (95% CI=0.19-0.91; p=0.028). Using the median nuclear CRBN expression as an arbitrary cut-off, a significant separation of the lines representing high and low expression could be found for PFS, but not for OS (Figure 1). None of the other markers were associated with survival in the current limited set.Six patients had high-risk FISH (deletion of 17p and/or translocation t(4;14) and/or translocation t(14;16)) out of 24 patients with known FISH status. These patients did not demonstrate a higher or lower expression of any of the markers evaluated, and showed no association with PFS (log rank p=0.2) but a clear association with shorter OS (log rank p=0.008). As expected, no association between arm and survival was seen.ConclusionsIn this study we demonstrate that higher expression of nuclear CRBN in myeloma cells in bone marrow of patients with MM was associated with a superior PFS and OS. These are early data from an ongoing analysis; a total of 113 bone marrow samples were selected up to now. [Display omitted] DisclosuresCouto:Celgene: Employment, Equity Ownership. Ren:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Qian:Celgene: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Broyl:Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Zweegman:Amgen: Other: advisory board participation; Takeda: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Celgene: Other: advisory board participation, Research Funding. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.

The Leeds Risk Profile Predicts Outcome for Older Myeloma Patients: A Prognostic Score Using Frailty Biomarkers Derived and Tested Using 2371 Clinical Trial Patients

Introduction:Multiple myeloma (MM) is molecularly heterogeneous but so too are the patients it affects. This heterogeneity becomes more significant in older, less fit patients in whom factors affecting their ability to withstand treatment may be more important than disease biology. Treatment tolerability does not deteriorate linearly with age and is better defined as ‘frailty’. Patient-reported activities of daily living and comorbidities have been combined with age to derive the IMWG Frailty Score (Palumbo A et al, Blood 2015), which can predict outcome. This requires completion of 3 patient questionnaires and may be open to bias.Several biochemical markers of frailty have been associated with adverse outcomes including inflammatory markers such as CRP, renal dysfunction and the ratio of lymphocytes to total white cells (L:W). Using biochemical surrogates to measure patient frailty is objective and avoids the need for potentially burdensome questionnaires. Here we describe a novel prognostic score (Leeds Risk Profile; LRP) that combines readily available laboratory measures of patient frailty with age and WHO performance status (PS) to predict outcomes in transplant non-eligible (TNE) MM patients.Methods:1852 TNE patients recruited to the NCRI Myeloma XI (MyXI) trial were used as a training set and 520 TNE patients recruited to the MRC Myeloma IX (MyIX) trial used as a validation set. MyXI compared IMiD-containing triplet combinations: cyclophosphamide and dexamethasone with thalidomide (CTD) or lenalidomide (CRD). Patients with a suboptimal response (<VGPR) were eligible for further induction with a PI-based triplet (cyclophosphamide, bortezomib and dexamethasone). There was a maintenance randomisation between lenalidomide and observation. MyIX compared induction with melphalan and prednisolone to CTD and maintenance thalidomide to observation.Baseline variables considered included PS, LDH, CRP, international staging score (ISS), age and L:W. The primary objective was overall survival (OS). Missing data in the training set (MyXI) for the variables was imputed via multiple imputation by chained equations. The model was built using a Cox model with LASSO penalty within each imputed dataset. The final model was derived by combining the coefficients and standard errors by Rubin's rules. The model was internally validated by bootstrap sampling and externally validated in the test set using the prognostic separation D-statistic.Results:Univariate Cox-regression analysis demonstrated a significant effect of PS, CRP, ISS, Age and L:W (all p<0.001) but not LDH (p=0.333) on OS within the training set.The final multivariable model (LRP) included PS, Age, ISS and CRP. The discrimination and calibration of the model were good, with calibration better closer to trial entry. The model was successfully internally validated by bootstrap re-sampling according to pre-defined criteria. The combined prognostic index was divided into tertiles to define 3 groups: Fit, Intermediate-fitness, Frail. All variables increased in severity across the three groups. The groups predicted outcomes as shown in Figure 1a (median OS: Fit 60 months [95%CI 55-NR], Intermediate-fitness 44 [39-48] and Frail 25 [22-30] (Log-rank p<0.0001)).External validation was successfully carried out using patients from MyIX. The test data was split into three separate risk groups using the same cut-offs derived and implemented within the training data. Significant differences in OS were again predicted (Figure 1b) (median OS: Fit 43 months [35-NR], Intermediate-fitness 34 [27-38] and Frail 20 [14-25] (Log-rank p<0.0001)).In exploratory analyses the risk groups derived for overall survival were applied to progression-free survival, early mortality and treatment delivery modifications and predicted outcome as expected. Predictive ability was maintained in those patients who were exposed to both IMiD and PI therapy.Conclusion:We have defined a novel score predictive of outcome in TNE MM patients (LRP). This score uses only factors already collected at baseline for MM patients using objective laboratory bloods tests combined with age and a simple WHO PS assessment. As such it would be easy and quick to use in the clinic and apply within clinical trials. The LRP will be prospectively validated, including a comparison to the IMWG Frailty Score, within the UK-MRA Myeloma XIV trial (FITNESS). [Display omitted] DisclosuresCook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetcs: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pawlyn:Takeda: Honoraria, Other: Travel support; Janssen: Other: Travel support; Celgene: Honoraria, Other: Travel support. Gregory:Janssen: Honoraria; Celgene: Consultancy, Honoraria. Davies:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Jackson:Chugai: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; J&J: Honoraria.

Coexistence of multiple myeloma and chronic myeloleukosis in one patient

Intoduction. Multiple myeloma (MM) and chronic myelogenous leukaemia (CML) are two haematological malignancies developing through tumour transformation of lymphoid and myeloid progenitor cells, respectively, not sharing a common ancestry. Coexistence of the two diseases is extremely rare.Aim. Clinical description of a patient diagnosed with CML in a few months after start of MM therapy.Main findings. We report a clinical case of MM and CML in a 62 years-old female patient. MM was diagnosed newly and followed by 5 VD chemotherapy cycles. Treatment discontinued due to severe polyneuropathy. The patient was transferred to thalidomide maintenance therapy. CML was diagnosed 12 months after initiation of thalidomide therapy: BCR-ABL (p190), BCR-ABL (p210). Since imatinib produced short-term effect, dasatinib therapy was started. Following 16 months after the onset of dasatinib therapy, MM relapse and CML progression were diagnosed.

The Real-Word Treatment Outcome of Symptomatic Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia in Chinese Patients

Objective:lymphoplasmacytic lymphoma/Waldenström Macroglobulinemia(LPL/WM) is a rare and incurable lymphoid malignancy. The treatment outcomes in Chinese patients had never been studies. In this study, we systematically reviewed the treatment outcome in a consecutive cohort from a single center in the past 20 years to explore the efficacy of different treatment regimens in real word in China. Methods:The clinical data of 269 newly diagnosis patients with LPL/WM admitted to our hospital in the past 20 years (2000-2020) were retrospectively analyzed. Therapy efficacy and survival were compared between different groups. Results:The median age of 269 patients was 62 years (range 32-87) and the male to female ratio was 2.7(196/73). Nearly half patients were high risk group of ISSWM (48%). Of 269 patients,192 patients received combined chemotherapy.The most common symptoms for initial chemotherapy wereanemia(75.7%), thrombocytopenia (36.9%), followed by IgM-related (33.7%) and constitutional symptoms(21.2%).Of the 192 patients, 109 patients received the novel agents for first-line therapy,83 patients received traditional chemotherapy.180 of192 patients would evaluated. The overall response rate(ORR) and major response rate(MRR) in the novel agent group were significantly higher than the traditional group(ORR:81.7% vs 61.8%,P=0.003; MRR:68.3% vs 48.7%,P=0.008) .In the traditional group, 41 patients received oral alkylating agent-based therapy and 42 patients received conventional intravenous cytotoxicity agents-basedtherapy. The ORR and MRR in the intravenous group were higher than oral group(ORR:75% vs 47.2%,P=0.013;MRR:62.5% vs33.3%,P=0.011).With a median observation time of 36 months, the median overall survival (OS) and progression-free survival (PFS) were 60 months and not reached in the novel agent groups which were also significantly higher than traditional groups(PFS: 60 vs 42,P=0.009,OS:NR vs 89,P=0.000). Intriguingly, In the traditional group, the PFS and OS were no significantly differentbetween conventional intravenous and oralgroup(PFS oral vs intravenous: 42 vs 40,P=0.849,OS oral vs intravenous:62vs 114,P=0.260). In novel agent group, 36 patients had received RCHOP regiment,20 patients received DRC,21 patients received BCD,8 patients received BRD,16 patients received TCD and 8 patients received RFC regiment. Patients who received RCHOP,DRC,BCD,BDR or RFC had similar ORR (82%-87.5%)which were slightly higher than TCD (58.3%)regiment. The median PFS and OS in different subgroups were also similar. But BDR regiment showed a trend of better OS(5 year 100%) and TCD showed a worse OS(5 year 46.4%). For all the patients, 35 patients received maintenance therapy, including 16 patients with rituximab maintenance and 19 patients with thalidomide maintenance. Maintenance was associated with better PFS(60 vs 47,p=0.083) and OS(5 year OS were 96.3% and 64.8%,p=0.006) and patients who received rituximab maintenance had better survival than thalidomide maintenance. In novel agent subgroup, maintenance with rituximab also had a trend of better PFS and OS. But maintenance thalidomide had no significantly different with no maintenance group. Conclusion:Combined with novel agent can tremendously improve the short-term and long-term therapeutic effects in Chinese LPL/WM patients. Different novel agent regiment might had similar efficacy, BRD regiment had a trend of better survival. Maintenance with rituximab would further improve the effect even in novel agent age. Disclosures No relevant conflicts of interest to declare.

Thalidomide Plus Prednisone and Methotrexate for Symptomatic Large Granular Lymphocyte Leukemia: A Prospective, Single-Center, Pilot Study

Background: Large granular lymphocyte leukemia (LGLL) is one type of chronic lymphocytic proliferative disorders, which commonly manifests as infiltration of large granular lymphocytes in both peripheral blood and bone marrow. LGLL now includes two entities with similar clinical course, treatment strategy and outcomes: T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of NK cells. The standard therapy for LGLL is still elusive. Here, we presented the efficacy and safety of combinatorial oral immunoregulatory regimen thalidomide, prednisone, and methotrexate (TPM regimen) in a prospective phase 2 clinical trial. Methods: We designed this phase 2 investigator-initiated clinical trial (NCT04453345) to evaluate the clinical response and safety of the combination of thalidomide, prednisone, and methotrexate in symptomatic treatment naïve LGLL patients. The TPM regimen includes thalidomide 50-100mg per night, prednisone 0.5-1.0mg/kg qod and methotrexate 10mg/m2 per week. This regimen will be administrated for up to 12 months until disease progression or intolerable. Then, thalidomide maintenance will continue for another year or until intolerance. Meanwhile, we set Cyclosporin A (CsA) alone or plus steroids as control. Treatment dosage for CsA was 3-5mg/Kg/day with or without steroids (prednisone) 0.5-1 mg/Kg/day. The primary endpoint of this study was the complete response rate. Results: From Aug 2013, to Jan 2020, twenty-eight patients were enrolled in this study. The median follow-up time was 26 months (range: 7-96). Twenty-five patients (89%) achieved hematologic and symptomatic response. Among them, 21 patients (75%) achieved complete response (CR) and four patients achieved partial response. The median time to best clinical response was 6 months (2-18). The 3-years progression-free-survival (PFS) rate was 90%, and 3-years overall survival (OS) rate was 92%. The median PFS time was not reached in TPM group. The curative effect was better for TPM treatment group, both for overall response (OR) (TPM 89% (25/28) vs CsA 49% (49/99), P=0.000) and CR (TPM 75% (21/28) vs CsA 20% (20/99), P=0.000). Adverse events were uncommon, two patients had grade 1-2 nausea and one had grade 3 nausea. Two patients had grade 1-2 constipation and one patient experienced grade 1-2 peripheral neuritis. Conclusion: The efficacy of this TPM regimen is higher than the history reports with limited adverse events. The multiple-center clinical trial has been initiated to validate this conclusion. Disclosures No relevant conflicts of interest to declare.

Efficacy and safety of frontline regimens for older transplant-ineligible patients with multiple myeloma: A systematic review and meta-analysis

IntroductionSeveral treatment options are available for the management of older adults with newly diagnosed patients with Multiple Myeloma (MM) who are ineligible for hematopoietic cell transplantation (tiMM). We aimed to identify treatment options that provide the best balance in terms of efficacy and safety. MethodsWe searched bibliographic databases and meeting libraries for search terms reflecting newly diagnosed and older and/or transplant-ineligible patients from inception to October 21, 2018. Phase II/III randomized trials comparing at least two first line treatment regimens for newly diagnosed tiMM were included. We extracted data on efficacy (progression free survival, PFS, overall survival and overall response rate) and safety (grade ¾ toxicities) and conducted network meta-analysis using Bayesian methods and random effects models. Relative ranking of treatment regimens was assessed using Surface under the cumulative ranking (SUCRA) probabilities. ResultsWe identified 27 trials involving 12,194 patients. For PFS, the four most effective regimens were: Daratumumab, Bortezomib, Melphalan and Prednisone (SUCRA 0.960) followed by Daratumumab, lenalidomide and dexamethasone (Dara_RD, SUCRA 0.847), Bortezomib, melphalan, prednisone, thalidomide maintenance with bortezomib-thalidomide (SUCRA 0.834) and Bortezomib, Lenalidomide and Dexamethasone (SUCRA 0.739). Among these four most efficacious regimens, toxicity profile was most favorable for Dara_RD (median additional AEs per patient vs dexamethasone = 0.74; 95% CrI 0.51–1.17; SUCRA 0.430). ConclusionAmong first line tiMM regimens, increasing efficacy is associated with increased toxicity. We provide relative ranking of these regimens for both efficacy and safety. Future studies should incorporate geriatric assessments and frailty biomarkers to refine treatment decision-making for each individual patient.

R-MACLO-IVAM Is an Effective Regimen to Induce Long Term Remission in Untreated Mantle Cell Lymphoma

R-MACLO-IVAM Is an Effective Regimen to Induce Long Term Remission in Untreated Mantle Cell Lymphoma