REAL-WORLD ITALIAN EXPERIENCE OF POMALIDOMIDE IN RELAPSED-REFRACTORY MYELOMA: RETROSPECTIVE MULTICENTER STUDY BY THE RETE EMATOLOGICA PUGLIESE AND BASILICATA

Background: The POM+LoDEX combination was approved for patients with RRMM who have received at least two prior therapies including lenalidomide and bortezomib. Aims: We report here retrospective analysis of 94 patients with RRMM treated with POM+LoDEX as salvage therapy at 12 hematological centers in the Puglia and Basilicata Network to describe the outcomes and toxicities in a daily practice setting outside clinical trials. Methods: From January 2016 to September 2018, 94 patients (60 F and 34 M) were treated in our haematogical Institutions. Sixty-three patients of them (67%) had relapsed MM and 31 patients (33%) MM refractory to two or more previous treatment lines. The median age was 73 years (range 42–86). Twenty-four patients (23,3%) had EMD. Patients received a median 3 previous lines of therapy. The last treatment received was bortezomib-based regimens in 29% of patients, lenalidomide-based regimens in 50% of patients, and bendamustine containing regimen in 18% of patients. Results: The median number of cycles administered was 5 (range 1–27). The ORR was 51%. Higher ORR was recorded in the patient group with relapsed MM compared to those with refractory disease (p < 0.05). There were no statistically significant differences in terms of response between patients who had received two or more previous lines of therapy (p NS) and between patients aged over or under 70 years (p 0.25). After median follow-up of 9.5 months, median TTP and median OS in the ITT population were respectively, 10 months (range 7–17) and 16 months (range 11–24). The median TTP was significantly longer in patients who achieved the haematological response (p < 0.001) and in patients aged >70 years (p 0.03). The median OS was significantly longer for fit patients (p 0.03). The “disease status’’, the “prior exposure to lenalidomide-based strategies’’, the “number of previous lines of therapy’’ did not influence the TTP and the OS. Multivariate analysis of median TTP identified the “high LDH levels’’ as negative variable (p < 0.001) and the “age >70 years’’ as positive prognostic factor (p < 0.001). Multivariate analysis of median OS identified the “frailty score’’ and confirmed “high LDH levels’’ as statistically significant variables (p < 0.001). Median TTNT was 30 months (range 18–30). Neutropenia was the most common hematologic adverse event and occurred in 32% of patients. The most frequent grade 3–4 non-haematologic toxicities were fatigue (6%) and infections (4%). Summary/Conclusion: POM+LoDEX resulted in a longer OS and TTP compared to data reported from clinical trials. This advantage was observed mainly in elderly patients and in those with haematologic response and the outcome benefit remained consistent regardless of number of prior and last therapy received. The good toxicity profile and the all-oral administration of POM+LoDEX make this combination a recommended therapeutic opportunity also in older patients and should be recommended mainly in patients living far from the hospital

DARA-VD VERSUS DARA-RD AS SALVAGE THERAPY FOR PATIENTS WITH MYELOMA. INITIAL FOLLOW-UP OF AN ITALIAN MULTICENTER RETROSPECTIVE CLINICAL EXPERIENCE BY RETE EMATOLOGICA PUGLIESE

Background: Daratumumab is a CD38 monoclonal antibody approved in monotherapy or in combination with bortezomib and dexamethasone (Dara-Vd) or lenalidomide and dexamethasone (Dara-Rd) for the treatment of relapsed or refractory myeloma (rrMM). Aims: We report here an initial multicenter retrospective analysis of 126 consecutive patients with rrMM treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centers in Puglia, conducted to evaluate the outcomes, as well as the toxicity profile of these combination in a daily practice setting outside clinical trials. Methods: Of 126 patients, 122 were evaluable for response and toxicity. Forty-two patients (33%) (15 F and 27 M) received Dara-Vd and 84 patients (67%) (41 F and 43 M) with Dara-Rd; 74% of them had relapsed MM and 26% MM refractory to one or more previous treatment lines. The median age at diagnosis was 62 years (range 36-77) in the Vd-group, 66 years (range 32-83) in the Rd-group. The median time to initiation of daratumumab from diagnosis was 5 years (range 3-9) in the Vd-group, 3 years (range 1-10) in the Rd-group. Patients had received a median 2 prior lines of therapy (range 1-6) in the Vd-group, a median 1 prior course of therapy (range 1-4) in the Rd-group. Twenty patients (48%) in the Vd-group and 30 patients (37%) in the Rd-group had previously undergone single or tandem ASCT. In the Vd-group all patients were previously exposed to at least one proteasome inhibitor (91% of patients to bortezomib, 37% of patients to carfilzomib), in the Rd-group only 18% of patients was exposed to lenalidomide. Results: The median number of administered cycles was 9 (range 1-23) in the VD-group and 8.5 (range 1-23) in the Rd-group. The ORR was 68.2% in the Vd-group (CR 4.8%, VGPR 12.2%, PR 51.2%) and 81.5% in the Rd-group (CR 21%, VGPR 35.8%, pr 24.7%). Median TTR was 2 months (range 1-6) in the Vd-group and 1.5 months (range 1-5) in the Rd-group. Median PFS was 10 months (range 8-16; 95% > CI) in the Vd-group; median PFS was not reached in the Rd-group (fig.1). Grade 3/4 neutropenia (37%) was the most common adverse event in the Rd-group, grade 3/4 thrombocytopenia (24%) was the most common adverse event in the Vd-group. Seventeen (41%) patients in the Vd-group discontinued treatment due to relapse, 16 patients (19%) in the Rd-group because of haematological toxicity (4.5%), relapse (7.5%), death (6%) and the development of urological cancer (1%). Summary/Conclusion: A higher rate of ORR (81.5% vs 68.2%) and very good partial response or better (responses > VGPR 56.8% vs 17%) was observed in the Dara-Rd group compared to Dara-Vd group. This difference could be due to the fact that: 1) in the Dara- Rd group the patients had received a lower number of prior antimyeloma therapies compared to Dara-Vd group; 2) the patients in the Dara-Rd group had a more indolent myeloma (median ISS 1) compared to the patients in the Dara-Vd group, who had a more advanced disease (median ISS 3); 3) in the Rd-group only 18% of patients was exposed to lenalidomide, in the Vd-group all patients were previously exposed to at least one proteasome inhibitor. Unfortunately, the interference of daratumumab with immunofixation and serum protein electrophoresis assays may lead to underestimation of CR

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets

CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS: THE REAL LIFE EXPERIENCE OF RETE EMATOLOGICA PUGLIESE (REP)

Background: Carfilzomib, lenalidomide and dexamethasone (KRd) has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. Aims: We retrospectively evaluated 120 consecutive RRMM patients treated with KRd, in 9 hematology departments of Rete Ematologica Pugliese (REP), with the aim to evaluate the efficacy and safety with KRd treatment in a real world setting. Methods: Between December of 2015 and August 2018,120 RRMM patients were analyzed.The patients’ baseline characteristics are presented in Table 1. Median patient’s age was 66 years and 41 patients(34%) were older than 70 years. The median number of previous treatment lines was 1 (range 1–11). The 94% of the patients had been already treated with bortezomib-based regimens and 33% with both lenalidomide- and bortezomib-based regimens. Moreover, half of the patients (52%) had a previous autologous stem cell transplant. The median time from the diagnosis to start of treatment with KRd was 40 months (range 5–295) and 30 patients were treated with KRd early (≤18 months from diagnosis).Disease status at the start of treatment with KRd was refractory in 33 patients(29%) and 13 patients(12%) were refractory to lenalidomide. Twenty-four patients(21%) were refractory at last therapy before KRd enrollment. Results: The overall response rate (ORR) was 84%(n = 93),with 23%(25) complete response (CR) and 50%(55) very good partial response(VGPR).The median duration of response was 12,9 months (range, 3,33– 27,7). ORR was higher in patients relapsed after a previous autologous transplant (ASCT;56% vs 37% in those relapsed without prior ASCT;p 0,05).Patients treated in late relapse had a better ORR (44%) vs those in early relapse (19%; p 0,02). After a median follow-up of 13,4 months, median PFS was not reached (NR) and 2y-PFS was 61%, Figure 1. PFS was longer in responding patients (achieving at least PR) to those with less than PR (median PFS NR vs 4,9 months;p 0,0001).Median PFS in patients relapsed after a prior ASCT was NR vs 20 months in those without prior ASCT, (p 0,002).Patients achieving ASCT after KRD had a better PFS in confront to those without ASCT (median NR vs 9 months, p 0,001).Several baseline patient characteristics, such as the III ISS scoring, older age, prior exposure to lenalidomide and early relapse were found to negatively impact PFS.Twenty-eight patients(24%) performed 4 KRd cycles as bridge treatment to ASCT. The 64% of patients reached a VGPR and 67% received ASCT, with 9 upgraded from VGPR to complete response (CR) after ASCT.The treatment discontinuation rate due to adverse events (AEs) was 13%, most commonly related to lenalidomide(8%). KRd dose reduction was necessary in 11% of patients (2,5% for carfilzomib and 8% for lenalidomide).The most frequent AE was neutropenia(43%) and anemia (41%). Infections occurred in 10% of patients.Adverse Cardiovascular toxicity (Atrial fibrillation and pulmonary hypertension)occurred in 8% of patients. Summary/Conclusion: Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients 24th Congress of the European Hematology Association 276 | 2019;3:S1 achieving at least a partial response (PR), relapsing after previous ASCT and in those with the possibility to perform ASCT after KRd treatment. Accordingly,KRd should be used as an optimal bridge regimen to ASCT. Previous ASCT should not hamper the option for KRd therap

Outcomes and prognostic indicators in daratumumab-refractory multiple myeloma: a multicenter real-world study of elotuzumab, pomalidomide, and dexamethasone in 247 patients

Background: Daratumumab-refractory multiple myeloma (Dara-R MM) presents a significant treatment challenge. This study aimed to evaluate the efficacy and survival outcomes of elotuzumab, pomalidomide, and dexamethasone (EloPd) in a large, real-world cohort of patients with Dara-R MM, with particular focus on progression-free survival (PFS) and overall survival (OS). Materials and methods: This retrospective analysis included 247 Dara-R MM patients treated with EloPd. All patients were also refractory to lenalidomide, with 51.4% to a proteasome inhibitor, thus classified as triple-class refractory (TCR). Survival risk-scoring systems for PFS (progression-free risk score-PRSDaraR) and OS (survival risk score-SRSDaraR) were developed to stratify patients based on their risk profiles. Results: The overall response rate was 52.6%, with a median PFS and OS of 6.6 and 17.0 months, respectively. The International Staging System (ISS) stages II and III, low hemoglobin (Hb) levels, the last therapy being daratumumab, and symptomatic relapse were identified as significant independent predictors of shorter PFS in multivariable analysis. In addition to advanced ISS stages, low Hb levels (<10.6 g/dl), symptomatic relapse, and refractory disease exhibited an independent negative impact on OS. Importantly, no significant differences in both PFS and OS were observed between TCR and non-TCR patients. Based on these multivariable analyses, we developed PRSDaraR and SRSDaraR according to the magnitude of the hazard ratio. In PRSDaraR, 10.1% were low-risk, 41.3% intermediate, 43.3% high, and 5.3% very high-risk. The 12-month PFS probabilities were 86.3% (low), 67.6% (intermediate), 52.9% (high), and 31.8% (very high). For SRSDaraR, 6.1% were low-risk, 47.8% intermediate, 19.4% high, and 26.7% very high. The 12-month OS probabilities were 90.9% (low), 75.7% (intermediate), 55.9% (high), and 32.6% (very high). Conclusions: This study supports EloPd as an effective treatment option in Dara-R MM patients, providing valuable disease control and acting as a potential bridge to newer therapies, such as CAR-T and bispecific antibodies

Survival Risk Scores for Real-Life Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab or Carfilzomib In Combination With Lenalidomide and Dexamethasone as Salvage Therapy: Analysis of 919 Cases Outside Clinical Trials

The present study aimed to develop two survival risk scores (RS) for overall survival (OS, SRSKRd/EloRd) and progression-free survival (PFS, PRSKRd/EloRd) in 919 relapsed/refractory multiple myeloma (RRMM) patients who received carfilzomib, lenalidomide, and dexamethasone (KRd)/elotuzumab, lenalidomide, and dexamethasone (EloRd). The median OS was 35.4 months, with no significant difference between the KRd arm versus the EloRd arm. In the multivariate analysis, advanced ISS (HR = 1.31; P = 0.025), interval diagnosis–therapy (HR = 1.46; P = 0.001), number of previous lines of therapies (HR = 1.96; P < 0.0001), older age (HR = 1.72; P < 0.0001), and prior lenalidomide exposure (HR = 1.30; P = 0.026) remained independently associated with death. The median PFS was 20.3 months, with no difference between the two strategies. The multivariate model identified a significant progression/death risk increase for ISS III (HR = 1.37; P = 0.002), >3 previous lines of therapies (HR = 1.67; P < 0.0001), older age (HR = 1.64; P < 0.0001), and prior lenalidomide exposure (HR = 1.35; P = 0.003). Three risk SRSKRd/EloRd categories were generated: low-risk (134 cases, 16.5%), intermediate-risk (467 cases, 57.3%), and high-risk categories (213 cases, 26.2%). The 1- and 2-year OS probability rates were 92.3% and 83.8% for the low-risk (HR = 1, reference category), 81.1% and 60.6% (HR = 2.73; P < 0.0001) for the intermediate-risk, and 65.5% and 42.5% (HR = 4.91; P < 0.0001) for the high-risk groups, respectively. Notably, unlike the low-risk group, which did not cross the median timeline, the OS median values were 36.6 and 18.6 months for the intermediate- and high-risk cases, respectively. Similarly, three PRSKRd/EloRd risk categories were engendered. Based on such grouping, 338 (41.5%) cases were allocated in the low-, 248 (30.5%) in the intermediate-, and 228 (28.0%) in the high-risk groups. The 1- and 2-year PFS probability rates were 71.4% and 54.5% for the low-risk (HR = 1, reference category), 68.9% and 43.7% (HR = 1.95; P < 0.0001) for the intermediate-risk, and 48.0% and 27.1% (HR = 3.73; P < 0.0001) for the high-risk groups, respectively. The PFS median values were 29.0, 21.0, and 11.7 months for the low-, intermediate-, and high-risk cases. This analysis showed 2.7- and 4.9-fold increased risk of death for the intermediate- and high-risk cases treated with KRd/EloRd as salvage therapy. The combined progression/death risks of the two categories were increased 1.3- and 2.2-fold compared to the low-risk group. In conclusion, SRSKRd/EloRd and PRSKRd/EloRd may represent accessible and globally applicable models in daily clinical practice and ultimately represent a prognostic tool for RRMM patients who received KRd or EloRd

Prognostic Significance of +1q Alterations in Relapsed/Refractory Multiple Myeloma Treated With Daratumumab-, Elotuzumab-, and Carfilzomib-Based Triplet Regimens: A Multicenter Real-World Analysis of 635 Patients

Relapsed/refractory multiple myeloma (RRMM) research on the impact of +1q abnormalities in real-world settings is limited. This study evaluated the prognostic and predictive significance of 1q gain [gain(1q)] and amplification [ampl(1q)] in 635 RRMM patients treated with daratumumab-, elotuzumab-, and carfilzomib-based triplet regimens. Patients with +1q abnormalities had lower deep response rates [≥ CR: 9.4% for gain(1q), 11.6% for ampl(1q)] versus 20.2% in +1q-negative patients. Multivariable ordinal logistic analysis showed significantly lower odds of achieving ≥ CR in patients with gain(1q) (OR = 0.49, p < 0.001) or ampl(1q) (OR = 0.58, p = 0.0037). Progression-free survival (PFS) was longer in +1q-negative patients (28 months) compared to those with gain(1q) (8 months) or ampl(1q) (7.4 months). Multivariable models identified gain(1q) (HR = 1.9, p < 0.001) and ampl(1q) (HR = 2.2, p < 0.001) as independent negative prognostic factors alongside del17p, t(4;14), creatinine clearance < 60 mL/min, and ISS Stages II and III. Similarly, overall survival (OS) was reduced for patients with gain(1q) (25 months) and ampl(1q) (19.5 months) versus 42.2 months in +1q-negative patients. Multivariable analysis showed gain(1q) (HR = 1.6, p = 0.007) and ampl(1q) (HR = 2.0, p = 0.002) as independent predictors of increased mortality. Ancillary +1q abnormalities associated with high-risk cytogenetic changes were linked to both shorter PFS and OS. Stratification into no-hit, single-hit, double-hit, and triple-hit groups showed significant survival differences, emphasizing the impact of cumulative cytogenetic abnormalities on outcomes. In conclusion, +1q abnormalities significantly impact prognosis in RRMM and should be considered in risk stratification. The study emphasizes the importance of comprehensive cytogenetic profiling in real-world settings and highlights the need for personalized treatment strategies to improve patient outcomes