An open-label phase 2 study treating patients with first or second relapse of multiple myeloma with carfilzomib, pomalidomide, and dexamethasone (KPd): SELECT study.

Once-weekly carfilzomib at 56 mg/m2 plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10-5) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory.

Approach to Acute Myeloid Leukemia with Increased Eosinophils and Basophils.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. The identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus, clinicians must be vigilant in searching for the cause of eosinophilia and basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article, we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and give prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

How to improve RCHOP as frontline therapy for diffuse large B-cell lymphoma: a systematic review and meta-analysis of 21 randomized controlled trials.

RCHOP is the standard of care for patients with diffuse large b-cell lymphoma (DLBCL) but failures occur in approximately 40% of them. We performed a meta-analysis of 21 randomized controlled trials (RCTs) comparing experimental regimens with RCHOP. We searched the database of PubMed with proper criteria, and data of efficacy (Progression Free Survival-PFS) in the ITT population were extracted and analyzed. Cross comparisons of RCTs were performed by using the CINEMA software. Odds ratio (OR) and 95% confidence intervals (95%, CI) are reported. The literature search yielded 21 RCTs including 5785 patients in the RCHOP arm and 5648 patients in the experimental arm. Odds ratio (OR) for PFS in the total cohort was OR (95%, CI): 0.87 (0.76-0.99), p=0.02. Among different strategies to improve RCHOP, addition of a novel agent on RCHOP improved PFS. In total 1740 patients in the RCHOP arm were compared with 1755 in the RCHOP plus a novel agent arm, and the OR (95% CI) for PFS was 0.84 (0.71-0.97), p=0.02. Indirect comparisons of nine studies adding a novel agent on RCHOP does not give prominence to any agent. Subgroup analysis according to cell of origin was performed for non-GC DLBCL patients. In this subgroup, 1546 patients treated with RCHOP were compared with 1538 patients treated with experimental regimens. The OR (95% CI) for PFS was 0.86 (0.73-1.02), p=0.34. Overall survival data extracted from 18 studies showed no superiority of experimental regimens over RCHOP. Efficacy of RCHOP backbone is marginally improved when adding a novel anti-lymphoma agent.

Does the Simultaneous Introduction of Several Pharmaceuticals in the Post-Lenalidomide Era Translate to Better Outcomes in Relapse Refractory Multiple Myeloma? Findings from the Real-World Innovation in Multiple Myeloma (REAL IMM) Study.

Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies.

Improved survival of patients with primary plasma cell leukemia with VRd or daratumumab-based quadruplets: A multicenter study by the Greek myeloma study group.

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) versus previous anti-myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow-up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/µL, independently predicted OS (p < .05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL.

Portal Vein Thrombosis after C-Section in a Patient with Polycythemia Vera (PV) Due to Pregnancy and Iron Deficiency Anemia (IDA).

Polycythemia vera (PV) is one of the three main classic disorders of Philadelphia-negative myeloproliferative neoplasms (MPNs), with the other two being essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV may develop (15%) in women of childbearing age (15-45 years), with an anticipated rate of roughly 0.3 per 100,000 people, although maintaining a male to female ratio predominance of about 2:1 and a peak prevalence in the sixth and seventh decades of life. Without always being presented with its actual clinical manifestations due to pregnancy itself, and most commonly due to iron deficiency, PV can be frequently missed and therefore belatedly diagnosed. We describe the case of a primipara woman in her 40s, without risk factors for thrombosis, who developed a portal vein occlusion 1.5 month postpartum after C-section and who had a delayed diagnosis of PV.

Pomalidomide Plus Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World "POWERFUL" Study.

The "POWERFUL" multicenter, retrospective, and prospective study investigated the effectiveness of pomalidomide plus low-dose dexamethasone (POM/LoDex) therapy in relapsed/refractory multiple myeloma in routine care in Greece. Ninety-nine eligible adult patients treated with POM/LoDex according to the approved label after having received ≥2 prior therapies, including lenalidomide and bortezomib, were consecutively enrolled between 16 November 2017 and 21 February 2019 in 18 hematology departments. Fifty patients (50.5%) started POM/LoDex as third-line treatment. During the treatment period (median: 8.3 months; range: 0.3-47.6 months), the median POM dose was 4 mg/day, and 31.3% of the patients received additional antimyeloma agents. The overall response rate was 32.3%. During a median follow-up period of 13.8 months (Kaplan-Meier estimate), the median progression-free survival (PFS) was 10.5 months (95% CI: 7.4-14.4). The PFS was not significantly different between patients receiving POM/LoDex in the third versus later line of therapy, nor between patients receiving concomitant antimyeloma therapy versus POM/LoDEx doublet. During the prospective safety data collection period (median: 7.6 months) among patients with prospective follow-up (N = 75), POM-related adverse event incidence rate was 42.7% (serious: 18.7%; grade ≥ 3 hematological POM-related adverse events: 8.0%). Only neutropenia (13.3%) was reported at a frequency ≥10%. In conclusion, in this real-world study, POM/LoDex displayed a long PFS with no new safety signals emerging.

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study.

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

Socioeconomic Status is Globally a Prognostic Factor for Overall Survival of Multiple Myeloma Patients: Synthesis of Studies and Review of the Literature.

BACKGROUND: Socioeconomic status (SES) is reflecting differences in sociodemographic factors affecting cancer survivorship. Deprived, low SES populations have a higher prevalence of multiple myeloma and worst survival, a condition which widens over time. METHODS: We performed a meta-analysis of 16 studies (registries and cohorts) reporting myeloma patients' survival data according to SES. Ten studies reported Hazzard Ratio (H.R.) (95 % CI), and 16 studies reported p values. We combined the H.R. from 10 studies, and by using the Mosteller-Bush formula, we performed a synthesis of p values according to the area of the globe. RESULTS: Combination of H.R. from 10 studies including 85198 myeloma patients weighted to sample size of each study and adopting the hypothesis of random effect returned a combined H.R.: 1,26 (1,13-1,31) in favor of high SES patients.USA: Synthesis of p values coming from 6 studies (n=89807 pts) by using the Mosteller and Bush formula extracted a p-value of <0.0001 favoring high SES patients.Oceania: Synthesis of p values in two cohorts from Australia and New Zealand (n= 10196 pts) returned a p-value of 0,022 favoring high SES patients.Europe: The synthesis of p values from the U.K. and Greece studies (n=18533 pts) returned a p-value of <0,0001 favoring high SES patients.Asia: Synthesis of 2 studies from Asia (n=915 pts) returned a p-value of <0,0001 favoring high SES patients. CONCLUSIONS: Across the globe and widening over decades, the socioeconomic status remains a gap for equality in myeloma care.

Socioeconomic Status Is an Independent Prognostic Factor for Overall Survival in Patients With Multiple Myeloma: Real-World Data From a Cohort of 223 Patients.

INTRODUCTION: Socioeconomic status (SES) has been shown to be a prognostic factor for overall survival in a variety of hematologic malignancies, especially for patients who require continuous care such as those with multiple myeloma (MM). PATIENTS AND METHODS: We retrospectively collected data from 223 patients with symptomatic MM diagnosed and treated in our department from January 2005 to December 2019. The modified Kuppuswamy scale, slightly modified, was used for the SES assessment. The Kaplan-Meier estimator of survival and Cox regression analysis were used. RESULTS: In our cohort of 223 patients with MM, low SES was an independent poor prognostic factor for overall survival (OS), in addition to higher International Staging System stage and high-risk cytogenetics (hazard ratio for low SES on Cox regression analysis, 2.092; 95% confidence interval [CI], 1.36-3.2; log-rank P = .000). Patients with low SES had inferior survival compared with the whole patient cohort (median OS: low SES, 28 months; 95% CI, 18-37.9; high SES, 68 months; 95% CI, 55.6-80.4; log-rank P = .000). The low SES effect on OS was more evident for the elderly patients who were not transplant eligible and in those with a diagnosis of MM International Staging System stage I. The effect of low SES on OS was attenuated by time, and ethnic origin had no effect on OS. CONCLUSIONS: The results of the present study have shown that low SES is an independent poor prognostic factor for survival of patients with MM.

Navigating the Role of CD1d/Invariant Natural Killer T-cell/Glycolipid Immune Axis in Multiple Myeloma Evolution: Therapeutic Implications.

Multiple myeloma (MM) is an incurable B-cell malignancy. The immunotherapeutic approach for MM therapy is evolving. The Cd1d/invariant natural killer T-cell/glycolipid immune axis belongs to the innate immunity, and we have highlighted role in myeloma pathogenesis in the present study. The recent development of the chimeric antigen receptor (CAR19)-invariant natural killer T-cells resulted in our renewed interest in this immune system and offer new perspectives for future anti-MM immunotherapies.

Immunoporosis: A New Role for Invariant Natural Killer T (NKT) Cells Through Overexpression of Nuclear Factor-κB Ligand (RANKL).

BACKGROUND Osteoporosis affects millions of postmenopausal women worldwide. Invariant natural killer T cells (iNKT) are important cells for bone homeostasis. The sim of this study was to investigate the contribution of invariant natural killer T cells (iNKT) in the increased receptor activator of the nuclear factor-kappaB ligand (RANKL) pool and bone resorption, a characteristic of patients with osteoporosis. MATERIAL AND METHODS Whole blood was collected from 79 female patients. The dual energy x-absorptiometry scan was performed in all patients, and the T-score was calculated in order to classify our patients according to the World Human Organization (WHO) criteria for diagnosis and classification of osteoporosis. Eleven patients had a T-score -2.5 and were included in the osteoporosis group. We performed alpha-galactosylceramide activation of iNKT cells in vitro. Surface RANKL expression was detected by multicolor flow cytometry in naive and activated lymphocytes. Beta-Crosslaps (ß-CTx) levels were measured in whole blood plasma by ELISA (enzyme-linked immunosorbent assay). RESULTS Although iNKT cells were not clonally expanded in patients with osteoporosis, iNKT cells from osteoporotic patients overexpressed RANKL compared to ND and osteopenic patients. This is a distinctive feature of iNKT cells and is not seen in conventional T-lymphocytes. RANKL expression in iNKT cells was not related to ß-CTx levels in the blood. Finally, iNKT cell activation by the prototypal glycolipid ligand alpha-galactosylceramide increased by 8 times their RANKL expression. CONCLUSIONS In patients with osteoporosis, iNKT cells specifically overexpress RANKL, a cytokine that regulates osteoclast activity. It seems that iNKT cells have a long-standing effect of on the bone physiology, which plays an important role in the bone loss of patients with osteoporosis.

The JAK2V617F Point Mutation Increases the Osteoclast Forming Ability of Monocytes in Patients with Chronic Myeloproliferative Neoplasms and Makes their Osteoclasts more Susceptible to JAK2 Inhibition.

JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.

Correction to: Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

The original version of this article contained a mistake. The name of Eirini Katroditou should have been Eirini Katodritou. The original article has been corrected.

Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

Myeloid Neoplasms with Isolated Isochromosome 17q: a yet to be Defined Entity.

Myeloid neoplasms with isolated isochromosome 17q [MN i(17q)] has been described as a distinct entity with poor prognosis. However, literature reports show a considerable clinical and molecular heterogeneity. We describe a 58-year-old male patient who was diagnosed as refractory anemia with multilineage dysplasia and ringed sideroblasts with isolated i(17q). Though he initially responded well to erythropoietin, he gradually progressed to an aggressive form of MDS/MPN refractory to azacytidine and died 29 months after the first diagnosis. Notably, in contrast to disease advancement, his karyotype reverted to normal, whereas his mutational profile remained unchanged. To our knowledge, this is the first report of karyotype normalization during disease progression in patients with MN i(17q). It suggests that the i(17q) anomaly is dispensable for the leukemic transformation and highlighting the underlying clinical and molecular complexity which both has to be resolved before the establishment of MN with isolated i(17q) as a distinct entity.