Real-life effectiveness of carfilzomib in patients with relapsed multiple myeloma receiving treatment in the context of early access: The CARMYN study.

The real-life retrospective observational study CARMYN aimed at investigating the long-term efficacy and safety of carfilzomib in combination with dexamethasone and lenalidomide (KRd, 159 patients). These patients (62% in first and 38% in second relapse, median age 62 yo) were treated between 02/2014 and 02/2017. Most had been pre-exposed to bortezomib (98.2%) and to an IMID (75.4%). At the time of collection, 90% had permanently discontinued carfilzomib. Data collection was conducted from January to July 2021 in 27 participating sites, after a median of 39 months follow-up. For patients treated with KRd, an overall response rate of 78.4% translated in a median progression free survival (PFS) of 24.0 months (95% CI 18.8-27.6) and a median overall survival (OS) of 51.1 months (95% CI 41.3-not reached). Results were poorer but difficult to interpret in the small cohort of Kd recipients. The study is one of the longest real-life studies of carfilzomib treatment in patients in first or second relapse. CARMYN confirmed the real-life long-term efficacy of carfilzomib in combination with lenalidomide and dexamethasone with results similar to those of clinical trials. The KRd regimen is thus an option to consider for late relapses in the current context of MM management.

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study.

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37-82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3-12). The median number of BM cycles administered was three (range, 1-22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study.

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

Humoral response to mRNA anti-COVID-19 vaccines BNT162b2 and mRNA-1273 in patients with chronic lymphocytic leukemia.

Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study.

Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14-56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8-73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46-65%) and 71% (95% CI: 49-84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant-related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high-risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients.

Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia.

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×109/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.

Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.

This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

[Malignant blood diseases in the elderly]. / Les hémopathies malignes du sujet âgé.

Hematological malignancies are more frequent in elderly patients. Treatment efficacy has been improved during the last decade. Long term remission can be achieved.The challenge is to identify elderly patients illegible for a curative treatment.This highlights the role of geriatric involvement in the management of patients with hematological malignancies.

Prevalence of monoclonal gammopathy in HIV patients in 2014.

INTRODUCTION: In non-HIV patients, Monoclonal Gammopathy of Undetermined Significance (MGUS) is associated with an increased risk of subsequent development of haematologic malignancies, especially multiple myeloma (MM) and it has been recently demonstrated that MM is always preceded by a MGUS phase. A higher prevalence of MGUS and MM has been observed in HIV patients compared to the general population. Nevertheless, it has been shown that MGUS in the context of HIV can disappear with antiretroviral therapy (ART). So, measuring MGUS prevalence in HIV patients in the recent period appears of special interest. MATERIALS AND METHODS: From January to June 2014, in each out-patient seen in our unit, a serum protein electrophoresis was performed. RESULTS: A total of 393 patients were screened. Eight patients with HIV2 and one patient with HIV1+HIV2 infection were excluded. Finally, 383 patients (173 female, 210 male) with HIV1 infection were analyzed. Characteristics of patients were as follows: median age 42.2 years (19.1-79.1), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection 47 (18.8%), median CD4 610 (2-1758), CD8 793 (113-4010), presence of a past AIDS event for 88 patients (23%). Median time with HIV infection was 11 years (0-30). Three hundred fifty-nine patients (93.7%) were on ART for a median duration of 105 months (0-287). For 320 patients (83.6%), viral load was below 50 viral copies/ml. Twelve cases of MGUS (3.1%) were observed: IgG Kappa (five cases), IgG Lambda (five cases), biclonal with two IgG Kappa (one case) and in one case, three monoclonal immunoglobulins were observed (IgG Kappa×2+IgG Lambda). The monoclonal immunoglobulin's level was low and below 1 g/l in all cases except two (2.1 and 11.6 g/l). No factor was found to be predictive of the presence of MGUS in particular age, CD4, HBV/HCV co-infection, viral load or ART. CONCLUSIONS: In the context of modern ART, the prevalence of MGUS remains above those observed in the general population. Even if the level of monoclonal spike observed in our cohort is generally low, an excess risk of subsequent development of MM could be present. Nevertheless, a prospective follow-up of HIV patients with MGUS is necessary to determine this risk.

High-output cardiac failure revealing primary plasma cell leukemia.

High-output cardiac failure in multiple myeloma (MM) is related to arteriovenous shunting in bone infiltrate disease. We describe such a complication in a patient with primary plasma cell leukemia (pPCL) without bone disease. We review the mechanisms that could be involved. As previously described, traditional cardiac failure therapy is not effective. pPCL therapy should not be delayed.

Anaplastic Large Cell Lymphoma Occurring in an HIV-Positive Patient.

Cases of anaplastic large-cell lymphoma (ALCL) of T phenotype are sparse in the setting of HIV patients. We report herein a case of T-ALCL, with an advanced stage, pulmonary involvement, high HIV viral load, and low CD4 level. Anaplastic lymphoma kinase (ALK) protein expression was negative. Anthracyclin-based chemotherapy was unsuccessful. The literature review was performed focusing on incidence, clinical characteristics, prognosis, and physiopathology of ALCL in HIV patients. More data are needed to improve the knowledge of such cases and to define a better treatment approach.

A multicenter study of gemcitabine-containing regimen in relapsed or refractory Hodgkin's lymphoma patients.

The aim of this study was to assess the efficacy of a gemcitabine-containing regimen in pretreated Hodgkin's lymphoma (HL) patients. Relapsed or refractory HL patients treated with gemcitabine, used alone or in combination with other cytotoxic agents, were retrospectively reviewed. Fifty-five patients were included in the study. Initial characteristics before gemcitabine administration were: Ann Arbor stage III-IV: 84%; International Prognostic Score less than 3 in 18/39 cases (46%); 31 primary refractory patients at the end of first-line therapy (56%); median number of previous chemotherapy regimens of 3. Twenty-nine patients received gemcitabine alone with a median maximal dose of 900 mg/m2 per injection (range: 300-1500 mg/m2). Gemcitabine was administered at a maximal dose of 1000 mg/m2 per injection (range: 650-1250) in combination with vinorelbine in 10 patients, oxaliplatin in 13 patients, and other drugs in three patients, with a median of six injections (range: 1-18). Reported toxicity was mainly hematologic. Overall response rate was 20% with 11% of complete remission. On univariate analysis, two adverse factors at progression were significant for response to gemcitabine-based regimen: stage III-IV disease and hemoglobin level was less than 10.5 g/dl. This study demonstrated the limited efficacy of gemcitabine-containing regimen in heavily pretreated HL patients.