Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

A glimpse into relapsed refractory multiple myeloma treatment in real-world practice in Spain: the GeminiS study.

OBJECTIVES: To describe the incorporation of monoclonal antibodies (mAb) in real-world (RW) practice for the treatment of patients with relapsed refractory multiple myeloma (RRMM) in a setting with other treatment alternatives. METHODS: This was an observational, multicenter, ambispective study of RRMM treated with or without a mAb. RESULTS: A total of 171 patients were included. For the group treated without mAb, the median (95% CI) progression-free survival (PFS) to relapse was 22.4 (17.8-27.0) months; partial response or better (≥PR) and complete response or better (≥CR) was observed in 74.1% and 24.1% of patients, respectively; and median time to first response in first relapse was 2.0 months and in second relapse was 2.5 months. For the group of patients treated with mAb in first or second relapse, the median PFS was 20.9 (95% CI, could not be evaluated) months; the ≥ PR and ≥ CR rates were 76,2% and 28.6%, respectively; and the median time to first response in first relapse was 1.2 month and in second relapse was 1.0 months. The safety profiles for the combinations were consistent with those expected. CONCLUSIONS: The incorporation of mAb in RW practice for the treatment of RRMM has shown good quality and speed of response with a similar safety profile shown in randomized clinical trials.

Single versus tandem autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma and high-risk cytogenetics. A retrospective, open-label study of the PETHEMA/Spanish Myeloma Group (GEM).

Tandem ASCT has been suggested as a valid approach to improve the prognosis of patients with MM and HR cytogenetic. In this observational, retrospective study, 213 patients with newly diagnosed MM and HR cytogenetic in 35 hospitals from the Spanish Myeloma Group underwent single or tandem ASCT between January 2015 and December 2019 after induction with VTD/VRD. HR cytogenetic was defined as having ≥1 of the following: del17p, t(4;14), t(14;16) or gain 1q21. More patients in the tandem group had R-ISS 3 and >1 cytogenetic abnormality at diagnosis. With a median follow-up of 31 months (range, 10-82), PFS after single ASCT was 41 months versus 48 months with tandem ASCT (p = 0.33). PFS in patients with del17p undergoing single ASCT was 41 months, while 52% of patients undergoing tandem ASCT were alive and disease free at 48 months. In conclusion, tandem ASCT partly overcomes the bad prognosis of HR cytogenetic.

Treatment patterns and outcomes among nontransplant newly diagnosed multiple myeloma patients in Spain.

Aim: To describe treatment patterns and outcomes in nontransplant newly diagnosed multiple myeloma (NDMM) patients in Spain. Methods: This retrospective study included two cohorts of NDMM patients diagnosed between 1 January 2012 to 31 December 2013 and 1 April 2016 to 31 March 2017. Results: Among 113 patients, proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%) were the most common first-line (1L) therapies. Use of PI + immunomodulatory drug-based regimens increased between the cohorts; PI-based regimens without an alkylator/immunomodulatory drug decreased. Use of 1L oral regimens was low but increased over time; use of maintenance therapy was low across both periods. Median 1L duration of treatment was 6.9 months. Conclusion: Short 1L duration of treatment and low use of 1L oral regimens and maintenance therapy highlight unmet needs in NDMM.

Lay abstract This study describes treatment patterns and outcomes in newly diagnosed multiple myeloma (NDMM) patients in Spain who were not candidates for transplant. The study looked at two patient groups: patients diagnosed between 1 January 2012 and 31 December 2013 and those diagnosed between 1 April 2016 and 31 March 2017. Among the 113 patients considered, the most common first-line therapies were proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%). We saw increased use of PI with immunomodulators (which arm the immune system to battle disease) and decreased use of PI-based regimens without an alkylator or immunomodulator. First-line use of oral regimens was low but increased over time. The median length of first-line treatment for both groups combined was 6.9 months. Finding low use of first-line oral regimens and maintenance therapy and a short duration of first-line treatment, our study highlights the unmet needs that exist in NDMM patients who are not transplant candidates in Spain.

Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin's lymphoma: report on three cases and literature review.

The poor prognosis of refractory or relapsed (R/R) classical Hodgkin's lymphoma (cHL) after autologous stem cell transplantation has improved greatly due to the introduction of brentuximab vedotin and PD-1 inhibitors. However, the duration of response achieved with these novel agents is too short. The information about the management of patients after anti-PD-1 therapy failure is very limited in cHL, although chemotherapy alone or combined with PD-1 inhibitors has shown encouraging results. We report three cases of heavily pretreated cHL, refractory to nivolumab monotherapy, successfully rescued with the addition of chemotherapy to nivolumab, as a bridge to allogeneic stem cell transplantation (allo-SCT). All three patients presented poor clinical features such as three to four previous lines including brentuximab vedotin and autologous stem cell transplantation, refractoriness to the last line of therapy previous to nivolumab, and rapid disease progression. Notwithstanding these characteristics and nivolumab failure, they achieved a complete response after the addition of chemotherapy, were consolidated with allo-SCT, and still remain in complete response. There are few studies concerning the combination of PD-1 inhibitors and chemotherapy after nivolumab failure, including one retrospective study and one phase II trial with nivolumab plus bendamustine. Therefore, only few patients are consolidated with allo-SCT. However, there are several ongoing trials investigating new combinations of chemotherapy and PD-1 inhibitors in R/R cHL, as well as in first line. All these data suggest that anti-PD-1 therapy may reprogram the immune system, activating and inhibiting effector and immunosuppressive cells, respectively, leading to overtake of chemorefractoriness. Allo-SCT can increase the immune-related events of patients treated with anti-PD-1 previously, consistent on acute graft-versus-host disease, sinusoidal obstruction syndrome, and noninfectious febrile syndrome. In conclusion, the combination of PD-1 inhibitor and chemotherapy may be a feasible therapy after anti-PD-1 treatment failure as a bridge to allo-SCT.

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial.

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.

Pomalidomide, Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Real-World Analysis of the Pethema-GEM Experience.

INTRODUCTION: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations. PATIENTS AND METHODS: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy. RESULTS: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease. CONCLUSION: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.

Partial T Cell-Depleted Peripheral Blood Stem Cell Transplantation from HLA-Identical Sibling Donors for Patients with Severe Aplastic Anemia.

We analyzed the outcomes of 26 consecutive patients with acquired severe aplastic anemia (SAA) undergoing peripheral blood stem cell transplantation (PBSCT) with partial ex vivo T cell depletion with a targeted T cell dose from HLA-identical sibling donors. The median patient age was 37 years (range, 3 to 63 years). Four patients with uncontrolled pneumonia at the time of transplantation died, on days +1, +2, +21, and +26. All evaluable patients engrafted, with a median time to neutrophil recovery of 11 days (range, 10 to 14 days) and a median time to platelet recovery of 19 days (range, 8 to 53 days). Two patients had transient grade I acute graft-versus-host disease (GVHD) with skin involvement, but no patients developed grade II-IV acute GVHD. Two patients had mild skin chronic GVHD, and 1 patient had moderate chronic GVHD with ocular involvement. No relapse was observed after a median follow-up of 114 months (range, 4 to 233 months). The overall cumulative incidence of TRM at 10 years was 19%, whereas it was 5% for those with a Karnofsky Performance Status (KPS) score >60 at the time of transplantation. Disease-free survival, overall survival, and GVHD and relapse-free survival at 10 years were 81%, 81%, and 80%, respectively, for all patients and 95%, 95%, and 90%, respectively, for patients with a KPS score >60 at transplantation. Our data indicate that PBSCT with partial ex vivo T cell-depleted targeted cell dose grafts from an HLA-identical sibling donor is a feasible, safe, and effective approach to reduce GVHD and cure patients with SAA.

Comparison of transfusion requirements in adult patients undergoing Haploidentical or single-unit umbilical cord blood stem cell transplantation.

OBJECTIVES: Umbilical cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) modalities have been developed to offset the lack of matched donors. In this study, we compare the transfusion requirements of patients undergoing UCBT and haplo-HSCT in a single institution with the aim of providing additional information for clinicians to choose the most adequate alternative graft for HSCT. METHODS: The study reviewed 67 and 46 patients undergoing UCBT and haplo-HSCT, respectively. RESULTS: There were no significant differences for RBC and PLT requirements according to the transplantation modality. Median time to RBC transfusion independence was 35 and 25.5 days in patients who received an UCBT and haplo-HSCT, respectively (P = 0.38), while median time to platelet transfusion independence was 31 days for UCBT patients and 23 for haplo-HSCT patients (P < 0.001). Days until neutrophils > 0.5 × 109 /L were the only variable that significantly influenced RBC and PLT requirements for both transplantation modalities. Cumulative incidence of RBC and PLT transfusion independence at 90 days after transplantation was similar for both UCBT and haplo-HSCT. CONCLUSIONS: Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy.

Further psychometric validation of the GAH scale: Responsiveness and effect size.

OBJECTIVES: The purpose of this study was to assess the responsiveness of the newly developed Geriatric Assessment in Hematology (GAH) scale to clinical change in older patients diagnosed with hematologic malignancies. METHODS: A prospective observational study conducted in 164 patients aged ≥65years and diagnosed with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphocytic leukemia (CLL). Responsiveness of the GAH scales was studied by means of the Eastern Cooperative Oncology Group (ECOG) score, the Karnofsky performance status (KPS) score, the visual analog scale (VAS), and the physician's subjective assessment, used as clinical anchors to identify whether patients had changed clinically (either improved or worsened) or not since the baseline visit. Responsiveness was evaluated on the basis of effect size (ES). RESULTS: 164 patients (men, 63.7%; median age, 77.0 (72.8-81.4) participated. Statistically significant correlations were obtained between the investigator's qualitative assessment and changes in ECOG, KPS, and VAS scores. Likewise, a statistically significant correlation was obtained between the investigator's qualitative assessment and changes in the GAH scale score. Responsiveness of the GAH scale to detect clinical change was satisfactory (ES 0.34). CONCLUSION: Findings confirm that the GAH scale is responsive to clinical changes in patients' health status. Additionally, the GAH scale is a promising tool to improve clinical decision-making in older patients with hematological malignancies.

Diagnóstico de tuberculosis genito-urinaria y reacción en cadena de la polimerasa / Diagnosis of genitourinary tuberculosis by PCR technique

No disponible