Pokrok v léčbě mnohočetného myelomu (MM) je mimořádný. Kombinované režimy, které se u nové diagnózy dostávají do standardně používané terapie, dosahují doby do progrese více než sedm let. V České republice očekáváme v roce 2025 schválení čtyřkombinace anti-CD38 monoklonální protilátky (mAb) spolu s proteasomovým inhibitorem (PI), imunomodulační látkou (IMiD) a dexametazonem. Není zatím jasné, zda konsolidace autologní transplantaci při této čtyřkombinaci bude přínosem stran prodloužení doby do progrese. Doslova exploze nastala ve vývoji imunoterapie. Autologní T-lymfocyty s chiméricky upraveným receptorem (CAR T-lymfocyty) cíleným na BCMA antigen se v USA již dostaly do druhé linie léčby. Vývoj je ještě rychlejší u bispecifických protilátek (bsAb). V pozdním relapsu máme k dispozici bsAb, které cílí na BCMA a GPRC5D antigen. V rámci klinických studií se zkouší další terapeutické cíle (např. FcRH5) i kombinované režimy (např. bsAb, PI, IMiD). Účinnost těchto kombinací v první linii je 90–100 %, přičemž vysoké procento pacientů dosahuje negativní minimální reziduální nemoci (MRD). Vyhodnocování MRD v klinických studiích bylo v roce 2024 schváleno jako primární výsledkový cíl a je pravděpodobné, že směřujeme do období MRD řízené terapie.

Progress in multiple myeloma (MM) treatment is remarkable. Combined regimens for newly diagnosed MM patients achieve progression-free survival of more than seven years. In the Czech Republic, the approval of a four-drug combination of anti-CD38 monoclonal antibody (mAb) with a proteasome inhibitor (PI), immunomodulatory agent (IMiD) and dexamethasone is expecting in 2025. It is not yet clear whether consolidation with autologous transplantation will be beneficial in terms of extending the time to progression. The development of immunotherapy has literally exploded. Autologous chimeric antigen receptor T-cell therapy (CAR T-cells) targeting the BCMA antigen have already been approved for second-line therapy in the USA. The development of bispecific antibodies (bsAb) is even faster. Bispecific antibodies targeting BCMA and GPRC5D antigens are available in late relapse. Clinical trials are testing additional therapeutic targets (e.g., FcRH5) and combination regimens (e.g., bsAb, PI, IMiD). Response rates to these combinations in the first line treatment are 90-100 %, with a high percentage of patients achieving minimal residual disease (MRD) negativity. In 2024, assessment of MRD was approved as a primary outcome in clinical trials and it is likely that we are now moving to wals an era of MRD-driven therapy.

• MeSH
• chimerické antigenní receptory terapeutické užití   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• protilátky bispecifické farmakologie   terapeutické užití   MeSH
• reziduální nádor MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Daratumumab, lenalidomid (Revlimid) a dexamethason (DRd) je léčebná kombinace indikovaná pro pacienty s nově diagnostikovaným, ale i relabujícím mnohočetným myelomem. Účinnost DRd v léčbě myelomu nelze zpochybnit. U pacientky, kterou popisuje náš příspěvek, byl diagnostikován kromě myelomu i nekrobiotický xantogranulom (NXG) se závažnými komplikacemi. Vzhledem k raritnímu výskytu této histocytární nemoci není stanoven žádný optimální léčebný postup. S cílem léčby mnohočetného myelomu a s ním spojeného NXG jsme použili režim DRd v kombinaci s intravenózní aplikací imunoglobulinů. Kombinovaná léčba vedla k významné regresi NXG a k vymizení potíží, které byly s NXG spojeny.

Daratumumab, lenalidomid and dexamethason (DRd) is a combination treatment indicated for newly diagnosed as well as relapsed multiple myeloma. The efficacy of DRd in the treatment of myeloma is unquestionable. In the case of the patient described in our report, in addition to myeloma, necrobiotic xanthogranuloma (NXG) with significant complications was also diagnosed. Given the rare occurrence of this histiocytic disease, no optimal treatment protocol has been established. With the aim of myeloma treating and associated NXG, we used the DRd regimen in combination with intravenous administration of immunoglobulins. The combined treatment led to significant regression of NXG and the disappearance of symptoms associated with NXG.

BACKGROUND: Multiple myeloma (MM) represents the second most common hematological malignancy characterized by the infiltration of the bone marrow by plasma cells that produce monoclonal immunoglobulin. While the quality and length of life of MM patients have significantly increased, MM remains a hard-to-treat disease; almost all patients relapse. As MM is highly heterogenous, patients relapse at different times. It is currently not possible to predict when relapse will occur; numerous studies investigating the dysregulation of non-coding RNA molecules in cancer suggest that microRNAs could be good markers of relapse. RESULTS: Using small RNA sequencing, we profiled microRNA expression in peripheral blood in three groups of MM patients who relapsed at different intervals. In total, 24 microRNAs were significantly dysregulated among analyzed subgroups. Independent validation by RT-qPCR confirmed changed levels of miR-598-3p in MM patients with different times to relapse. At the same time, differences in the mass spectra between groups were identified using matrix-assisted laser desorption/ionization time of flight mass spectrometry. All results were analyzed by machine learning. CONCLUSION: Mass spectrometry coupled with machine learning shows potential as a reliable, rapid, and cost-effective preliminary screening technique to supplement current diagnostics.

• Publikační typ
• časopisecké články MeSH

The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.

• MeSH
• dexamethason terapeutické užití   aplikace a dávkování   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * patologie   farmakoterapie   mortalita   diagnóza   MeSH
• oligopeptidy terapeutické užití   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• staging nádorů * MeSH
• thalidomid analogy a deriváty   terapeutické užití   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• validační studie MeSH

BACKGROUND: In multiple myeloma (MM), improving our understanding of routine clinical practice and the effectiveness of agents outside of clinical trials is important. TOURMALINE-MM1 data resulted in approval of ixazomib for MM patients who have received ≥ 1 prior therapy. PATIENTS AND METHODS: UVEA-IXA comprised a retrospective chart review in the early access program, and a prospective 1-year follow-up period. Eligible patients had had a biochemical and/or symptomatic relapse after 1-3 prior lines of therapy; no anti-MM therapy for > 3 cycles at the start of ixazomib therapy; and an Eastern Cooperative Oncology Group performance score of 0-2. Lenalidomide- or proteasome inhibitor (PI)-refractory patients were ineligible. Primary endpoints were response and progression-free survival (PFS). RESULTS: Of 357 enrolled patients, 309 were evaluable; most patients received ixazomib alongside lenalidomide (98%) and dexamethasone (97%); 61% had received 2-3 prior lines of therapy. Median PFS was 15.6 months (95% confidence interval [CI]: 12.0-20.6) in all evaluable patients, and 19.6 (95% CI: 12.1-27.0) and 13.9 (95% CI: 10.1-18.1) months in patients who received 1 and ≥ 2 prior lines of therapy, respectively. The overall response rate was 67% in all evaluable patients, and 72% and 63%, respectively, in patients who received 1 and ≥ 2 prior lines of therapy. Median overall survival was 35.5 months. The ixazomib safety profile was consistent with previous reports. CONCLUSION: This study supports ixazomib-based therapy as an effective and tolerable treatment in the real-world. Outcomes were favorable in patients with 1 or ≥ 2 prior lines of therapy who were not lenalidomide- or PI-refractory.

• MeSH
• dexamethason terapeutické užití   MeSH
• glycin analogy a deriváty   MeSH
• lenalidomid terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mnohočetný myelom * MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• retrospektivní studie MeSH
• sloučeniny boru * MeSH
• uvea MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Twice-weekly carfilzomib (27 mg/m2) plus lenalidomide and dexamethasone (KRd27) is a standard of care in relapsed/refractory multiple myeloma (RRMM). Once-weekly carfilzomib regimens have shown clinical benefits with improved patient convenience. This open-label, phase 3, multicenter, randomized study aimed to demonstrate noninferiority of the overall response rate (ORR) for once-weekly carfilzomib (56 mg/m2) plus Rd (KRd56) vs twice-weekly KRd27 in RRMM. A total of 454 patients were randomized (1:1) to receive carfilzomib as once-weekly 30-minute infusions of 56 mg/m2 (KRd56; n = 228) or twice-weekly 10-minute infusions of 27 mg/m2 (KRd27; n = 226). Baseline characteristics were balanced between groups. ORR was 82.5% (95% confidence interval [CI], 76.9-87.2) in the once-weekly group vs 86.3% (95% CI, 81.1-90.5) in the twice-weekly group (risk ratio, 0.954 [95% CI, 0.882-1.032]) and did not meet the threshold for statistical significance of noninferiority (P = .0666). Complete response (CR) or better was obtained in 46.9% of patients in the once-weekly arm and 36.3% in the twice-weekly arm. The proportions of patients who achieved CR and were also assessed negative for minimal residual disease were 21.5% and 18.1%, respectively (odds ratio, 1.235 [95% CI, 0.775-1.970]). Progression-free survival was comparable between groups (hazard ratio, 0.945 [95% CI, 0.617-1.447]). The safety profile was similar for both groups. In conclusion, although statistical significance for noninferiority of ORR was not achieved, the efficacy and safety of once-weekly KRd56 were similar to those of twice-weekly KRd27, and once-weekly KRd56 may be an effective and convenient treatment option for patients with RRMM. This trial was registered at www.ClinicalTrials.gov as #NCT03859427.

• MeSH
• dexamethason * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• lenalidomid * aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   mortalita   MeSH
• oligopeptidy * aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• recidiva MeSH
• rozvrh dávkování léků MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab-exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not-triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), p = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) p = .003). Similar to OS, there was improved PFS in patients, that were not triple-refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), p = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple-refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR).

• MeSH
• chemorezistence * MeSH
• dexamethason * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• glycin * analogy a deriváty   aplikace a dávkování   terapeutické užití   MeSH
• lenalidomid * aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   mortalita   MeSH
• monoklonální protilátky * terapeutické užití   aplikace a dávkování   MeSH
• opakovaná terapie MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sloučeniny boru * aplikace a dávkování   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Elranatamab je humanizovaná bispecifická protilátka zaměřená proti antigenu zrání B-buněk (BCMA) exprimovanému na myelomových buňkách a molekule CD3 na T-buňkách, která aktivuje T-lymfocyty a směřuje je k cytotoxické T-buněčné odpovědi proti myelomovým buňkám. Klíčovou studií elranatamabu u pacientů s relabujícím či refrakterním mnohočetným myelomem (RR MM) byla studie II. fáze MagnetisMM-3, ve které byla prokázána jeho vysoká protinádorová účinnost a zvládnutelná toxicita. Elranatamab je v ČR indikován k monoterapii pacientů s RR MM, kteří podstoupili alespoň tři předchozí terapie, včetně imunomodulancia, inhibitoru proteazomu a anti-CD38 protilátky, a při poslední terapii u nich došlo k progresi onemocnění.

Elranatamab is a humanized bispecific antibody directed against B-cell maturation antigen (BCMA) expressed on myeloma cells and CD3 molecule on T-cells that activates T-lymphocytes and directs them to induce a cytotoxic T-cell response against myeloma cells. The pivotal study of elranatamab in patients with relapsed or refractory multiple myeloma (RR MM) was the phase II MagnetisMM-3 trial, in which it was shown to have high antitumour efficacy and manageable toxicity. In the Czech Republic, elranatamab is indicated for monotherapy in patients with RR MM who have undergone at least three prior therapies, including an immunomodulator, proteasome inhibitor and anti-CD38 antibody, and had disease progression on their last therapy

MP0250 is a designed ankyrin repeat protein that specifically inhibits both vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor (HGF), aiming at potentiating cancer therapy by disrupting the tumour microenvironment. Encouraging results from a phase 1 trial of MP0250 in patients with solid tumours prompted further investigation in multiple myeloma (MM) as both MP0250 targets are reported to be drivers of MM pathogenesis. In this open-label, single-arm phase 1b/2 study (NCT03136653) in patients with proteasome inhibitor- and/or immunomodulatory drug-relapsed or refractory MM, MP0250 was administered every 3 weeks with standard bortezomib/dexamethasone regimen. Thirty-three patients received at least one dose of MP0250. The most frequent treatment-related adverse events were arterial hypertension (58.1%), thrombocytopenia (32.3%), proteinuria (29.0%) and peripheral oedema (19.4%). Of the 28 patients evaluable for response (median age: 60 [range 44-75]), nine achieved at least partial response, corresponding to an overall response rate of 32.1% (95% confidence interval [CI]: 17.9%, 50.7%), with a median duration of response of 8 months (95% CI 5-NR). An additional three patients achieved minimal response and nine stable diseases as the best overall response. Overall median progression-free survival was 4.2 months (95% CI 1.9-7.1). These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Isatuximab is an anti-CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma. Previous analyses of the IKEMA trial showed prolonged progression-free survival in patients with this disease who received isatuximab in combination with carfilzomib-dexamethasone as compared with those who received carfilzomib-dexamethasone alone. Herein, we report the analysis of overall survival from the IKEMA trial. METHODS: This prospective, randomised, open-label, active-controlled, phase 3 study included patients with relapsed or refractory multiple myeloma aged 18 years or older, who had received one to three previous lines of treatment from 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were randomly allocated (3:2) to treatment with either isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). In the isatuximab group, patients received intravenous isatuximab (10 mg/kg on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of subsequent 28-day cycles). In both treatment groups, intravenous carfilzomib (20 mg/m2 on days 1 and 2 of the first cycle; and 56 mg/m2 on days 8, 9, 15, and 16 of the first cycle, and days 1, 2, 8, 9, 15, and 16 of subsequent cycles) and intravenous or oral dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) were administered. The primary endpoint of the trial was progression-free survival, which was reported previously. Treatment continued until progression, unacceptable toxicity, or patient request to discontine. The overall survival analysis reported here was planned to be conducted 3 years after the primary progression-free survival analysis in the intention-to-treat population. Additional analyses were conducted on the secondary endpoints of time to next treatment and second-progression-free survival. Reported p values are non-inferential due to hierarchical testing. This trial is registered with ClinicalTrials.gov (NCT03275285). FINDINGS: Between Nov 15, 2017, and March 21, 2019, 302 patients were enrolled and randomly allocated: 179 (59%) to the isatuximab group and 123 (41%) to the control group. 169 (56%) patients were male, 133 (44%) were female, 214 (71%) were White, 50 (17%) were Asian, nine (3%) were Black or African American, and three (1%) were multiracial. At data cutoff for this overall survival analysis (Feb 7, 2023), 79 (44%) overall survival events in the isatuximab group and 59 (48%) in the control group had occurred (median follow-up 56·61 months [IQR 54·90-58·02]). Median overall survival (in months) was not reached (NR; 95% CI 52·17-NR) in the isatuximab group and was 50·60 months (38·93-NR) in the control group (hazard ratio [HR] 0·855 [95% CI 0·608-1·202], nominal one-sided p=0·18). Survival probability at 48 months was 59·7% (95% CI 52·0-66·7) in the isatuximab group and 52·2% (95% CI 42·7-60·8) in the control group (based on Kaplan-Meier analysis). Improvements in time to next treatment (HR 0·583 [95% CI 0·429-0·792], nominal one-sided p=0·0002) and second-progression-free survival (0·663 [0·491-0·895], nominal one-sided p=0·0035) were observed in the isatuximab group. The most common treatment-emergent adverse events were infusion reactions (82 [46%] patients in the isatuximab group and four [3%] in the control group) and upper respiratory tract infections (71 [40%] and 34 [28%], respectively). Discontinuations due to treatment-emergent adverse events were similar between treatment groups (24 [14%] in the isatuximab group and 22 [18%] in the control group), despite an additional 30 weeks of exposure in the isatuximab group. 12 (7%) patients in the isatuximab group and six (5%) patients in the control group had a treatment-related adverse event with a fatal outcome during study treatment. INTERPRETATION: At the time of the current analysis, a difference in overall survival could not be detected between the treatment groups, and no new safety signals were observed. Collectively, the evidence suggests that isatuximab plus carfilzomib-dexamethasone is a key treatment for patients with relapsed or refractory multiple myeloma. FUNDING: Sanofi.

• MeSH
• analýza přežití MeSH
• dexamethason * aplikace a dávkování   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   mortalita   MeSH
• mnohočetný myelom * farmakoterapie   mortalita   MeSH
• oligopeptidy * terapeutické užití   aplikace a dávkování   MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH