ABSTRACT
Background: The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. Method(s): This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the ECOG performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. The MRD was evaluated by next-generation flow (NGF) 10-6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method and PFS analysis were performed based on the different response rates. (Data cut-off was April 2022) Results: A total of 24 pts were included. The median age being 58 (range 37- 67 years), 15 (62.5%) pts were female, 22 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. By ITT analysis, 22 pts (91.6%) achieved (> PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10-6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p = 0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p = 0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27m. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Summary/Conclusion: The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome. Copyright © 2022
ABSTRACT
Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most availableinductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth andduration of the response. We hypothesized that the combination of Dara and CTd could be safe and allow deeper activityas an alternative protocol. Aims: The primary endpoint was to evaluate the VGPR after two consolidation cycles post-autologousstem cell transplantation (ASCT). Secondary endpoints were the overall response rate during alltreatment phases and minimal residual disease (MRD), based on the International Myeloma WorkingGroup (IMWG) criteria that includes the next-generation flow (NGF) by the EuroFlow®and PET-CTand the safety profile. Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TENDMM, creatinine clearance > 30 mL/min, normal cardiac, renal and liver function and the EasterCooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for upto four 28-day induction cycles: C-500 mg oral (PO) on days 1,8 and 15, T at 100-200 mg PO on days1 to 28, (d) at 40 mg PO on days 1,8,15 and 22 and Dara at 16 mg/kg/dose intravenous (IV) on days1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All ptsreceived up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16 mg/kg and (d) at 40 mg every other week, associated with T at 100 mg PO on days 1 - 28. Dara at 16 mg/kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used forstem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. All pts receivedantiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Results: The first pts was enrolled in November 2018. A total of 21 pts were included, the median age being 56 (range 37– 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completedinduction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilizationfailure was observed, and five (26%) pts needed plerixafor use. In an intention to treatment analysis, after the end ofinduction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity byNGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 12(70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PETCTnegativity. Three pts died from infection, one before transplant because of Covid infection, on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological adverse events (AEs) grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: This is the first study that combined Dara with CTd as induction for TE NDMM pts. This presentdata has shown that the association of Dara-CTd achieved the primary end point once > 90% of the pts achieved VGPRafter two consolidations cycles, and safety profile was acceptable. Clinical trial information: NCT03792620.
ABSTRACT
Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that Dara and CTd combination could be safe and allow deeper activity as an alternative protocol. Aims: The aims of this analysis were to evaluate Progression Free Survival (PFS) of Dara-CTd treatment and minimal residual disease (MRD) after one year of Dara maintenance. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. The MRD was evaluated by next-generation flow (NGF) based and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Data cut-off was June 15, 2021. Results: The first pts was enrolled in November 2018. A total of 24 pts were included, the median age being 60 (range 37- 67 years), 23 (92%) were non-white, 5 (21%) had an R-ISS = 1, 12 (54%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Six (25%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 20 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis after a median follow up of 20 months the PFS at 12 and 18 months was 86%. No PFS difference was observed between different subgroups. Regarding response rates, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 13 (76%) obtained MRD negativity by NGF and 10 (58%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Six pts completed one year of maintenance and five of them (83%) still MRD negativity by NGF. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Two pts have discontinued treatment due to progression - 1 before ASCT e 1 during maintenance. The most common adverse events (AEs) grades 3 and 4 were neutropenia (n = 12), infusion reaction (n = 7), neuropathy (n = 6), lymphopenia (n = 4), infection (n = 3), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: The Daratumumab - CTd protocol is an active regimen capable of producing deep and sustainable responses and improve the PFS of NDMM TE pts with a favorable safety profile. Clinical trial information: NCT03792620. Disclosures: De Queiroz Crusoe: Janssen: Research Fund ng. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel;Takeda: Honoraria;Abbvie: Honoraria;Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel.
ABSTRACT
Patients with multiple myeloma (MM) have an increased risk for severe infections due to both the disease and anti-myeloma therapies. During the COVID-19 pandemic, case series of MM patients have demonstrated a poor outcome in those who required hospitalization due to COVID-19, and there are few data regarding those managed out of hospitals or risk factors for hospitalization. In Brazil, where the scenario is of restricted resources to treat MM patients and large numbers of COVID-19 cases and related death, the outcome can be even worse. Objective: To assess risk factors and outcomes of COVID-19 in Brazilian patients with MM. This retrospective case series investigated 81 MM patients with documented COVID-19, managed in and out-hospital, from 8 states, representing 4 of 5 regions in Brazil. This study has been conducted by “Grupo Brasileiro de Mieloma” (GBRAM), and the present analyses included cases from April 2020 to July 2021. Clinical features and risk factors were analyzed with the severity of COVID-19 and outcomes (hospital admissions, intensive care unit (ICU) admission, ventilatory support, and death). The frequency of MM treatment modification due to COVID-19 was also accessed. There were 81 MM patients (male 50%;median age 63 years;and ISS III at diagnosis 25%) diagnosed with COVID-19. At least one comorbidity was present in 47 (58%) patients: most frequently hypertension and diabetes (56% and 27%). Twenty-eight (35%) patients had more than one comorbidity. At COVID episode, 21 (26%) patients had an active disease or progression disease, and 40% received at least two prior lines of treatment. COVID-19 management required hospitalization in 49 (61%), ventilatory support in 30 (40%) and ICU in 28 (35%). Hospitalization was associated with age (p=0.008), presence of comorbidity (p=0.02), hypertension (p=0.02), presence of fever (p=0.005) and low respiratory symptoms (p=0.003). Ventilatory support was more frequent in patients with cardiac disease (p=0.05), receiving immunomodulatory (p=0.03), or monoclonal drugs (p=0.006). Patients receiving corticosteroids (p=0.02), immunomodulatory (p=0.06), or monoclonal drugs (p=0.06) in MM treatment had a higher frequency of ICU admission. By adjusted multivariate analysis, age, the clinical presentation with fever and low respiratory symptoms (p<0.001, p=0.05 and p=0.001, respectively) were independent associated with hospitalization;low respiratory symptoms and MM therapy including monoclonal drugs (p=0.07 and p=0.02) were associated with ventilatory support;therapy with corticosteroids and immunomodulatory drugs (p=0.019 and p=0.05) were associated with ICU admission. Overall mortality was 29%. Mortality rates were 47%, 68%, and 77% in hospitalized, ventilatory support, and ICU patients, respectively. By univariate analysis, age, ECOG performance status, and MM therapy including corticosteroids, were associated with increased mortality. By multivariate model, only ECOG performance status remained as an independent risk factor for death. ISS, prior lines of therapy, prior stem cell transplantation, and disease status at COVID-19 were not associated with any analyzed outcomes. MM patients who recovered from COVID had the current MM treatment delayed in 61% of cases. In this series, COVID-19 MM patients had a very high frequency of hospitalization, ventilatory support requirement, ICU admission, and deaths due to COVID-19. Although not associated with increased mortality, prior therapy drug classes were associated with severity of manifestation in our series. We also observed a high frequency of MM treatment delay in recovered patients, and the post-COVID clinical impact should be more explored. The high mortality observed reinforces the importance of preventing COVID-19, such as social distancing, wearing masks, and vaccination. Disclosures: De Queiroz Crusoe: Janssen: Research Funding. Hungria: Takeda: Honoraria;Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/tr vel;Abbvie: Honoraria;Sanofi: Honoraria, Other: Support for attending meetings/travel.
ABSTRACT
Background: Newly drugs access for MM treatment still a challenge. One of the available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)- (CTd). We hypothesized that the Daratumumab and CTd combo could be safe and allow deeper activity as an alternative protocol. Primary endpoint was to evaluate the VGPR after two consolidation cycles post-ASCT. Secondary endpoints were the ORR during all treatment phases and MRD, based on the IMWG criteria that includes the NGF by the EuroFlow® and PET-CT and the safety profile Method: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, CrCl > 30 ml/min, normal cardiac, renal and liver function and the ECOG performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg PO on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose IV- QW during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor if needed. All pts received anti(viral, pneumocystis and thrombotic) prophylaxis. Results: A total of 21 pts were included, the median age being 56 (range 37 – 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had HR [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and five (26%) pts needed plerixafor use. In an ITT analysis, after the end of induction (cycle 4), 19 (90%) of the pts obtained?> PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained?> VGPR, 12 (70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Three pts died from infection, one before transplant because of Covid, one on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological AEs grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). Conclusion: This is the first study that combined Dara with CTd as induction for TE NDMM pts. This present data has shown that the association of Dara-CTd achieved the primary end point once > 90% of the pts achieved VGPR after two consolidations cycles, and safety profile was acceptable. Clinical trial information: NCT03792620.
ABSTRACT
Background: High-risk smoldering multiple myeloma (HR-SMM) is associated with a greater risk of progression to symptomatic disease, suggesting the need for early, efficacious therapeutic interventions to improve outcomes. The ongoing, randomized Phase 3 ITHACA study (NCT04270409) is evaluating efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with lenalidomide (R) and dexamethasone (d) (Isa-Rd) vs Rd in patients (pts) with HR-SMM. We report here preliminary results from the safety run-in part of this trial. Methods: The primary objective was to confirm the recommended dose of Isa in combination with Rd. Pts were eligible if diagnosed with SMM within 5 years and HR-SMM defined by the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Minimal residual disease and imaging by MRI and low-dose whole-body CT/PET-CT will be assessed at fixed time points. Results: As of April 12, 2021, 23 pts (median age, 63 [28–85] years;median time from initial diagnosis, 1.14 [0.1–5.2] years) had received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd. The median number of cycles was 7 (range, 4–10) and median duration of treatment exposure was 29.7 (range, 16.0–38.0) weeks. Two pts met the Mayo clinical model criteria, 13 pts the PETHEMA model criteria, and 8 pts both models’ criteria for HR-SMM. No pt presented with focal lesions at baseline. Seven (30.4%) pts developed 8 grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs): COVID-19 pneumonia, insomnia (2 each), papular rash, muscle spasm, retinal detachment and hyperglycemia (1 each);no pt experienced a grade 5 TEAE and no pt discontinued treatment due to a TEAE. Serious TEAEs were COVID-19 pneumonia (n=2, grade ≥3) and pneumonia, musculoskeletal chest pain and pyrexia (n=1 each, grade <3). The most common, mostly grade 1–2 TEAEs were insomnia (39%) and constipation, headache, and peripheral edema (22% each). Infusion reactions were reported in 2 pts (8.7%) (grade 2, infusion day 1/cycle 1). By laboratory results, no grade 3–4 anemia or thrombocytopenia was observed;grade 3 neutropenia was reported in 5 pts (21.7%), with no grade 4. Isa exposure and CD38 receptor occupancy were in accordance with other MM studies, reaching target saturation in bone marrow plasma cells. The overall response rate was 86.9%;21.7%, 17.4%, and 4.3% of pts have so far achieved very good partial response (VGPR), complete response (CR) and stringent CR (sCR), respectively. Conclusions: Addition of Isa 10 mg/kg QW-Q2W to Rd was associated with a favorable safety profile in pts with HR-SMM, which compares well with Rd literature data in the same patient population. Isa-Rd has shown encouraging preliminary efficacy (21.7% sCR/CR and 43.4% ≥VGPR rates) in pts with HR-SMM. These results confirm the recommended dose of Isa for the randomized part of the Phase 3 ITHACA study, which will further evaluate efficacy and safety of Isa-Rd in HR-SMM. Funding: Sanofi.
ABSTRACT
Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)- (CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that the combination of Dara and CTd could be safe and allow deeper activity as an alternative protocol. Aims: The primary endpoint was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Secondary endpoints were the overall response rate during all treatment phases and minimal residual disease (MRD), based on the International Myeloma Working Group (IMWG) criteria that includes the next-generation flow (NGF) by the EuroFlow. and PET-CT and the safety profile. Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance ≥ 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Results: The first pts was enrolled in November 2018. A total of 21 pts were included, the median age being 56 (range 37 - 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and five (26%) pts needed plerixafor use. In an intention to treatment analysis, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained ≥VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained ≥ VGPR as best response, 12 (70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Three pts died from infection, one before transplant because of Covid infection, on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological adverse events (AEs) grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: This is the first study that combined Dara with CTd as induction for TE NDMM pts. This present data has shown that the association of Dara-CTd achieved the primary end point once ≥ 90% of the pts achieved VGPR after two consolidations cycles, and safety profile was acceptable. Clinical trial information: NCT03792620.