A real-life study of daratumumab combinations in newly diagnosed patients with light chain (AL) amyloidosis.

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.

Immunomodulator adherence in multiple myeloma patients with lower socioeconomic status: a retrospective study.

OBJECTIVE: Poor adherence to oral chemotherapy adversely impacts clinical outcomes and escalates overall healthcare costs. Despite barriers to medication adherence, a significant gap remains in assessing adherence to oral chemotherapy among multiple myeloma (MM) patients with lower socioeconomic status. Hence, our study aims to evaluate immunomodulator adherence in MM patients at a county hospital, primarily serving underrepresented and indigent individuals with low socioeconomic status across the greater Houston area. METHODS: Inclusion criteria composed of patients diagnosed with MM, aged at least 18 years, and treated with lenalidomide or pomalidomide-two widely used immunomodulators-for a minimum of 2 months or having two or more records of dispensation between May 2019 and May 2021. Adherence was gauged using an adjusted version of the medication possession ratio (MPR). RESULTS: Sixty-two patients were enrolled, yielding a mean MPR value of 88% (SD, ± 18.9). Of these, 43 patients (69.3%) demonstrated adherence with an MPR of ≥ 0.90. A significant difference was found in treatment duration between the adherent (mean 8.8 months; SD, ± 7.2) and non-adherent (mean 13.4 months; SD, ± 7.9) groups (p = 0.027). Notably, race/ethnicity demonstrated a significant difference (p = 0.048), driven by disparities in African American and Hispanic representation across adherence levels. CONCLUSION: In summary, our findings highlight race and treatment duration to be predictors of immunomodulator adherence among MM patients with lower socioeconomic status. Further research is imperative to devise and test innovative interventions aimed at enhancing medication adherence, thereby contributing to improved survival and healthcare quality in this population.

The role of upfront lenalidomide maintenance for primary central nervous system lymphoma following first-line methotrexate treatment: A retrospective study.

BACKGROUND: Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single-center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly-diagnosed PCNSL. METHODS: Sixty-nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. RESULTS: After a median follow-up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression-free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. CONCLUSIONS: The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory.

Target trial emulation of carfilzomib safety among patients with relapsed/refractory multiple myeloma using a nationwide observational data in Korea.

PURPOSE: Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib's safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database. METHODS: The retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial. RESULTS: This study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24-3.35], hypertension [HR 1.58; 95% CI 1.15-2.17]) had the highest risk in the KRd group. CONCLUSION: The safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.

Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant.

We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10-5 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT® system and liquid chromatography-mass spectrometry (LC-MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10-5 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10-6 MRD negative rate improved with treatment beyond C8. Agreement between EXENT® and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3-4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial.

BACKGROUND: Isatuximab is a CD38 monoclonal antibody approved for relapsed or refractory multiple myeloma. We aimed to evaluate the addition of isatuximab to weekly carfilzomib (K), lenalidomide (R), and dexamethasone (d; Isa-KRd) in transplant-eligible patients with newly diagnosed multiple myeloma and stratified maintenance by cytogenetic risk. METHODS: This single-arm phase 2 trial was done at three cancer centres (two hospitals and a cancer institute) in Boston (MA, USA). Eligible patients were aged at least 18 years and had transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 2 or less. Patients received four 28-day cycles of Isa-KRd, including isatuximab 10 mg/kg intravenously weekly for 8 weeks, then every other week for 16 weeks, and every 4 weeks thereafter; carfilzomib 56 mg/m2 intravenously on days 1, 8, and 15 (20 mg/m2 for cycle 1 day 1); lenalidomide 25 mg orally on days 1-21; and dexamethasone 20 mg orally the day of and day after all doses of carfilzomib and isatuximab. Consolidation involved either upfront haematopoietic stem-cell transplantation (HSCT) with two additional cycles or deferred HSCT with four additional cycles of treatment. The primary endpoint was complete response after four cycles of treatment. Analyses were by intention-to-treat. All patients who received one dose of study drug were included in the safety analyses. This study was registered at ClinicalTrials.gov, NCT04430894, and has completed enrolment. FINDINGS: Between July 31, 2020 and Jan 31, 2022, 50 patients were enrolled. Median age was 59 years (range 40-70), 54% (27 of 50 patients) were male, and 44 (88%) were White. 46% (23 of 50) of patients had high-risk cytogenetics. Median follow-up was 26 months (IQR 20·7-30·1). 32% (16 of 50 patients) achieved a complete response after four cycles. The overall response rate (ORR) was 90% (45 patients) and 78% (39 patients) achieved a very good partial response (VGPR) or better. After completion of consolidation, 58% (29 patients) achieved a complete response; the ORR was 90% (45 patients) and 86% (43 patients) achieved a VGPR or better. The most common grade 3 or 4 side-effects (≥two patients) included neutropenia (13 [26%] of 50 patients), elevated alanine aminotransferase (six [12%] patients), fatigue (three [6%] patients), thrombocytopenia (three [6%] patients), acute kidney injury (two [4%] patients), anaemia (two [4%] patients), and febrile neutropenia (two [4%] patients). Grade 1-2 infusion-related reactions were seen in 20% (ten patients), with none grade 3. Grade 1-2 hypertension was seen in 14% (seven patients) with one grade 3 (one [2%] patient). There were two deaths assessed as unrelated to treatment. INTERPRETATION: Although the study did not achieve the prespecified complete response threshold, Isa-KRd induced deep and durable responses in transplant-eligible patients with newly diagnosed multiple myeloma. The treatment proved safe and consistent with similar regimens in this setting. FUNDING: Amgen, Sanofi, and Adaptive.

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for Bruton's tyrosine kinase inhibitors (BTKis) single and its combination therapy.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. RESEARCH DESIGN AND METHODS: The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. RESULTS: We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47-10.32)) in zanubrutinib and rash (6.97 (5.42-8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11-7.70)), atrial fibrillation (27.96 (22.61-34.58)) and myelosuppression (10.09 (8.89-11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57-6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18-2.87) vs 3.60 (3.52-3.68)). CONCLUSIONS: The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.

Lenalidomide, rituximab (R2), and ixazomib for frontline treatment of high risk follicular and indolent non-Hodgkin lymphoma.

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis.

BACKGROUND: Advancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. METHODS: This was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. RESULTS: Forty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. CONCLUSION: The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FUNDING: The funders had no role in the study.

Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta-analysis.

Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta-analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24-4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient-level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta-analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM.

ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma.

ABSTRACT: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

Phase 1b dose-finding study of rituximab, lenalidomide, and ibrutinib (R2I) in patients with relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n = 25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1-21) and ibrutinib 560 mg (days 1-28) of 28-day cycles. The MTD for lenalidomide was 20 mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92 months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67 > 30%). R2I was safe and tolerable in patients with R/R MCL.