Editor’s Note: Currently, the highly anticipated 65th American Society of Hematology (ASH) Annual Meeting is underway in San Diego, USA. In the face of the annual pinnacle event in the field of hematologic malignancies, the front-line reporting team of “Hematology Frontier” delves deep, capturing the international cutting-edge developments and witnessing the outstanding performance of “China’s good voice” on the global stage. In the realm of Multiple Myeloma (MM), advancements in targeted therapy and cell immunotherapy continue to dominate, making it imperative to comprehensively grasp the therapeutic progress at this year’s ASH conference. “Hematology Frontier” had the privilege of interviewing Professor An Gang from the Hematology Hospital of the Chinese Academy of Medical Sciences, who brilliantly dissected the progress in MM.
Overview of MM Progress at ASH Conference
Professor An Gang: Multiple Myeloma (MM) remains a focal point in hematologic malignancy research, with significant progress in the past two years. However, this year’s advancements are relatively fewer, primarily supplementing previous research or focusing on mechanistic studies. Overall, immunotherapy continues to take center stage in MM research, encompassing monoclonal antibodies, bispecific antibodies, and CAR-T therapy. It’s noteworthy that the ASH conference this year showcased notable progress in the research of bispecific antibodies. I will now analyze three clinically significant studies that left a lasting impression:
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Phase 3 Randomized Study of Daratumumab(DARA)+Bortezomib,Lenalidomide,and Dexamethasone(VRd)Versus Vrd Alone in Patients(Pts)with Newly Diagnosed Multiple Myeloma(NDMM)Who Are Eligible for Autologous Stem Cell Transplantation(ASCT):Primary Results of the Perseus Trial
Introduction: DARA plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy has shown clinical benefit versus VTd alone and is approved for transplant-eligible pts with NDMM. VRd induction followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide (R) maintenance is also considered a standard of care for transplant-eligible NDMM. In the phase 2 GRIFFIN study, intravenous DARA combined with VRd (D-VRd) induction/consolidation followed by D-R maintenance improved depth of response and progression-free survival (PFS) versus VRd induction/consolidation and R maintenance in transplant-eligible pts with NDMM after >4 years of follow-up. The phase 3 PERSEUS study is evaluating subcutaneous DARA (DARA SC) in combination with VRd induction/consolidation followed by D-R maintenance versus VRd induction/consolidation and R maintenance in transplant-eligible NDMM. Here we report the primary analysis of PERSEUS.
Methods: Pts with NDMM who were aged 18-70 years and eligible for high-dose therapy and ASCT were randomized 1:1 to D-VRd or VRd, stratified by International Staging System (ISS) stage and cytogenetic risk. All pts received up to six 28-day cycles (4 pre-ASCT induction, 2 post-ASCT consolidation) of VRd (V: 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R: 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance therapy (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks during maintenance until PD. The primary endpoint is PFS; key secondary endpoints include overall complete response or better (≥CR) rate, overall minimal residual disease (MRD)–negativity rate (10–5 threshold; clonoSEQ®), and overall survival. Response and disease progression were assessed using a computerized algorithm based on IMWG response criteria. Overall MRD–negativity rate was defined as the proportion of pts who achieved MRD negativity and ≥CR at any time.
Results: 709 pts were randomized (D-VRd, n=355; VRd, n=354). Median (range) age was 60 (31-70) years; 14.8% had ISS stage III disease, and 21.7% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]). At clinical cutoff, 314 pts in the D-VRd arm and 299 pts in the VRd arm had completed all 4 induction and 2 consolidation cycles, 309 and 294 pts had undergone ASCT, and 322 and 300 pts entered maintenance. At a median follow-up of 47.5 months, PFS was significantly improved with D-VRd versus VRd (HR, 0.42; 95% CI, 0.30-0.59; P <0.0001 [crossing the prespecified stopping boundary of 0.0126]; Figure). Median PFS was not reached in either arm; estimated 48-month PFS rates were 84.3% for D-VRd versus 67.7% for VRd. Prespecified subgroup analyses showed a consistent PFS improvement with D-VRd versus VRd across clinically relevant subgroups, including pts with ISS stage III disease and pts with high cytogenetic risk. Overall rates of ≥CR (87.9% vs 70.1%; P <0.0001) and MRD negativity (75.2% vs 47.5%; P <0.0001) were significantly higher with D-VRd versus VRd. Overall survival was immature, with 78 deaths on study (D-VRd, 34 [9.6%]; VRd, 44 [12.4%]). Overall, 7 deaths due to COVID-19 occurred (D-VRd, 4; VRd, 3). The most frequent (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) for the D-VRd/VRd arms were neutropenia (62.1%/51.0%), thrombocytopenia (29.1%/17.3%), diarrhea (10.5%/7.8%), pneumonia (10.5%/6.1%), and febrile neutropenia (9.4%/10.1%). For D-VRd and VRd, serious TEAEs occurred in 57.0% versus 49.3% of pts, and TEAEs leading to treatment discontinuation occurred in 8.8% versus 21.3% of pts.
Conclusions: DARA SC combined with VRd in transplant-eligible pts with NDMM significantly improved PFS and increased depth of response (≥CR and MRD negativity), with consistent PFS benefit across clinically relevant subgroups. The safety profile was consistent with the known safety profiles for DARA SC and VRd. These data, together with results from the phase 2 GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet DARA plus VRd followed by D-R maintenance versus triplet VRd followed by R maintenance and support the combination of DARA plus VRd followed by D-R maintenance as a new standard of care for transplant-eligible NDMM.
Expert Commentary:
In this year’s LBA-1 study, the application of Daratumumab in combination with the VRD regimen (Bortezomib/Lenalidomide/Dexamethasone) as a first-line treatment for transplant-eligible multiple myeloma patients builds upon the Phase II GRIFFIN study. The Phase III results reveal that the Daratumumab+VRD regimen achieves remarkable efficacy in newly diagnosed multiple myeloma (NDMM) patients eligible for transplantation. The publication of these study findings is poised to propel Daratumumab into the forefront of first-line treatments for MM.
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Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04
Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) evaluated an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577).
Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Treatment strategy included Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance for 2 years. The primary endpoint was the feasibility of this intensive strategy.
Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers. Median age was 57 (range 38 -65). Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10, 20%). Four (8%) patients had extramedullary disease. At data cut-off, the study met the primary endpoint with 36 (72%) patients completing second transplant. Twenty-one patients (42%) discontinued the study, due to stem-cell collection failure (n=8), disease progression (n=8), adverse event (n=4), consent withdrawal (n=1). Grade 3-4 Dara-KRD induction/consolidation related adverse event (>5% of patients) were neutropenia (44%), anemia (22%), thrombocytopenia (24%) and infection (14%). Four patients discontinued treatment due to severe adverse event (COVID-19 infection, drug-induced hepatitis, JC virus related encephalopathy, intracerebral hemorrhage). Seven patients died, 5 due to disease progression and 2 due to infection. Responses deepened over time with an overall response rate before maintenance of 100%, including 81 % complete response. Among evaluable patients (33/36), pre maintenance Minimal Residual Disease negativity rate (NGS, 10-6) was 94%. After a median follow up of 32 months, the 24-months PFS is 87% (78-87%) and the 24-months OS is 94% (87-100%).
Conclusions: Dara-KRD induction/consolidation with tandem transplant was feasible in TE NDMM patients with high-risk cytogenetic profile, and resulted in high MRD negativity rate and high progression free survival.
Expert Commentary:
In the IFM-2018-04 study led by Professor Cyrille Touzeau and team (abstract 207), the application of Daratumumab in combination with the KRD regimen (Carfilzomib/Lenalidomide/Dexamethasone) plus tandem autologous stem cell transplantation (ASCT) was explored as a treatment for transplant-eligible high-risk, newly diagnosed multiple myeloma (HR-NDMM) patients. High-risk was defined as del17p, t(4;14), and/or t(14;16). The study results demonstrate an overall response rate (ORR) of 100% post-treatment, with 94% of patients achieving minimal residual disease (MRD) negativity. Achieving MRD negativity is crucial for HR-NDMM patients, making this regimen highly valuable for high-risk individuals.
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Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma
Background: Teclistamab is a B-cell maturation antigen (BCMA) targeting bispecific T-cell engager approved in October of 2022 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) based on the results of the pivotal MajesTEC-1 trial. In this multicenter retrospective study, we evaluated the real-world safety and efficacy of teclistamab, highlighting patterns of utilization and outcomes, including patients who would have been considered ineligible for MajesTEC-1 trial.
Methods: Five U.S. academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC), contributed data to this retrospective analysis, which included 102 patients with RRMM who received teclistamab as of 7/1/2023. Baseline characteristics were outlined by descriptive analysis. Teclistamab was administered in a step-up dosing manner as per the package insert. All patients had received at least the two step up doses and the first full dose of teclistamab. Patients received antimicrobial prophylaxis, supportive care, and toxicity management per institutional protocols. Responses to therapy including overall response rate (ORR), very good partial response (VGPR), and complete response or better (≥CR) were evaluated using the International Myeloma Working group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. The Kaplan-Meier method was used for progression free survival (PFS), duration of response (DOR), and overall survival (OS) calculation.
Results: Of the 102 patients included in this analysis, 25% were non-Hispanic Black and 44% had extramedullary disease (EMD); the median number of prior LOT was 6 (range 4–17). More than 80% (83/102) of the patients would not have met the MajesTEC-1 eligibility criteria; main reasons for ineligibility included: prior BCMA-directed therapy (BDT) (55%), ECOG performance status ≥2 (28%), and baseline cytopenias: grade 3-4 anemia (26%), and grade 3-4 thrombocytopenia (20%). All patients were triple class exposed and 92% were triple class refractory, 78% were penta-class exposed and 67% were penta-class refractory. More than half of the patients (55%) were refractory to prior BDT. Baseline characteristics are summarized in Table 1. Cytokine release syndrome (CRS) was observed in 65% of patients, all of which, except one, were grade 1-2 events, while immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 15% of the patients, with three patients having grade 3-4 events. The most common grade 3-4 hematological toxicities were neutropenia (23%), leukopenia (18%), thrombocytopenia (17%), and anemia (17%). Infections occurred in 28% of the patients, half of which were characterized as severe. The vast majority (80%) of infections involved the respiratory tract and 7% of patients discontinued teclistamab permanently due to recurrent or severe infections. After a median follow up of 3.2 months, the ORR was 64% for the entire cohort; ORR was 57%, 66% and 45% for patients who were BDT-refractory, penta-refractory, or had EMD, respectively. Of those who did respond, responses were found to be deep (72% ≥VGPR; 45% ≥CR). Patients that would have been ineligible for the MajesTEC-1 trial had an ORR of 59%. Detailed responses for the groups of interest are reported separately in Table 1. The estimated 6-month PFS, DOR, and OS of the entire cohort were 38% (95% CI, 26-56), 54% (95% CI, 34-85) and 68% (95% CI, 58-80), respectively (Figure 1). No treatment-related mortality was observed, although 26% of the patients had died at the time of data cut-off, with 89% of the deaths attributed to disease progression.
Conclusion: This is the largest real-world experience of the safety and efficacy of teclistamab for RRMM. Overall, teclistamab was well tolerated with no major safety concerns, despite worse performance status and cytopenias than the MajestTEC-1 trial population. Moreover, despite the increased incidence of high-risk features, including penta-refractoriness, BDT refractoriness, and presence of EMD in this heavily pre-treated RRMM patient population, early efficacy assessment of teclistamab in a real-world setting was encouraging.
Expert Commentary:
In a real-world study (abstract 91), five clinical research centers in the United States enrolled 102 heavily treated refractory/relapsed multiple myeloma patients (RRMM) for treatment with the BCMA/CD3 bispecific antibody Teclistamab. The results revealed an objective response rate (ORR) of 59%. It is noteworthy that this study demonstrates the efficacy of Teclistamab in a real-world setting with highly refractory patients, making the outcomes particularly encouraging.
In summary, immunotherapy stands as the most crucial direction for future multiple myeloma research, currently being a hot topic in the field. Further exploration of immunotherapy resistance mechanisms can contribute to enhancing its effectiveness.
Professor An Gang
Chinese Academy of Medical Sciences Hematology Hospital (Institute of Hematology)
National Clinical Research Center for Hematologic Diseases
State Key Laboratory of Experimental Hematology
Ph.D., Chief Physician, Associate Professor, Doctoral Supervisor
State Key Laboratory of Experimental Hematology Level II PI
Young Director of the Chinese Anti-Cancer Association
Deputy Director of the Second Youth Committee of the Hematologic Tumor Committee of the Chinese Anti-Cancer Association
Member of the 11th Youth Committee of the Hematology Branch of the Chinese Medical Association
Member of the Hematological Disease Transformation Committee of the Chinese Anti-Cancer Association
Member of the Tumor Nephrology Committee of the Chinese Anti-Cancer Association
Member and Secretary of the China Multiple Myeloma Research Alliance
Member of the Elderly Tumor Professional Committee of the Tianjin Anti-Cancer Association
Member of the Tianjin Genetic Counseling Committee
Graduated from Shandong Medical University in 2003; obtained master’s and doctoral degrees from Peking Union Medical College from 2006 to 2011; Postdoctoral fellow at Harvard University’s Dana-Farber Cancer Institute from November 2013 to June 2016. Published over 20 SCI papers as the first author or corresponding author in journals such as Blood, Leukemia, Clinical Cancer Research, Haematologica, Blood Advances, The Journal for ImmunoTherapy, etc. Edited one monograph “Difficult Cases in Internal Medicine – Hematology Volume” (People’s Medical Publishing House); Deputy translator of “Williams Hematology Handbook 9th-10th Edition”; Principal investigator for 4 National Natural Science Foundation projects. Received the 2020 Chinese Cancer Youth Scientist Award; First-level talent in Tianjin’s “131” Innovative Talent Cultivation Project; Young medical talent in Tianjin Health and Family Planning Industry High-level Talent Selection and Training Project.
