María-Victoria Mateos, MD, PhD, Borja Puertas MD and Veronica González-Calle MD, PhD
Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Biología Molecular y Celular del Cáncer (Universidad de Salamanca-Consejo Superior de Investigaciones Científicas), CIBERONC, Salamanca, Spain
In 2021, the annual congress of the European Hematology Association (EHA) was again held in a virtual format due to restrictions arising from the COVID-19 pandemic. Despite the challenges involved in delivering an interactive meeting, a full program dedicated to clinical research and practice, and basic and translational research in hematology were provided for access by attendees worldwide.
Multiple myeloma (MM), featured as a highlight of the Late-Breaking Abstracts session, was the updated results of the phase 3 MAIA trial, in which daratumumab plus lenalidomide and dexamethasone (DRd) was confirmed as superior in survival benefit over lenalidomide and dexamethasone (Rd) in patients with newly-diagnosed MM (NDMM) and ineligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).1 According to the prespecified interim analysis, estimated five-year overall survival (OS) rates were 66.3% vs 53.1%, respectively (HR, 0.68; 95% CI, 0.53-0.86; P = .0013). Median progression free survival (PFS) for DRd had not yet been reached vs 34.4 months with Rd; it is expected to reach around 60 months, the longest, so far reported for transplant-ineligible NDMM patients, supporting its use as the control arm regimen in upcoming phase 3 trials.
If PFS remains the required primary endpoint of these trials, however, new combinations will take many years to demonstrate superiority and so new surrogate markers are needed. At EHA 2021, the prognostic value of undetectable measurable residual disease (MRD) was once again confirmed in MM. Quantitative immunoprecipitation mass spectrometry (QIP-MS) was shown to have higher sensitivity than conventional serum protein electrophoresis and immunofixation (SPEP/IFE) and is complementary to MRD evaluation, according to results reported from the GEM2012MENOS65 trial GEM2012MENOS65 trial in transplant-eligible NDMM patients.2 Both methods were in agreement (MRD+/MS+ and MRD-/MS-) in around 80% of cases post induction with bortezomib, lenalidomide, and dexamethasone (VRd), post-transplant, and post-consolidation with VRd and, of note, the prognostic value of each technique in terms of PFS was consistent at all time-points.
Other MM highlights included encouraging data in transplant-eligible NDMM focused on the unmet medical need for treatment in patients with high-risk cytogenetic abnormalities (HRCA). In the CARDAMON trial, PFS outcomes with ASCT were comparable to those with carfilzomib, cyclophosphamide and dexamethasone (KCd) as induction and consolidation. In patients with HRCA, however, ASCT median PFS was 4.7 years vs 1.2 years on the consolidation atm. Thus, transplant is still necessary in HRCA patients, but skipping transplant might be feasible in patients at standard risk and undetectable MRD. These data were consistent with a subgroup analysis of the FORTE trial presented in EHA 2021 which demonstrated PFS and sustained MRD-negativity in patients with HRCA who received upfront transplant, especially, in the KRd.4 The update of the phase 2 GMMM-CONCEPT trial focused on NDMM with HR features treated with isatuximab plus KRd as part of induction, consolidation, and maintenance and including ASCT, if eligible, and showed encouraging results: all patients responded; MRD after induction was undetectable in 61%; and after a median follow-up of 25 months 75% remained alive and progression-free.5 Myeloma UK investigators reported preliminary efficacy data from the MUKnine OPTIMUM trial, conducted in NDMM patients at ultra high-risk MM, based on the presence of double-hit genetics or gene expression SKY92 profiling. Treatment consisted of 6 cycles of daratumumab, bortezomib, lenalidomide, cyclophosphamide, and dexamethasone (Dara-CVRd) followed by augmented high-dose melphalan (HDMEL) and bortezomib-augmented ASCT, then Dara-VRd consolidation and Dara-R maintenance.6 On day 100-120 post-ASCT, the overall response rate (ORR) was 93% and MRD 82%.
Maintenance after transplant and its optimal duration has again come under debate following presentation of results of the CASSIOPEIA trial. Our concerns about these data are first, the control arm was observation and the experimental arm included D for two years. Second, the outcome was similar to patients treated with D-VTd as induction and consolidation with or without maintenance, and also to those treated with VTd as induction and consolidation with D maintenance. We consider that longer follow-up is required and maintenance is necessary to maintain the response achieved. The deepest the response, the better the outcome; indeed D-VTd followed by maintenance with D resulted in the highest CR rate (76.4%) and undetectable MRD rate (64.2%) (7). New options are under evaluation like DR8 or KR4 with promising data. For treatment of relapse after 1 to 3 prior lines of therapy, subgroup analyses of phase 3 trials were presented, In the ICARIA-MM trial a notable trend in OS benefit was reported for isatuximab plus pomalidomide and low-dose dexamethasone (Isa-Pd) compared with Pd alone (24.6 vs 17.7 months, respectively) .9
Finally, presentations at EHA 2021 continued the big success story that emerged several years ago with the introduction of engineered B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. The pivotal KarMMa trial has been updated, showing that the OR rate of 73% with idecabtagene vicleucel (ide-cel) reported after median follow up of 13.3 months10 was maintained at median follow-up of 15.4 months, regardless of the number of prior lines of therapy, although the complete response rate (CRR) was of 53% in patients who had received 3 prior lines of therapy compared with 30% in those who had received ≥4.11 Median OS was 24.8 months for all patients and consistent in patients after 3 or ≥4 prior lines, patients age ≥65 years, and patients with extramedullary or triple refractory disease. The CARTITUDE-1 trial also had updated results for 97 patients treated with ciltacabtagene autoleucel (cilta-cel) ORR was 97.9%, with 80.4% achieving a stringent CR.12 The median PFS is not yet mature, but 66% of patients remained alive and progression-free at 18 months. Of note, no new safety signals were reported, and the late neurotoxicity initially reported was controlled with some strategies, including the use of more potent bridging therapy, close monitoring, and aggressive management of cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS).13 In addition, cilta-cel showed promising efficacy and safety data in 20 patients treated after only 1-3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug) and who were lenalidomide refractory (CARTITUDE-2).14
Studies with other CAR-T cell therapies were presented, including CT103A, a fully human BCMA CAR-T15 and GC012F, a dual BCMA and CD19 targeting CAR-T,+16 with promising data for efficacy, safety, and duration of persistence. Preliminary results of IMMUNICY-1, showed acceptable safety of CYAD-211, a non-gene edited allogeneic CAR T candidate engineered to co-express a BCMA-targeting CAR and a single hairpin RNA (shRNA). Of 5 evaluable patients dosed at the first two levels, 2 (each with 3 prior lines of therapy) achieved a PR and 3 additional patients had stable disease.17 The efficacy of BCMA bispecific antibodies was also confirmed through updated data for teclistamab and elranatamab, which target BCMA and CD3.18,19 These agents, in subcutaneous and weekly administration and at the recommended phase 2 dose, resulted in ORR of 65% and 75, respectively, each with a manageable toxicity profile.
Overall, EHA 2021 confirmed how proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies are moving to the first line of therapy and how BCMA-targeted therapies cover the previously unmet medical need for triple-drug class exposed patients. Although we have other possibilities, BCMA-targeted therapies must move to earlier treatment if we want to continue the fight against, and build a curative platform for MM.
Dr. María-Victoria Mateos, MD, PhD, is Consultant Physician in the Haematology Department and Associate Professor of Medicine at the University of Salamanca, Spain. She is the director of the Myeloma Program and coordinates the Clinical Trials Unit. She serves as coordinator of GEM (Spanish Myeloma Group), with direct involvement in the design and development of clinical trials. She has coordinated many clinical trials, especially in the setting of transplant ineligible and smoldering myeloma; these trials have profoundly influenced current options for the management of these patient populations. She has published over 300 papers in international journals with an h-index of 79 and 60 since 2015. She is also a member of the IMWG (International MM Working Group), IMS (International MM Society), EHA and ASH. She has served on the ASH Scientific Committee on plasma cell diseases between 2015-2019 and on the EHA’s Scientific Program Committee and Advisory Board since 2013 until 2020, being chair of the Scientific Program Committee in 2019. She has been Councilor on the EHA Board since 2015 for a four-year mandate and she remains a member of the IMS executive board and member of the European School of Haematology (ESH) Scientific committee. She received the Briand Durie Award in 2019, recognizing excellence in myeloma research.
- Overall survival results with daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant- ineligible newly diagnosed multiple myeloma: phase 3 MAIA study. EHA Meeting Library. EHA2021 Virtual: Late-breaking abstracts. Abstract LB1901. https://library.ehaweb.org/eha/2021/eha2021-virtual-congress/330171/thierry.facon.overall.survival.results.with.daratumumab.lenalidomide.and.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2035%2Amarker%3D1284
- Assessment of treatment response by mass spectrometry in newly diagnosed multiple myeloma patients from the GEM2012MENOS65 clinical trial: comparison with standard SPEP/IFE. HemaSphere. 2021;5(S2):478. Abstract EP1012. DOI: 10.1097/HS9.0000000000000566
- Efficacy Of carfilzomib-based induction/consolidation with or without autologous transplant and lenalidomide or carfilzomib-lenalidomide maintenance in high-risk patients in the FORTE trial. HemaSphere. 2021;5(S2): 46-47. Abstract S182. DOI: 10.1097/HS9.0000000000000566
- AM, et al. Updated interim analysis of the gmmgconcept trial investigating isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in frontline treatment of high-risk multiple myeloma. HemaSphere. 2021;5(S2):47. Abstract S183. DOI: 10.1097/HS9.0000000000000566
- Daratumumab maintenance vs observation in patients with newly diagnosed multiple myeloma treated with bortezomib, thalidomide, and dexamethasone and daratumumab and ASCT: CASSIOPEIA Part 2 Results. HemaSphere. 2021;5(S2):45-46. Abstract S180. DOI: 10.1097/HS9.0000000000000566
- DOI: https://doi.org/10.1056/NEJMoa2024850
- Idecabtagene vicleucel (ide-cel, Bb2121), A BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: updated KarMMa results. HemaSphere. 2021;5(S2):476. Abstract EP1009. DOI: http://dx.doi.org/10.1097/HS9.0000000000000566
- Updated CARTITUDE-1 results of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. HemaSphere. 2021;5(S2):451. Abstract EP964. DOI: http://dx.doi.org/10.1097/HS9.0000000000000566
- Efficacy and safety of the BCMA-directed car-t cell therapy, ciltacabtagene autoleucel, in patients with progressive multiple myeloma after 1–3 prior lines of therapy: initial results from CARTITUDE-2. HemaSphere. 2021;5(S2):51. Abstract S190. DOI: 10.1097/HS9.0000000000000566
- An updated phase 1 study of a novel fully human BCMA-targeting CAR-T cells (CT103A) In patients with relapsed/refractory multiple myeloma. HemaSphere. 2021;5:(S2):53. Abstract S194. DOI: 10.1097/HS9.0000000000000566
- Long-term follow-up results of a multicenter first-In-human study of the dual BCMA/CD19 targeted fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma. HemaSphere. 2021;5(S2):450. Abstract EP962. DOI: 10.1097/HS9.0000000000000566
- Teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: updated phase 1 results. HemaSphere. 2021;5(S2):53. Abstract S193. DOI: 10.1097/HS9.0000000000000566
- S192 MagnetisMM-1: Phase 1 study of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA) targeted CD3-engaging bispecific antibody, for patients with relapsed or refractory multiple myeloma (MM). HemaSphere. 2021;5(S2): 52. Abstract S192. DOI: 10.1097/HS9.0000000000000566