Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Multiple myeloma: my highlights at ASH 2020

Multiple myeloma: my highlights at ASH 2020 review memo (2021) 14:231–234 https://doi.org/10.1007/s12254-021-00746-w Eberhard Gunsilius Received: 14 May 2021 / Accepted: 25 June 2021 / Published online: 13 August 2021 © The Author(s) 2021 Summary The meeting focused in particular on new at the 12-month maintenance cut-off, the percentage strategies such as chimeric antigen receptor (CAR)- of patients in stringent complete response (sCR) was T cells and bispecific antibodies. Updates of clinical 63.6% in the D-arm vs. 47.4% in the control arm [1]. trials regarding induction treatment in transplantable The frequency of MRD-negative patients was 62.5% and non-transplantable status were presented. Fur- (durable ≥ 6 months 37.5%) in the daratumumab arm thermore, minimal residual disease negativity (MRD) and 27.2% (durable ≥ 6 months 7.8%) in the control or, in other words, a status characterized by no mea- arm. Toxicity was mainly hematologic with 43% grade surable disease, using standardized multicolor-flow III/IV neutropenia in the daratumumab arm and 24% cytometry or next-generation sequencing techniques in the control arm. Grade III/IV thrombocytopenia becomes increasingly important as an endpoint in was 15% and 9%, respectively. Upper respiratory tract clinical trials. A subjectively assessed overview of the infections occurred in 68% (5% grade III/IV) of pa- current contributions to the treatment of multiple tients receiving D-VRd and in 50% (2% grade III/IV) myeloma is given here. in the control arm. In all, 43% of patients in the D-VRdgroup and6% in the control arm experienced Keywords Multiple myeloma · Minimal residual infusion-related reactions. Thus, the addition of disease · Modern treatment · CAR-T cells · Bispecific daratumumab substantially improved the depth of antibodies response in newly diagnosed patients in this patient group with manageable toxicity. The risk of infec- tions has to be kept in mind when daratumumab is First-line treatment in transplant-eligible patients administered over a long time period. The randomized phase-II GRIFFIN trial compared In the three-armed FORTE trial carfilzomib- induction with bortezomib-lenalidomide-dexametha- lenalidomide-dexamethasone (KRd) induction-ASCT- sone (VRD) + daratumumab (VRD + D), followed by KRd consolidation (KRd-ASCT) was compared to KC autologous stem-cell transplantation (ASCT) and (cyclophosphamide) induction-ASCT-KCd consolida- consolidation with VRD + D and lenalidomide + D tion (KCd-ASCT) or 12 cycles of KRd (KRd12). In maintenance with VRD, ASCT, VRD consolidation the transplant arms, four cycles were given for both and lenalidomide maintenance in 207 newly diag- induction and consolidation. In a second randomiza- nosed transplant-eligible multiple myeloma (MM) tion maintenance treatment with KR versus R, both patients. Daratumumab was given intravenously until progression, was compared. (subcutaneous daratumumab is given in the ran- After a follow-up of 45 months, the progression-free domized phase-III PERSEUS trial VRD vs VRD-D in survival (PFS) in the KRD-ASCT arm was not reached transplant-eligible newly diagnosed MM [NDMM]). at 57 months in the KRD12 and 53 months KCD-ASCT Updated results presented at ASH 2020 showed that, arm [2]. The superiority of KRD-ASCT was especially beneficial in patients with high-risk cytogenetic fea- tures. KR maintenance improved PFS (3-year PFS after E. Gunsilius () the second randomization 75% vs. 68%), showing for Department of Hematology & Oncology, Medical University the first time the benefit of adding a proteasome in- Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria eberhard.gunsilius@i-med.ac.at hibitor to lenalidomide maintenance in a randomized K Multiple myeloma: my highlights at ASH 2020 231 review setting. A total of 46% of patients that were MRD- MRD negativity for > 12 months was achieved in 13% positive at the beginning of maintenance treatment (DRd) and 3% (Rd), respectively. The triplet was well converted to a MRD negative status compared to 32% tolerated. In all, 11% of patients in the DRd arm and of patients receiving maintenance with lenalidomide 22% in the RD arm discontinued treatment due to alone. Achieving negative MRD disease was associ- adverse events. The most important grade 3/4 ad- ated with prolonged PFS and overall survival (OS). verse events were neutropenia (DRd/Rd; 53%/37%), Additional evidence for the superiority of ASCT pneumonia (18%/11%), lymphopenia (16%/11%) and comes from the updated data of the IFM 2009 trial, infections (40%/29%). These data support DRd as which compared VRD induction (three cycles) fol- a standard for first-line treatment in transplant non- lowed by ASCT and two cycles VRD consolidation eligible myeloma patients. to eight cycles VRD without ASCT [3]. Both arms The randomized phase-III TOURMALINE-MM2 received lenalidomide maintenance for 12 months. trial compared the oral proteasome-inhibitor ixa- With a follow-up of nearly 8 years the median PFS zomib in combination with lenalidomide and dexam- was significantly longer in patients receiving ASCT ethasone (IRd) and lenalidomide-dexamethasone (Rd) (47.3 months) compared to 35 months in the patients alone in transplant-ineligible patients with NDMM. receiving lenalidomide, bortezomib, and dexametha- The PFS was 13.5 months longer in the IRd arm, al- sone (RVd) alone. Achieving MRD negativity pre- though not statistically significant [6]. Despite this dicted a longer PFS and OS. Median overall survival lack of significance, this total oral combination can was not reached in both groups, the 8-year OS rate be an option for some patients. was 62.2 months in the ASCT group and 60.2 months An update of the randomized phase-III ALCYONE in the non-ASCT group. In the EMN02/HO95 trial trial comparing D-VMP (daratumumab, bortezomib, 1197 patients were randomized either to upfront melphalan, prednisone) including daratumumab ASCT after 3–4 cycles of VCD (bortezomib, cyclophos- maintenance and VMP as induction treatment in phamide, dexamethasone) inductionortofourcycles transplant non-eligible patients with NDMM showed of bortezomib-melphalan-prednisone (VMP) and, in that D-VMP significantly increased the rates of ≥ com- a second randomization, to consolidation with two plete remission (CR) (46% vs 25%) and MRD negativ- cycles of bortezomib, lenalidomide, dexamethasone ity (28% vs 7%), as well as progression-free and overall or no consolidation, both followed by lenalidomide survival [7], The ≥ CR rate improved from 44% at the maintenance. The overall survival after 75 months start of daratumumab maintenance treatment to 64% was significantly longer in the transplant arm (69% and 68% at 1 and 2 years, respectively. vs. 63%) [4]. The data from these studies support once more the Relapsed/refractory disease established practice of offering high-dose chemother- apy and ASCT to eligible patients as a first-line treat- The anti-CD38 antibody daratumumab in com- ment. bination with pomalidomide and dexamethasone (DPd) versus pomalidomide dexamethasone alone was tested in a randomized setting in the phase-III First-line treatment in transplant-ineligible APOLLO trial which included 304 patients [8]. Ini- patients tially, daratumumab was given subcutaneously, after An update of the randomized MAIA trial, which com- an amendment (i.v. patients also switched to s.c.). pared lenalidomide-dexamethasone-daratumumab Treatment was given until progression or unaccept- (DRd, n = 368) and lenalidomide-dexamethasone (Rd, able toxicity in both groups. The mean age of the n = 369) as induction treatment in NDMM patients patients was 67 years and approximately 20% were not eligible for autologous transplantation was pre- ≥75 years old. The International Staging System (ISS) sented (median age 73 years). The treatment duration stage was I in 45% of patients in both groups. The was until progression or unacceptable toxicity. The median number of prior treatments was two. Remark- median treatment duration was 43 months in the DRd ably, 80% of patients were, by definition, refractory arm and 23 months in the RD arm. After a median to lenalidomide and 80% of patients were refractory follow up of 48 months 34% of the patients in the DRd to their last treatment. In all, 50% were refractory arm had sCR and the PFS was 60% in the DRd arm to proteasome inhibitors, and 42% were refractory to and 38% in the RD arm [5]. Older patients ≥ 75 years both substance classes. and patients with high-risk characteristics also ben- Overall response rates were 69% for DPd and 46% efitted from the addition of daratumumab in terms for Pd, in which the ≥ CR rates were 24% vs. 4%. For of PFS. Duration of response was not reached for patients receiving DPd the 12-month PFS was 52% DRd and 44.3 for RD. At this 48-month update, 31% (median PFS: 12.4 months) compared to 35 for Pd of the patients in the daratumumab arm were MRD- (median PFS: 6.9 months). The risk of progression or negative (23% of patients with high-risk cytogenetics) death was reduced by 37%. For those that were refrac- compared to only 10% of patients in the control arm tory to lenalidomide, median PFS was 9.9 months with (2% of patients with high-risk cytogenetics). Sustained D-Pd vs 6.5 months with Pd. No new safety signals 232 Multiple myeloma: my highlights at ASH 2020 K review were observed. Hematotoxicity was the most com- to immunomodulatory drugs (IMIDs), proteasome in- mon adverse effect with grade III/IV neutropenia in hibitors and an anti-CD38 antibody. Roughly a third 58% (DPd) and 51% of patients. The infection rate had high-risk cytogenetics. The presented data con- was higher in the DPd arm (70% vs. 55%). A total firmed the high response rate of 76% in heavily pre- of 5% of patients experienced mild infusion-related treated RRMM patients (n = 62). The rate of com- reactions. These data, together with the results of plete responses was 39% and 30 out of 37 evaluable the MM-014 trial (DPd in patients that progressed un- patients became MRD-negative. Three quarters of der lenalidomide as their direct prior treatment [9]), the patients experienced cytokine-release syndrome show that DPd is an option for pretreated patients (CRS) and 42 neurotoxicity (NT). Grade III/IV CRS and that are refractory to lenalidomide, which is used in NT was observed in 7% and 2%, respectively. many patients in the first-line setting. The benefit Data from the CARTITUDE-1 trial (ciltacabtagen in terms of PFS of another anti-CD38 antibody, isat- Autoleucel; Cilta-Cel), a phase-I/II trial (n = 113 with uximab, when added to pomalidomide and dexam- a median of six pretreatments, 88% triple-refractory) ethasone, has already been shown in the IKARIA trial showed an impressive response rate of 97% with 67% in relapsed/refractory MM (RRMM) patients after at stringent remissions. The median time to first re- least two prior lines of treatment [10]. sponse was 1 month. The 1-year PFS for patients An update of the CANDOR trial was also presented in sCR was 84.5%. Grade ≥ III/IV infections were at ASH 2020. Patients with RRMM and 1–3 prior seen in 19.6% and grade III/IV CRS in only 4.1% and treatment lines were randomized between daratu- grade III/IV neurotoxicity in 9.3%. Virtually 90% of the mumab + carfilzomib-dexamethasone (KDd, n = 312) patients received steroids and/or tocilizumab for CRS, or carfilzomib/dexamethasone (KD, n = 154) [11]. The which resolved in 99% within 14 days. Of 14 deaths median PFS was nearly doubled in the KDd arm during the trial, five were due to progressive disease (28.6 m. vs 15.2 m.), whereby patients with early re- and six deaths due to a combination of infections, lapse (< 1 year after the last therapy) comparably ben- CRS, and neurotoxicity. After Cilta-CEL cytokine re- efitted from the treatment. Also, patients with high- lease syndromes occur later than after Ide-Cel and risk features do better with the triple combination. the duration of cytopenia is shorter. The second novel anti-CD38 antibody isatux- Another promising immunotherapeutic strategy imab was tested in the randomized phase-III trial are bispecific antibodies, called BITEs (bispecific- IKEMA together with carfilzomib and dexamethasone T-cell enhancer), which target T-cells and an anti- (IKd) against carfilzomib and dexamethasone alone gen on myeloma cells (e.g., BCMA) simultaneously, in RRMM patients after 1–3 prior treatment lines. thereby creating an “immunological synapse” that ThemedianPFS was not reachedinthe IKd arm leads to the killing of myeloma cells. One advan- after a median follow-up of 20.7 months and after tage of BITEs is the “off-the shelf” availability of the 19.2 months in the KD arm (p = 0.0007). The rate of products, their disadvantage being the necessity of MRD negativity was doubled in the isatuximab arm repeated dosing. One of these BITEs, shown here as (30% vs 13%). As in other studies, MRD negativity was an example, is teclistamab, a CD3/BCMA-targeting associated with prolonged PFS [12]. Treatment with antibody that can be applied subcutaneously, which isatuximab was well tolerated with 0.6% grade III/IV is convenient for the patients. An update of a phase-I infusion-associated reactions (grade I–IV 45.8%). In- trial in 149 patients with a median pretreatment of terestingly, if the response assessment was performed six lines (five lines in the 33 patients that received using mass spectroscopy, the rate of CRs increased the recommended phase-II dose of 1500 ug/kg s.c.) by 6% due to the interference of the anti-CD38 anti- [14]. Nearly 70% of the patients were penta-exposed body with immunofixation (can produce false positive and 90% were refractory to their last line of therapy. immunofixation results). In the s.c. group, the overall response rate was 73%, with ≥ very good partial response (VGPR) in 55%. CRS occurred in 50% of those patients and was exclusively Novel treatment strategies grade I/II. An important focus of the last ASH meeting was The data presented at the meeting show the enor- again the implementation of CAR-T cells, bispecific mous potential of CAR-T cells and BITEs to control antibodies and drug-immunoconjugates in the treat- disease in heavily pretreated myeloma patients. Al- ment. The predominant target for such strategies is though no definitive plateau in thecurvesiscurrently the B-cell maturation antigen (BCMA) expressed on visible, immunologic strategies are highly efficient and malignant plasma cells. the future will tell us if the results are durable, espe- An update of the phase-I CRB-401 trial “Idecab- cially if these treatments are applied in earlier stages tagene Vicleucel (Ide-cel, bb2121), a BCMA-Directed of disease. CAR T Cell Therapy, in Patients with Relapsed and Re- Funding Open access funding provided by University of Inns- fractory Multiple Myeloma” was presented [13]. The bruck and Medical University of Innsbruck. patients had received a median of six previous lines of therapy (range: 3–17) and 64% were triple-refractory K Multiple myeloma: my highlights at ASH 2020 233 review Conflict of interest E. Gunsilius declares that he has no com- related quality of life (HRQoL) by response status for Borte- peting interests. zomib, Melphalan, and Prednisone (VMP) ± Daratumumab (DARA) in alcyone. Blood. 2020;136(Supplement1):43–4. Open Access This article is licensed under a Creative Com- 8. Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, mons Attribution 4.0 International License, which permits Beksac M, Katodritou E, et al. Apollo: phase 3 random- use, sharing, adaptation, distribution and reproduction in ized study of subcutaneous Daratumumab plus Pomalido- any medium or format, as long as you give appropriate credit mide and Dexamethasone (D-Pd) versus Pomalidomide to the original author(s) and the source, provide a link to and Dexamethasone (Pd) alone in patients (pts) with the Creative Commons licence, and indicate if changes were relapsed/refractory multiple myeloma (RRMM). Blood. made. The images or other third party material in this article 2020;136(Supplement1):5–6. are included in the article’s Creative Commons licence, unless 9. SiegelDS,SchillerGJ,SamarasCJ,SebagM,BerdejaJG,Gan- indicated otherwise in a credit line to the material. If material guly S, et al. Pomalidomide, Dexamethasone, and Dara- is not included in the article’s Creative Commons licence and tumumab after Lenalidomide treatment in relapsed refrac- your intended use is not permitted by statutory regulation or tory multiple myeloma: updated results from an open- exceeds the permitted use, you will need to obtain permis- label, multicenter, phase 2 trial. Blood. 2020;136(Supple- sion directly from the copyright holder. To view a copy of this ment1):16–7. licence, visit http://creativecommons.org/licenses/by/4.0/. 10.Attal M,RichardsonPG, Rajkumar SV,San-Miguel J, Beksac M, Spicka I, et al. Isatuximab plus pomalido- mide and low-dose dexamethasone versus pomalidomide References and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a ran- 1. Kaufman JL, Laubach JP, Sborov D, Reeves B, Rodriguez C, domised, multicentre, open-label, phase 3 study. Lancet. Chari A, et al. Daratumumab (DARA) plus lenalidomide, 2019;394(10214):2096–107. bortezomib, and dexamethasone (RVd) in patients with 11. Dimopoulos MA, Quach H, Mateos M-V, Landgren O, transplant-eligible newly diagnosed multiple myeloma Leleu X, Siegel DS, et al. Carfilzomib, Dexamethasone, (NDMM): updated analysis of griffin after 12 months and Daratumumab versus Carfilzomib and Dexametha- of maintenance therapy. Blood. 2020;136(Supplement sone in relapsed or refractory multiple myeloma: updated 1):45–6. efficacy and safety results of the phase 3 candor study. 2. Gay F, Musto P, Rota Scalabrini D, Galli M, Belotti A, Za- Blood. 2020;136(Supplement1):26–7. magni E, et al. Survival analysis of newly diagnosed 12. Moreau P, et al. Isatuximab plus Carfilzomib and Dexam- transplant-eligible multiple myeloma patients in the ran- ethasone vs Carfilzomib and Dexamethasone in relapsed/ domizedfortetrial. Blood. 2020;136(Supplement1):35–7. refractory multiple myeloma (IKEMA): interim analysis of 3. Perrot A, Lauwers-Cances V, Cazaubiel T, Facon T, Caillot D, a phase 3, randomized, open-label study. In: ASH 2020, Clement-Filliatre L, et al. Early versus late autologous virtual edition, abstract2316. 2020. stem cell transplant in newly diagnosed multiple myeloma: 13. LinY,RajeNS,BerdejaJG,SiegelDS,JagannathS,MadduriD, long-term follow-up analysis of the IFM 2009 trial. Blood. et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA- 2020;136(Supplement1):39–39. directed CAR T cell therapy, in patients with relapsed and 4. Cavo M, GayF,Beksac M,DimopoulosMA, PantaniL, refractory multiple myeloma: updated results from phase 1 Petrucci MT, et al. Upfront autologous hematopoietic CRB-401 study. Blood. 2020;136(Supplement1):26–7. stem-cell transplantation improves overall survival in com- 14. Garfall AL, Usmani SZ, Mateos M-V, Nahi H, van de parison with bortezomib-based intensification therapy in Donk NWCJ, San-Miguel JF, et al. Updated phase 1 re- newly diagnosed multiple myeloma: long-term follow-up sults of teclistamab, a B-cell maturation antigen (BCMA) analysis of the randomized phase 3 EMN02/HO95 study. x CD3 bispecific antibody, in relapsed and/or refractory Blood. 2020;136(Supplement1):37–8. multiple myeloma (RRMM). Blood. 2020;136(Supplement 5. KumarSK, FaconT, UsmaniSZ, PlesnerT,OrlowskiRZ, 1):27–27. Touzeau C, et al. Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-rd) versus lenalido- Publisher’s Note Springer Nature remains neutral with regard mide and dexamethasone (rd) in patients with transplant- to jurisdictional claims in published maps and institutional ineligible newly diagnosed multiple myeloma (NDMM): affiliations. the phase 3 Maia study. Blood. 2020;136(Supplement 1):24–6. 6. Facon T, et al. The phase 3 TOURMALINE-MM2 trial: 7 For latest news from interna- oral Ixazomib, Lenalidomide, and Dexamethasone (Ird) vs placebo-rd for transplant-ineligible patients with newly tional oncology congresses see: diagnosed multiple myeloma (NDMM). In: ASH 2020, http://www.springermedizin.at/ virtual edition, abstract551. 2020. memo-inoncology 7. Rodriguez-OteroP,BoccadoroM,HajekR,FujisakiT,LeeJH, Martinez-Lopez J, et al. Long-term outcomes and health- 234 Multiple myeloma: my highlights at ASH 2020 K http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Multiple myeloma: my highlights at ASH 2020

Download PDF
4 pages

Loading next page...
 
/lp/springer-journals/multiple-myeloma-my-highlights-at-ash-2020-PJarKJM0jX

References (14)

Publisher
Springer Journals
Copyright
2021 The Author(s)
ISSN
1865-5041
eISSN
1865-5076
DOI
10.1007/s12254-021-00746-w
Publisher site
See Article on Publisher Site

Abstract

review memo (2021) 14:231–234 https://doi.org/10.1007/s12254-021-00746-w Eberhard Gunsilius Received: 14 May 2021 / Accepted: 25 June 2021 / Published online: 13 August 2021 © The Author(s) 2021 Summary The meeting focused in particular on new at the 12-month maintenance cut-off, the percentage strategies such as chimeric antigen receptor (CAR)- of patients in stringent complete response (sCR) was T cells and bispecific antibodies. Updates of clinical 63.6% in the D-arm vs. 47.4% in the control arm [1]. trials regarding induction treatment in transplantable The frequency of MRD-negative patients was 62.5% and non-transplantable status were presented. Fur- (durable ≥ 6 months 37.5%) in the daratumumab arm thermore, minimal residual disease negativity (MRD) and 27.2% (durable ≥ 6 months 7.8%) in the control or, in other words, a status characterized by no mea- arm. Toxicity was mainly hematologic with 43% grade surable disease, using standardized multicolor-flow III/IV neutropenia in the daratumumab arm and 24% cytometry or next-generation sequencing techniques in the control arm. Grade III/IV thrombocytopenia becomes increasingly important as an endpoint in was 15% and 9%, respectively. Upper respiratory tract clinical trials. A subjectively assessed overview of the infections occurred in 68% (5% grade III/IV) of pa- current contributions to the treatment of multiple tients receiving D-VRd and in 50% (2% grade III/IV) myeloma is given here. in the control arm. In all, 43% of patients in the D-VRdgroup and6% in the control arm experienced Keywords Multiple myeloma · Minimal residual infusion-related reactions. Thus, the addition of disease · Modern treatment · CAR-T cells · Bispecific daratumumab substantially improved the depth of antibodies response in newly diagnosed patients in this patient group with manageable toxicity. The risk of infec- tions has to be kept in mind when daratumumab is First-line treatment in transplant-eligible patients administered over a long time period. The randomized phase-II GRIFFIN trial compared In the three-armed FORTE trial carfilzomib- induction with bortezomib-lenalidomide-dexametha- lenalidomide-dexamethasone (KRd) induction-ASCT- sone (VRD) + daratumumab (VRD + D), followed by KRd consolidation (KRd-ASCT) was compared to KC autologous stem-cell transplantation (ASCT) and (cyclophosphamide) induction-ASCT-KCd consolida- consolidation with VRD + D and lenalidomide + D tion (KCd-ASCT) or 12 cycles of KRd (KRd12). In maintenance with VRD, ASCT, VRD consolidation the transplant arms, four cycles were given for both and lenalidomide maintenance in 207 newly diag- induction and consolidation. In a second randomiza- nosed transplant-eligible multiple myeloma (MM) tion maintenance treatment with KR versus R, both patients. Daratumumab was given intravenously until progression, was compared. (subcutaneous daratumumab is given in the ran- After a follow-up of 45 months, the progression-free domized phase-III PERSEUS trial VRD vs VRD-D in survival (PFS) in the KRD-ASCT arm was not reached transplant-eligible newly diagnosed MM [NDMM]). at 57 months in the KRD12 and 53 months KCD-ASCT Updated results presented at ASH 2020 showed that, arm [2]. The superiority of KRD-ASCT was especially beneficial in patients with high-risk cytogenetic fea- tures. KR maintenance improved PFS (3-year PFS after E. Gunsilius () the second randomization 75% vs. 68%), showing for Department of Hematology & Oncology, Medical University the first time the benefit of adding a proteasome in- Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria eberhard.gunsilius@i-med.ac.at hibitor to lenalidomide maintenance in a randomized K Multiple myeloma: my highlights at ASH 2020 231 review setting. A total of 46% of patients that were MRD- MRD negativity for > 12 months was achieved in 13% positive at the beginning of maintenance treatment (DRd) and 3% (Rd), respectively. The triplet was well converted to a MRD negative status compared to 32% tolerated. In all, 11% of patients in the DRd arm and of patients receiving maintenance with lenalidomide 22% in the RD arm discontinued treatment due to alone. Achieving negative MRD disease was associ- adverse events. The most important grade 3/4 ad- ated with prolonged PFS and overall survival (OS). verse events were neutropenia (DRd/Rd; 53%/37%), Additional evidence for the superiority of ASCT pneumonia (18%/11%), lymphopenia (16%/11%) and comes from the updated data of the IFM 2009 trial, infections (40%/29%). These data support DRd as which compared VRD induction (three cycles) fol- a standard for first-line treatment in transplant non- lowed by ASCT and two cycles VRD consolidation eligible myeloma patients. to eight cycles VRD without ASCT [3]. Both arms The randomized phase-III TOURMALINE-MM2 received lenalidomide maintenance for 12 months. trial compared the oral proteasome-inhibitor ixa- With a follow-up of nearly 8 years the median PFS zomib in combination with lenalidomide and dexam- was significantly longer in patients receiving ASCT ethasone (IRd) and lenalidomide-dexamethasone (Rd) (47.3 months) compared to 35 months in the patients alone in transplant-ineligible patients with NDMM. receiving lenalidomide, bortezomib, and dexametha- The PFS was 13.5 months longer in the IRd arm, al- sone (RVd) alone. Achieving MRD negativity pre- though not statistically significant [6]. Despite this dicted a longer PFS and OS. Median overall survival lack of significance, this total oral combination can was not reached in both groups, the 8-year OS rate be an option for some patients. was 62.2 months in the ASCT group and 60.2 months An update of the randomized phase-III ALCYONE in the non-ASCT group. In the EMN02/HO95 trial trial comparing D-VMP (daratumumab, bortezomib, 1197 patients were randomized either to upfront melphalan, prednisone) including daratumumab ASCT after 3–4 cycles of VCD (bortezomib, cyclophos- maintenance and VMP as induction treatment in phamide, dexamethasone) inductionortofourcycles transplant non-eligible patients with NDMM showed of bortezomib-melphalan-prednisone (VMP) and, in that D-VMP significantly increased the rates of ≥ com- a second randomization, to consolidation with two plete remission (CR) (46% vs 25%) and MRD negativ- cycles of bortezomib, lenalidomide, dexamethasone ity (28% vs 7%), as well as progression-free and overall or no consolidation, both followed by lenalidomide survival [7], The ≥ CR rate improved from 44% at the maintenance. The overall survival after 75 months start of daratumumab maintenance treatment to 64% was significantly longer in the transplant arm (69% and 68% at 1 and 2 years, respectively. vs. 63%) [4]. The data from these studies support once more the Relapsed/refractory disease established practice of offering high-dose chemother- apy and ASCT to eligible patients as a first-line treat- The anti-CD38 antibody daratumumab in com- ment. bination with pomalidomide and dexamethasone (DPd) versus pomalidomide dexamethasone alone was tested in a randomized setting in the phase-III First-line treatment in transplant-ineligible APOLLO trial which included 304 patients [8]. Ini- patients tially, daratumumab was given subcutaneously, after An update of the randomized MAIA trial, which com- an amendment (i.v. patients also switched to s.c.). pared lenalidomide-dexamethasone-daratumumab Treatment was given until progression or unaccept- (DRd, n = 368) and lenalidomide-dexamethasone (Rd, able toxicity in both groups. The mean age of the n = 369) as induction treatment in NDMM patients patients was 67 years and approximately 20% were not eligible for autologous transplantation was pre- ≥75 years old. The International Staging System (ISS) sented (median age 73 years). The treatment duration stage was I in 45% of patients in both groups. The was until progression or unacceptable toxicity. The median number of prior treatments was two. Remark- median treatment duration was 43 months in the DRd ably, 80% of patients were, by definition, refractory arm and 23 months in the RD arm. After a median to lenalidomide and 80% of patients were refractory follow up of 48 months 34% of the patients in the DRd to their last treatment. In all, 50% were refractory arm had sCR and the PFS was 60% in the DRd arm to proteasome inhibitors, and 42% were refractory to and 38% in the RD arm [5]. Older patients ≥ 75 years both substance classes. and patients with high-risk characteristics also ben- Overall response rates were 69% for DPd and 46% efitted from the addition of daratumumab in terms for Pd, in which the ≥ CR rates were 24% vs. 4%. For of PFS. Duration of response was not reached for patients receiving DPd the 12-month PFS was 52% DRd and 44.3 for RD. At this 48-month update, 31% (median PFS: 12.4 months) compared to 35 for Pd of the patients in the daratumumab arm were MRD- (median PFS: 6.9 months). The risk of progression or negative (23% of patients with high-risk cytogenetics) death was reduced by 37%. For those that were refrac- compared to only 10% of patients in the control arm tory to lenalidomide, median PFS was 9.9 months with (2% of patients with high-risk cytogenetics). Sustained D-Pd vs 6.5 months with Pd. No new safety signals 232 Multiple myeloma: my highlights at ASH 2020 K review were observed. Hematotoxicity was the most com- to immunomodulatory drugs (IMIDs), proteasome in- mon adverse effect with grade III/IV neutropenia in hibitors and an anti-CD38 antibody. Roughly a third 58% (DPd) and 51% of patients. The infection rate had high-risk cytogenetics. The presented data con- was higher in the DPd arm (70% vs. 55%). A total firmed the high response rate of 76% in heavily pre- of 5% of patients experienced mild infusion-related treated RRMM patients (n = 62). The rate of com- reactions. These data, together with the results of plete responses was 39% and 30 out of 37 evaluable the MM-014 trial (DPd in patients that progressed un- patients became MRD-negative. Three quarters of der lenalidomide as their direct prior treatment [9]), the patients experienced cytokine-release syndrome show that DPd is an option for pretreated patients (CRS) and 42 neurotoxicity (NT). Grade III/IV CRS and that are refractory to lenalidomide, which is used in NT was observed in 7% and 2%, respectively. many patients in the first-line setting. The benefit Data from the CARTITUDE-1 trial (ciltacabtagen in terms of PFS of another anti-CD38 antibody, isat- Autoleucel; Cilta-Cel), a phase-I/II trial (n = 113 with uximab, when added to pomalidomide and dexam- a median of six pretreatments, 88% triple-refractory) ethasone, has already been shown in the IKARIA trial showed an impressive response rate of 97% with 67% in relapsed/refractory MM (RRMM) patients after at stringent remissions. The median time to first re- least two prior lines of treatment [10]. sponse was 1 month. The 1-year PFS for patients An update of the CANDOR trial was also presented in sCR was 84.5%. Grade ≥ III/IV infections were at ASH 2020. Patients with RRMM and 1–3 prior seen in 19.6% and grade III/IV CRS in only 4.1% and treatment lines were randomized between daratu- grade III/IV neurotoxicity in 9.3%. Virtually 90% of the mumab + carfilzomib-dexamethasone (KDd, n = 312) patients received steroids and/or tocilizumab for CRS, or carfilzomib/dexamethasone (KD, n = 154) [11]. The which resolved in 99% within 14 days. Of 14 deaths median PFS was nearly doubled in the KDd arm during the trial, five were due to progressive disease (28.6 m. vs 15.2 m.), whereby patients with early re- and six deaths due to a combination of infections, lapse (< 1 year after the last therapy) comparably ben- CRS, and neurotoxicity. After Cilta-CEL cytokine re- efitted from the treatment. Also, patients with high- lease syndromes occur later than after Ide-Cel and risk features do better with the triple combination. the duration of cytopenia is shorter. The second novel anti-CD38 antibody isatux- Another promising immunotherapeutic strategy imab was tested in the randomized phase-III trial are bispecific antibodies, called BITEs (bispecific- IKEMA together with carfilzomib and dexamethasone T-cell enhancer), which target T-cells and an anti- (IKd) against carfilzomib and dexamethasone alone gen on myeloma cells (e.g., BCMA) simultaneously, in RRMM patients after 1–3 prior treatment lines. thereby creating an “immunological synapse” that ThemedianPFS was not reachedinthe IKd arm leads to the killing of myeloma cells. One advan- after a median follow-up of 20.7 months and after tage of BITEs is the “off-the shelf” availability of the 19.2 months in the KD arm (p = 0.0007). The rate of products, their disadvantage being the necessity of MRD negativity was doubled in the isatuximab arm repeated dosing. One of these BITEs, shown here as (30% vs 13%). As in other studies, MRD negativity was an example, is teclistamab, a CD3/BCMA-targeting associated with prolonged PFS [12]. Treatment with antibody that can be applied subcutaneously, which isatuximab was well tolerated with 0.6% grade III/IV is convenient for the patients. An update of a phase-I infusion-associated reactions (grade I–IV 45.8%). In- trial in 149 patients with a median pretreatment of terestingly, if the response assessment was performed six lines (five lines in the 33 patients that received using mass spectroscopy, the rate of CRs increased the recommended phase-II dose of 1500 ug/kg s.c.) by 6% due to the interference of the anti-CD38 anti- [14]. Nearly 70% of the patients were penta-exposed body with immunofixation (can produce false positive and 90% were refractory to their last line of therapy. immunofixation results). In the s.c. group, the overall response rate was 73%, with ≥ very good partial response (VGPR) in 55%. CRS occurred in 50% of those patients and was exclusively Novel treatment strategies grade I/II. An important focus of the last ASH meeting was The data presented at the meeting show the enor- again the implementation of CAR-T cells, bispecific mous potential of CAR-T cells and BITEs to control antibodies and drug-immunoconjugates in the treat- disease in heavily pretreated myeloma patients. Al- ment. The predominant target for such strategies is though no definitive plateau in thecurvesiscurrently the B-cell maturation antigen (BCMA) expressed on visible, immunologic strategies are highly efficient and malignant plasma cells. the future will tell us if the results are durable, espe- An update of the phase-I CRB-401 trial “Idecab- cially if these treatments are applied in earlier stages tagene Vicleucel (Ide-cel, bb2121), a BCMA-Directed of disease. CAR T Cell Therapy, in Patients with Relapsed and Re- Funding Open access funding provided by University of Inns- fractory Multiple Myeloma” was presented [13]. The bruck and Medical University of Innsbruck. patients had received a median of six previous lines of therapy (range: 3–17) and 64% were triple-refractory K Multiple myeloma: my highlights at ASH 2020 233 review Conflict of interest E. Gunsilius declares that he has no com- related quality of life (HRQoL) by response status for Borte- peting interests. zomib, Melphalan, and Prednisone (VMP) ± Daratumumab (DARA) in alcyone. Blood. 2020;136(Supplement1):43–4. Open Access This article is licensed under a Creative Com- 8. Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, mons Attribution 4.0 International License, which permits Beksac M, Katodritou E, et al. Apollo: phase 3 random- use, sharing, adaptation, distribution and reproduction in ized study of subcutaneous Daratumumab plus Pomalido- any medium or format, as long as you give appropriate credit mide and Dexamethasone (D-Pd) versus Pomalidomide to the original author(s) and the source, provide a link to and Dexamethasone (Pd) alone in patients (pts) with the Creative Commons licence, and indicate if changes were relapsed/refractory multiple myeloma (RRMM). Blood. made. The images or other third party material in this article 2020;136(Supplement1):5–6. are included in the article’s Creative Commons licence, unless 9. SiegelDS,SchillerGJ,SamarasCJ,SebagM,BerdejaJG,Gan- indicated otherwise in a credit line to the material. If material guly S, et al. Pomalidomide, Dexamethasone, and Dara- is not included in the article’s Creative Commons licence and tumumab after Lenalidomide treatment in relapsed refrac- your intended use is not permitted by statutory regulation or tory multiple myeloma: updated results from an open- exceeds the permitted use, you will need to obtain permis- label, multicenter, phase 2 trial. Blood. 2020;136(Supple- sion directly from the copyright holder. To view a copy of this ment1):16–7. licence, visit http://creativecommons.org/licenses/by/4.0/. 10.Attal M,RichardsonPG, Rajkumar SV,San-Miguel J, Beksac M, Spicka I, et al. Isatuximab plus pomalido- mide and low-dose dexamethasone versus pomalidomide References and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a ran- 1. Kaufman JL, Laubach JP, Sborov D, Reeves B, Rodriguez C, domised, multicentre, open-label, phase 3 study. Lancet. Chari A, et al. Daratumumab (DARA) plus lenalidomide, 2019;394(10214):2096–107. bortezomib, and dexamethasone (RVd) in patients with 11. Dimopoulos MA, Quach H, Mateos M-V, Landgren O, transplant-eligible newly diagnosed multiple myeloma Leleu X, Siegel DS, et al. Carfilzomib, Dexamethasone, (NDMM): updated analysis of griffin after 12 months and Daratumumab versus Carfilzomib and Dexametha- of maintenance therapy. Blood. 2020;136(Supplement sone in relapsed or refractory multiple myeloma: updated 1):45–6. efficacy and safety results of the phase 3 candor study. 2. Gay F, Musto P, Rota Scalabrini D, Galli M, Belotti A, Za- Blood. 2020;136(Supplement1):26–7. magni E, et al. Survival analysis of newly diagnosed 12. Moreau P, et al. Isatuximab plus Carfilzomib and Dexam- transplant-eligible multiple myeloma patients in the ran- ethasone vs Carfilzomib and Dexamethasone in relapsed/ domizedfortetrial. Blood. 2020;136(Supplement1):35–7. refractory multiple myeloma (IKEMA): interim analysis of 3. Perrot A, Lauwers-Cances V, Cazaubiel T, Facon T, Caillot D, a phase 3, randomized, open-label study. In: ASH 2020, Clement-Filliatre L, et al. Early versus late autologous virtual edition, abstract2316. 2020. stem cell transplant in newly diagnosed multiple myeloma: 13. LinY,RajeNS,BerdejaJG,SiegelDS,JagannathS,MadduriD, long-term follow-up analysis of the IFM 2009 trial. Blood. et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA- 2020;136(Supplement1):39–39. directed CAR T cell therapy, in patients with relapsed and 4. Cavo M, GayF,Beksac M,DimopoulosMA, PantaniL, refractory multiple myeloma: updated results from phase 1 Petrucci MT, et al. Upfront autologous hematopoietic CRB-401 study. Blood. 2020;136(Supplement1):26–7. stem-cell transplantation improves overall survival in com- 14. Garfall AL, Usmani SZ, Mateos M-V, Nahi H, van de parison with bortezomib-based intensification therapy in Donk NWCJ, San-Miguel JF, et al. Updated phase 1 re- newly diagnosed multiple myeloma: long-term follow-up sults of teclistamab, a B-cell maturation antigen (BCMA) analysis of the randomized phase 3 EMN02/HO95 study. x CD3 bispecific antibody, in relapsed and/or refractory Blood. 2020;136(Supplement1):37–8. multiple myeloma (RRMM). Blood. 2020;136(Supplement 5. KumarSK, FaconT, UsmaniSZ, PlesnerT,OrlowskiRZ, 1):27–27. Touzeau C, et al. Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-rd) versus lenalido- Publisher’s Note Springer Nature remains neutral with regard mide and dexamethasone (rd) in patients with transplant- to jurisdictional claims in published maps and institutional ineligible newly diagnosed multiple myeloma (NDMM): affiliations. the phase 3 Maia study. Blood. 2020;136(Supplement 1):24–6. 6. Facon T, et al. The phase 3 TOURMALINE-MM2 trial: 7 For latest news from interna- oral Ixazomib, Lenalidomide, and Dexamethasone (Ird) vs placebo-rd for transplant-ineligible patients with newly tional oncology congresses see: diagnosed multiple myeloma (NDMM). In: ASH 2020, http://www.springermedizin.at/ virtual edition, abstract551. 2020. memo-inoncology 7. Rodriguez-OteroP,BoccadoroM,HajekR,FujisakiT,LeeJH, Martinez-Lopez J, et al. Long-term outcomes and health- 234 Multiple myeloma: my highlights at ASH 2020 K

Journal

memo - Magazine of European Medical Oncology – Springer Journals

Published: Sep 1, 2021

Keywords: oncology; medicine/public health, general

There are no references for this article.