Introduction: Non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients have a heterogeneous clinical outcome, depending of frailty level. The aim of this study was to prospectively investigate the efficacy and tolerability of Ixazomib-Daratumumab-low dose dexamethasone (IDd) in intermediate-fit NTE-NDMM patients. Methods: In this phase II multicenter HOVON-143 study, IWMG-frailty index based intermediate-fit patients were treated with nine induction cycles of IDd, followed by maintenance with IDd for a maximum of two years. Health related quality of life (HRQoL) was investigated at baseline, after 3 and 9 induction cycles and after 6, 12 and 24 months of maintenance treatment. Results: Sixty-five patients were included. The overall response rate during induction was 71% (95% confidence interval (CI) 63-73%). After a median follow-up of 41 months (range 28.9-53.8), median PFS was 18.2 months. Median PFS2 and OS were not reached, PFS2 at 2 years was 80% (95% CI 68-88%), OS at 3 years was 83% (95% CI 71-90%). (Figure 1) Thirty-five patients (54%) completed induction treatment and started maintenance therapy. During maintenance, 12/35 (34%) patients had an improvement of response. Reasons for discontinuation of induction treatment were progressive disease (PD) (19/30; 63%), toxicity (4/30; 13%), incompliance (3/30; 10%), sudden death (1/30; 3%) and other (3/30; 10%). Of the 35 patients who started maintenance therapy, 15 (43%) patients completed the protocol and 20 patients discontinued treatment due to PD (13/20; 65%), refusal (2/20; 10%), toxicity (2/20; 10%), death (1/20; 5%) or other reasons (2/20; 10%). Hematologic adverse events (AE) grade ≥3 during induction occurred in 12% of patients, of which neutropenia was most commonly reported (6%). During maintenance only 1 patients (1/35; 3%) experienced a grade 3 hematologic AE (thrombocytopenia). Non-hematologic AEs grade ≥3 during induction occurred in 51% of patients, of which most commonly gastro-intestinal AEs (14%) and central nervous system AEs (14%). All grade polyneuropathy (PNP) occurred in 42% of patients, including 5% grade 3 PNP. During the maintenance phase non-hematologic AEs grade ≥3 occurred in 46% of patients, which were most commonly gastro-intestinal AEs (11%) and infections (9%). There was no new onset of grade ≥3 PNP. Dose modifications of ixazomib occurred in 24/65 (37%) patients during induction treatment and in 19/35 (54%) patients during maintenance. Eight/35 (23%) patients discontinued ixazomib treatment during the maintenance phase, while continuing with daratumumab once every eight weeks. The global health status/quality of life improvement significantly during treatment and was clinically significant from the 9th induction cycle onwards. Of the patients who experienced PD, second line treatment was started in 40 out of 42 patients (95%). The remaining 23 patients were still free of progression (18) or died before the occurrence of PD (5). Second line therapy was most commonly lenalidomide based (35/40; 88%). Conclusion: IDd treatment in intermediate-fit patients with NDMM is safe and improves global quality of life. However, PFS is limited, partly explained by limited efficacy due to frequent dose modifications of ixazomib, mainly due to neurotoxicity. This underscores the need for more efficacious and tolerable regimens improving the outcome in non-fit patients.
Multiple myeloma (MM) patients who become refractory to anti-MM drugs have a very poor prognosis. Therefore, it is important to gain insight into the mechanisms of resistance to these drugs. Immunomodulatory drugs (IMiDs) have immune-stimulatory and anti-angiogenic properties as well as direct anti-
<p>Supplementary Figure 2 - PDF file 50K, Accessory cells protect MM cells from WT-1 specific CTLs. U266 cells were co-cultured with WT-1 specific T cells in presence and absence of different accessory cells. MM cell viability was determined 24h after addition of T cells by CS-BLI (A). Granzyme B production in the supernatant was determined by ELISA (B). Significance of inhibition of MM cell survival in the presence of accessory cells was tested by unpaired two tailed student's t test. *= p<0.05; **= p<0.01</p>
Acute leukemia is a clonal expansion of malignant hematopoietic cells leading to impaired production of normal blood cells in the bone marrow (BM). Acute leukemia can be classified, according to the lineage involved, into acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).[1][1] AML
G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799). Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC; range: 5.0–800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria. As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified. 30 patients received 405 μg/kg QW (median 61.5 years [range 46–80]; 63% male; 100% triple-class exposed; 80% penta-drug exposed; 77% triple-class refractory, 20% penta-drug refractory; 30% prior BCMA-directed therapy; median follow-up [mF/U]: 7.5 mo [range 0.9–15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47–84]; 48% male; 96% triple-class exposed; 70% penta-drug exposed; 65% triple-class refractory, 22% penta-drug refractory; 17% prior BCMA-directed therapy; mF/U: 3.7 mo [range 0.0–12.0]). No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%; 1 grade 3 CRS), neutropenia (67%; grade 3/4: 60%), and dysgeusia (60%; grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%; all grade 1/2), dry mouth (44%; all grade 1/2), and neutropenia (44%; grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D; 6-month DOR rate was 67% (95% CI: 41–84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines. SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2; NCT04634552) and in combination with other therapies in patients with RRMM is underway.
Clinical Practice Points•We report a case of symptomatic cytomegalovirus (CMV) reactivation upon initiation of daratumumab monotherapy treatment in a heavily pretreated patient with multiple myeloma (MM).•In patients with MM, the risk of CMV reactivation is increased following autologous stem cell transplantation.•Limited data is available on the incidence of CMV reactivation in patients with MM who did not receive a stem cell transplantation.•To our knowledge, this is the first report of a symptomatic CMV reactivation during daratumumab monotherapy treatment.•Although routine monitoring for CMV is not recommended, the possibility of a CMV reactivation should be considered in patients with MM treated with daratumumab and infectious symptoms that cannot otherwise be explained. •We report a case of symptomatic cytomegalovirus (CMV) reactivation upon initiation of daratumumab monotherapy treatment in a heavily pretreated patient with multiple myeloma (MM).•In patients with MM, the risk of CMV reactivation is increased following autologous stem cell transplantation.•Limited data is available on the incidence of CMV reactivation in patients with MM who did not receive a stem cell transplantation.•To our knowledge, this is the first report of a symptomatic CMV reactivation during daratumumab monotherapy treatment.•Although routine monitoring for CMV is not recommended, the possibility of a CMV reactivation should be considered in patients with MM treated with daratumumab and infectious symptoms that cannot otherwise be explained. We present the case of a 57-year-old woman with a symptomatic cytomegalovirus (CMV) infection during daratumumab monotherapy treatment for relapsed/refractory multiple myeloma (MM). The patient was diagnosed with monoclonal gammopathy of unknown significance in 2001, which progressed to smoldering MM in 2005, and to symptomatic MM requiring systemic treatment in 2010. In August 2017, the disease relapsed again, being refractory to immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), bortezomib, and alkylators (melphalan, cyclophosphamide), as well as the SLAMF7-targeting antibody elotuzumab at that time. Daratumumab monotherapy (16 mg/kg) was initiated as seventh line of treatment. After 2 infusions, she presented with fever. History and physical examination revealed no signs of infection. Blood, urine, and sputum cultures were negative for microorganisms. Chest x-ray showed no pulmonary infiltrates. She was treated empirically with broad-spectrum antibiotics, amoxicillin/clavulanate, for 1 week, and the peripherally inserted central venous catheter was removed. No pathogens were cultured on the tip. Because of persisting fever, additional diagnostic tests were performed. Repeated laboratory examinations showed no abnormalities, and there was no evidence for mycobacterial disease or respiratory viruses (influenza virus A/B, metapneumovirus, respiratory syncytial virus, parainfluenza virus [types 1-4], rhinovirus, and coronavirus). A computed tomography scan of the chest and abdomen, as part of the diagnostic workup of fever of unknown origin, revealed no explanation for her symptoms. Meanwhile, her clinical condition deteriorated with the development of night sweats, anorexia, weight loss (5 kg), and fatigue. At this time, her platelet count (131 to 53 × 109/L) and hemoglobin level (8.0 to 6.3 mmol/L) decreased in the absence of neutropenia. Upon the development of chills, 3 weeks after she first reported fever, she was admitted to the hospital. Repeated cultures of blood, urine, and sputum remained negative for microorganisms. Given the persistence of fever, her immunocompromised status, and, at this point, inconclusive workup, we analyzed the potential reactivation of viral infections. Epstein-Barr virus DNA was not present in blood samples. However, high levels of CMV-DNA were detected in blood by quantitative polymerase chain reaction assay (> 100.000 copies/mL) indicating a symptomatic CMV infection. There was no CMV end-organ disease such as pneumonitis or hepatitis. She reported abdominal discomfort and diarrhea coinciding with the onset of fever, suggesting a possible CMV-colitis. However, because she refused endoscopic evaluation, this diagnosis could not be confirmed. Importantly, serologic antibody tests in 2010 already showed positivity for CMV-specific IgG, indicating CMV reactivation and not primary infection in the current situation.1Ljungman P. Boeckh M. Hirsch H.H. et al.Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials.Clin Infect Dis. 2017; 64: 87-91Crossref PubMed Scopus (674) Google Scholar Treatment with intravenous ganciclovir 5 mg/kg twice daily was initiated, resulting in normalization of her temperature within 24 hours. After 48 hours, the CMV-DNA load decreased to 58.000 copies/mL. She was discharged with continuation of valganciclovir orally 900 mg twice daily, and 2 months after diagnosis, the CMV-DNA load was repeatedly below the detection limit (< 500 copies/mL) and eventually became negative. Her symptoms did not recur, while at the same time, platelet counts and hemoglobin levels returned to baseline values and her diarrhea resolved. When this symptomatic CMV reactivation occurred, the patient had already achieved a partial response to daratumumab treatment. Owing to her extensive MM treatment history, alternative treatment options were limited, and would all induce additional immunosuppression. This, in combination with the rapid response to ganciclovir treatment, led to the decision to continue daratumumab according to the recommended schedule with regular monitoring of CMV-DNA load. At the same time, dexamethasone, which was given as infusion-related reaction prophylaxis, was tapered. She achieved a very good partial response with a duration of 7 months, during which her CMV DNA-load remained negative. Here, we describe a patient who suffered from a symptomatic CMV infection upon initiation of daratumumab monotherapy treatment. The risk of recurrent CMV infection is increased in immunocompromised patients, such as patients with primary immunodeficiencies or HIV infection, solid organ transplant recipients, and patients on hemodialysis.2Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation.Infect Dis Ther. 2018; 7: 1-16Crossref PubMed Scopus (113) Google Scholar In patients with hematologic disorders, the risk of CMV infection is markedly increased following allogeneic stem cell transplantation or autologous stem cell transplantation (ASCT) with CD34+-selected cells, as well as following treatment with high-dose corticosteroids, alemtuzumab, cladribine, or fludarabine, as a result of lower levels and dysfunction of natural killer (NK) cells, CD8+ T-cells, and CD4+ T-cells.2Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation.Infect Dis Ther. 2018; 7: 1-16Crossref PubMed Scopus (113) Google Scholar, 3Marchesi F. Pimpinelli F. Ensoli F. Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant.Hematol Oncol. 2018; 36: 381-391Crossref PubMed Scopus (46) Google Scholar, 4Drylewicz J. Schellens I.M. Gaiser R. et al.Rapid reconstitution of CD4 T cells and NK cells protects against CMV-reactivation after allogeneic stem cell transplantation.J Transl Med. 2016; 14: 230Crossref PubMed Scopus (26) Google Scholar Patients with MM have increased susceptibility to infections as a result of myeloma-induced immune dysfunction, including impaired T- and NK-cell activity, and decreased polyclonal immunoglobulin production, as well as cumulative immunosuppression of anti-MM treatment regimens.5Schutt P. Brandhorst D. Stellberg W. et al.Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections.Leuk Lymphoma. 2006; 47: 1570-1582Crossref PubMed Scopus (103) Google Scholar The incidence of CMV DNAemia, defined as presence of CMV-DNA without CMV-related symptoms,1Ljungman P. Boeckh M. Hirsch H.H. et al.Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials.Clin Infect Dis. 2017; 64: 87-91Crossref PubMed Scopus (674) Google Scholar and CMV disease in patients with MM are best studied following ASCT. In prospective studies, the incidence of CMV-DNAemia without CMV-related symptoms post-ASCT ranges from 14.7% to 42.3%. Given the low rate of patients with CMV-DNAemia that develop a symptomatic CMV infection, prospective monitoring of CMV titers in these patients is not recommended.3Marchesi F. Pimpinelli F. Ensoli F. Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant.Hematol Oncol. 2018; 36: 381-391Crossref PubMed Scopus (46) Google Scholar When CMV-DNA quantification was performed on clinical indication, the rate of symptomatic CMV infection post-ASCT ranges from 0.7% to 30.7%.3Marchesi F. Pimpinelli F. Ensoli F. Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant.Hematol Oncol. 2018; 36: 381-391Crossref PubMed Scopus (46) Google Scholar Bortezomib-containing induction regimens are associated with a higher incidence of CMV reactivation post-ASCT.3Marchesi F. Pimpinelli F. Ensoli F. Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant.Hematol Oncol. 2018; 36: 381-391Crossref PubMed Scopus (46) Google Scholar, 6Hasegawa T. Aisa Y. Shimazaki K. Ito C. Nakazato T. Cytomegalovirus reactivation in patients with multiple myeloma.Eur J Haematol. 2016; 96: 78-82Google Scholar, 7Marchesi F. Mengarelli A. Giannotti F. et al.High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.Transpl Infect Dis. 2014; 16: 158-164Crossref PubMed Scopus (34) Google Scholar Daratumumab is a monoclonal IgG kappa antibody targeting CD38, which is highly and ubiquitously expressed on MM cells. Daratumumab induces killing of tumor cells via classical Fc-dependent immune effector mechanisms.8van de Donk N.W.C.J. Richardson P.G. Malavasi F. CD38 antibodies in multiple myeloma: back to the future.Blood. 2018; 131: 13-29Crossref PubMed Scopus (321) Google Scholar Furthermore, daratumumab depletes regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells, leading to increased T-cell numbers and clonal T-cell expansion, which may result in an improved host–anti-tumor immune response.9Krejcik J. Casneuf T. Nijhof I.S. et al.Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.Blood. 2016; 128: 384-394Crossref PubMed Scopus (668) Google Scholar Daratumumab has high single-agent efficacy in heavily pretreated patients with MM who have relapsed from and/or are refractory to immunomodulatory agents and proteasome inhibitors,10Lonial S. Weiss B.M. Usmani S.Z. et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.Lancet. 2016; 387: 1551-1560Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar, 11Lokhorst H.M. Plesner T. Laubach J.P. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (910) Google Scholar and combines well with several standards of care.12Dimopoulos M.A. Oriol A. Nahi H. et al.Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 1319-1331Crossref PubMed Scopus (1144) Google Scholar, 13Palumbo A. Chanan-Khan A. Weisel K. et al.Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 754-766Crossref PubMed Scopus (1178) Google Scholar During daratumumab monotherapy, infection-related serious adverse events occurred in 10% of patients treated in the GEN501 trial.11Lokhorst H.M. Plesner T. Laubach J.P. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (910) Google Scholar In a similar trial, 2 patients out of 106 discontinued treatment owing to H1N1 infections.10Lonial S. Weiss B.M. Usmani S.Z. et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.Lancet. 2016; 387: 1551-1560Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar When daratumumab is combined with bortezomib-dexamethasone, the incidence of grade ≥ 3 infections is slightly higher compared with daratumumab monotherapy, but similar to the bortezomib-dexamethasone control group (21.4% compared with 19.0%), whereas in patients treated with daratumumab and lenalidomide-dexamethasone, this risk was higher compared with lenalidomide-dexamethasone alone (28.3% vs. 22.8%). In these studies, the incidence of pneumonia did not differ between patients treated with a daratumumab-based combination and those treated with lenalidomide-dexamethasone or bortezomib-dexamethasone alone.12Dimopoulos M.A. Oriol A. Nahi H. et al.Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 1319-1331Crossref PubMed Scopus (1144) Google Scholar, 13Palumbo A. Chanan-Khan A. Weisel K. et al.Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 754-766Crossref PubMed Scopus (1178) Google Scholar Until now, no CMV infections have been reported during daratumumab monotherapy treatment. The CMV reactivation in this patient is thought to be the result of the cumulative immunosuppressive effects of prior MM treatment in combination with daratumumab-mediated effects. Indeed, additional investigations performed directly after the diagnosis of CMV reactivation, showed very low CD4+ T-cell (50 × 103/mL; reference value, 404-1612 × 103/mL) and B-cell counts (0.21 × 103/mL; reference value, 114-436 × 103/mL), probably as a result of treatment with pomalidomide plus low-dose cyclophosphamide and dexamethasone prior to daratumumab therapy (Table 1). In addition, daratumumab has been shown to rapidly decrease NK cell counts, which occurred in all patients and is already evident after the first infusion.14Krejcik J. Frerichs K.A. Nijhof I.S. et al.Monocytes and granulocytes reduce CD38 expression levels on myeloma cells in patients treated with daratumumab.Clin Cancer Res. 2017; 23: 7498-7511Crossref PubMed Scopus (130) Google Scholar, 15Casneuf T. Xu X.S. Adams 3rd, H. et al.Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma.Blood Adv. 2017; 1: 2105-2114Crossref PubMed Scopus (146) Google Scholar Indeed, our patient had a low number of circulating NK cells in peripheral blood (1.2 × 103/mL; reference value, 100-400 × 103/mL) (Table 1).Table 1Peripheral Blood Immunophenotyping at Time of CMV InfectionMeasured ValueReference ValueAbsolute leukocyte count3.0 × 106/mL3.0-10.0 × 106/mLAbsolute lymphocyte count0.3 × 106/mL0.6-2.9 × 106/mLLymphocyte subsets T-cells297 × 103/mL700-2100 × 103/mLCD4+ T-cells50 × 103/mL404-1612 × 103/mLCD8+ T-cells216 × 103/mL216-499 × 103/mL B-cells0.21 × 103/mL114-436 × 103/mL NK cells1.2 × 103/mL100-400 × 103/mLCD4/CD8 ratio0.21.0-3.6Abbreviations: CMV = cytomegalovirus; NK = natural killer. Open table in a new tab Abbreviations: CMV = cytomegalovirus; NK = natural killer. To further characterize potential CMV reactivation during daratumumab treatment, we performed a quantitative CMV-DNA polymerase chain reaction in a cross-sectional manner in 19 patients with relapsed/refractory MM (median of 4 prior lines of treatment; range, 2-11) treated with daratumumab as a single agent. There was no CMV-DNAemia in these patients. Altogether, routine screening of CMV does not seem beneficial in patients treated with daratumumab. However, the possibility of a CMV reactivation should be taken into consideration in case of unexplained fever or bone marrow suppression, such as occurred in our patient, or signs suggestive of CMV end-organ disease. In conclusion, to the best of our knowledge, we report for the first time a patient who developed fever, diarrhea, anemia, and thrombocytopenia owing to CMV reactivation during daratumumab monotherapy treatment, which was associated with low T-cell and NK cell counts. We currently do not recommend routine screening for CMV in patients with MM during daratumumab treatment. However, CMV reactivation should always be considered in patients with MM treated with daratumumab or other novel agents with immunosuppressive effects, who develop fever or other complaints that cannot be otherwise explained.
