Measurable residual disease in multiple myeloma.  

With increasing evidence that measurable residual disease (MRD) negativity is associated with clinical outcomes, MRD is now being used as a primary endpoint in randomized phase 3 trials.  Mass spectrometry (MS) can detect multiple myeloma (MM)-derived monoclonal proteins in peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for MRD. A recent study evaluated the significance of PB MS MRD negativity during post-transplant therapy in 138 patients with newly diagnosed MM treated in the phase 3 ATLAS trial (NCT02659293) of post-transplant maintenance (without availability of pretreatment samples). They used the EXENT Immunoglobulin isotypes assay, which utilizes matrix-assisted laser desorption-ionization time of flight (MALDI-TOF) MS. The median follow-up from randomization was 33.3 months (IQR: 19.2-40.7).  MS was positive in 21% of immunofixation electrophoresis negative samples. This further translated into better outcomes of patients in complete response who achieved MS negativity as a best response, compared to those who remained MS positive (hazard ratio [HR]=0.33 [95% CI 0.11-0.98], p=0.003). There was high agreement between MRD by MS in PB and paired bone marrow (BM) MRD results (≥10-5 sensitivity was considered MRD positive), assessed by either next generation sequencing (NGS) or multiparameter flow cytometry (MFC), 70% and 67%, respectively. 

With NGS as the reference standard, sensitivity and specificity of MS was 63% and 74%, respectively. Discordant cases were split between MS+/NGS- (56/349, 16%) and MS-/NGS+ (50/349, 14%) cases,  with the positive predictive value (PPV) of 60% and negative predictive value (NPV) of 76%. The highest values for NPV and specificity were observed at cycle 18, while PPV was highest at cycle 6, and sensitivity at screening.  With MFC as the reference standard, sensitivity and specificity of MS was 60% (49%-69%) and 69% (64%-73%), respectively.  Discrepancy between MRD by MFC and MS was mostly driven by MS+/MFC- patients (125/499, 25%), whereas MS-/MFC+ was less frequent (40/499, 8%). The PPV was 32% (28%-37%) and the NPV was 87% (84%-90%). Sensitivity and NPV were highest after cycle 6, specificity peaked after cycle 18, and the PPV was at its maximum at screening.  

Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which in landmark analysis reached statistical significance after 18 cycles post-transplant (HR=0.39 (0.17-0.91), p=0.025). Combined PB/BM MRD negativity by MFC or NGS (‘double-negative’) was associated with superior PFS compared to MRD negativity by only one modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, post-transplant MS assessment in PB was feasible and provided additional prognostic information to BM MRD negativity. 

“Minimal” residual disease in multiple myeloma.  

Recently published was an ancillary study of Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0702 (STaMINA, ClinicalTrials.gov identifier: NCT01109004). Minimal residual disease (MRD) was measured by next-generation multiparameter flow cytometry (MFC; 10 monoclonal antibodies measured via six-color) of marrow aspirates in 435 patients with multiple myeloma at baseline/pre-autologous hematopoietic cell transplant (BL/preAutoHCT),  pre-maintenance (PM), and 1 year (Y1) after AutoHCT with a sensitivity of 10–5 to –6.The primary objective was to assess MRD-negativity (MRDneg) at Y1 after AutoHCT as well as progression-free survival and overall survival (PFS/OS). MRDneg at all three time points was associated with significantly improved PFS, and MRDneg patients at Y1 had significantly longer OS. Multivariate analysis of PFS, adjusting for disease risk and treatment arm, demonstrated hazard ratios (HRs) in MRD-positive patients compared with MRDneg patients at BL, PM, and Y1 of 1.55 (p=0.0074), 1.83 (p=0.0007), and 3.61 (p<0.0001), respectively. Corresponding HRs for OS were 1.19 (p=0.48), 0.88 (p=0.68), and 3.36 (p<0.001). The trajectory of sustained versus converted MRDneg at Y1 post-transplant did not differ for OS or PFS, and consolidation transplant strategies did not affect these associations. 

Untreated mantle cell lymphoma. 

Given the challenges associated with autologous stem cell transplantation (ASCT), it is natural to ask whether Bruton’s tyrosine kinase inhibitors could benefit people with mantle cell lymphoma (MCL) as front-line therapy and perhaps even replace ASCT. The TRIANGLE trial was recently published (NCT02858258). This open-label, randomized, three-arm, parallel-group, superiority  trial in patients with previously untreated, stage II–IV MCL, aged 65 years or younger and suitable for ASCT were randomly assigned  to one of three groups (1:1:1), which were a standard-of-care intensive induction regimen (group A: six alternating cycles of R-CHOP/R-DHAP [n=288]) followed by ASCT, the same regimen plus  fixed-duration ibrutinib (group A+I [n=292], and the same induction regimen plus fixed-duration ibrutinib but without ASCT (group I [n=290]), stratified by study group and MCL international prognostic index (MIPI) risk groups. 

After 31 months median follow-up, the investigators report that the addition of ibrutinib to intensive induction therapy plus ASCT improved time to progression versus induction therapy with ASCT: group A+I was superior to group A with 3-year failure-free survival of 88% (95% confidence interval [CI] 84–92) versus 72% (67–79; hazard ratio [HR] 0.52 [98.3% CI 0–0.86]; p=0.0008).  Superiority of group A over group I was not shown with 3-year failure-free survival of 72% (67–79) versus 86% (82–91; HR 1.77 [98.3% CI 0–3.76]; p=0.9979). The comparison of group A+I versus group I is ongoing. 

There were no relevant differences in grade 3–5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3–5 hematological adverse events and infections were reported after ASCT plus ibrutinib. Whether ASCT adds efficacy to an ibrutinib-containing regimen outweighing the considerable toxicity of ASCT, is still to be determined.

Immune thrombotic thrombocytopenia purpura treatment

Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenia purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. Caplacizumab was approved as an addition to PEX and immunosuppression for treating iTTP based on  randomized placebo-controlled trials. They showed that caplacizumab induced a faster resolution of the acute iTTP episode (TITAN trial) and a lower incidence of a composite of iTTP-related death, recurrence of iTTP, or a thromboembolic event during the treatment period (HERCULES trial).

A recent study analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of TTP.  The study compared the time from iTTP diagnosis (equal to starting PEX) until ADAMTS13 recovery (≥20%) in acute iTTP episodes treated with caplacizumab within ≤3 days from starting PEX, caplacizumab started >3 days from starting PEX, and episodes without any caplacizumab treatment.  There was no difference in the time to achieve ADAMTS13 activity (≥20%) after PEX end between caplacizumab-treated and non-treated episodes (median [interquartile range], 14.5 [7.7-27.2] vs. 13.0 [8.0-29.0] days, p=0.653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs. 11.0 [3.5-20.0] days, p=0.003) or than in non-caplacizumab-treated episodes (p= 0.033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs. 15.0 [11.0-21.5] days, p<0.001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, p<0.001).  There were no differences in time to ADAMTS13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated, and non-caplacizumab-treated episodes). The delay observed when the time at which PEX ended was considered as baseline can be explained by the earlier completion of PEX therapy in those patients who were administered caplacizumab, especially when this was started concomitantly with PEX and corticosteroids. 

Relapsed or refractory primary mediastinal large B-cell lymphoma. 

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) respond poorly to salvage therapy. Published recently were the results of 11 patients, two of them who were enrolled in the CheckMate436 study, and 9 who were treated with brentuximab vedotin-nivolumab (BV-Nivo) in a real-life, off-label compassionate use program. After a median follow-up of 44 months, median progression-free survival (PFS) and overall survival (OS) were not reached, 3-year PFS and OS were 65% and 71%, respectively. Patients received a median of cycles. None received auto or allogeneic stem cell transplantation (SCT). For the six PMBL with localized disease, five underwent consolidation radiotherapy (CRT), the overall response rate (ORR) after 4 cycles was 67% the 3-year PFS was 83%. For the three disseminated PBML, the ORR was 33%, the 3-year PFS was 67%. Treatment tolerance was good with a limited number of cycles administered; one patient developed a grade 2 peripheral neuropathy. One patient developed grade 1 thyroiditis related to nivolumab, and another developed multilocular granulomatosis (lymph nodes, pulmonary condensation, and spleen invasion) confirmed by lung biopsy, with spontaneous favorable evolution without intervention. No significant acute toxicity was observed after CRT. These data suggest that BV-Nivo, eventually followed by CRT, may be a reasonable approach for the treatment of R/R PMBL, without the need for SCT, especially for patients with localized relapse.

Relapsed or refractory marginal zone lymphoma

The antibody-drug conjugate against CD19, loncastuximab tesirine-lpyl (Zynlonta; from ADC Therapeutics SA) elicited a high response rate with acceptable tolerability in patients with relapsed or refractory marginal zone lymphoma (R/R MZL) according to initial data from a 50-patient single-arm, open-label phase 2 trial (NCT05296070). As of the data cutoff date of March 30, 2024, 15 patients with R/R MZL previously treated with ≥1 line of systemic therapy were evaluable. Of these, 13 patients achieved a complete response (CR, primary end point, at 6 months and 12 months) and one patient achieved a partial response (PR) with loncastuximab tesirine (six cycles across 18 weeks). Loncastuximab tesirine was also found to have an acceptable toxicity profile, with only 2 treatment discontinuations. One patient discontinued after cycle 2 and continued to be in CR at 10 months, and the other patient discontinued after cycle 4 and continued to be in CR at 6 months. These initial data were presented by the trial’s lead investigator at the Lymphoma Research Foundation’s 2024 Marginal Zone Lymphoma Scientific Workshop.