Background: In patients (pts) with newly diagnosed multiple myeloma (NDMM), anti-CD38 monoclonal antibodies (CD38-mAb) increase efficacy of standard-of-care regimens. Addition of the CD38-mAb isatuximab (Isa) to lenalidomide, bortezomib, and dexamethasone (RVd) in pts with transplant-eligible NDMM met the primary endpoint of minimal residual disease (MRD) negativity in the bone marrow after induction therapy (Isa-RVd 50% vs. RVd 36%, OR 1.82, 95% CI 1.33-2.48, p<0.001; Goldschmidt H et al., 2022, Lancet Haematol.; NCT03617731). The present analysis compared the effect of induction therapy with Isa-RVd vs. RVd on secondary endpoint of progression-free survival (PFS). Methods: Pts with transplant-eligible NDMM at 67 sites in Germany were stratified by Revised International Staging System (R-ISS; Palumbo A et al., 2015, J Clin Oncol) and equally randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d po, d1-14 and d22-35; bortezomib 1.3 mg/m2 SC d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d po, d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33). In the Isa-RVd arm, Isa was added as follows: 10 mg/kg IV, cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29. Following induction therapy, pts underwent cyclophosphamide-based stem cell collection and subsequently proceeded to high-dose melphalan (200 mg/m2) and autologous hematopoietic stem cell transplant (ASCT). Second ASCT was recommended if pts achieved less than complete response (CR) after first ASCT or in case of high-risk cytogenetics. Pts were then randomized to receive maintenance with either lenalidomide alone (10 mg/d po continuously) or in combination with Isa (10 mg/kg IV, cycle 1: d 1, 8, 15, 22; cycles 2-3: d 1, 15; cycles 4-39: d 1) for up to 36 months. Cytogenetic risk status was defined as presence (high-risk) or absence (standard risk) of deletion17p, t(4;14), and/or t(14;16). PFS was defined as time from first randomization to progression or death from any cause, whichever occurred first. Weighted risk set estimator analyses accounting for second randomization (maintenance therapy) were applied to analyze PFS comparing Isa-RVd with RVd induction followed by lenalidomide maintenance. Data cut-off for the present analysis was January 31, 2024. Results: Between Oct 2018 and Sep 2020, 662 pts were included in the trial. The intention-to-treat analysis comprised 660 pts (Isa-RVd: 331 and RVd: 329). Baseline characteristics were well balanced. 225 (68%)/79 (24%) pts in the Isa-RVd arm and 179 (54%)/99 (30%) pts in the RVd arm received a single or tandem ASCT, respectively. After a median follow up of 47 months (95% CI 46-48), 179 PFS events occurred. Isa-RVd induction therapy significantly prolonged PFS compared with RVd (HR 0.70, 95% CI 0.52-0.94; stratified log-rank p=0.0184). 3-year PFS rates in the Isa-RVd and RVd arms were 83% (95% CI 79-87) and 75% (95% CI 70-80). The PFS benefit for Isa-RVd vs. RVd arm was confirmed on multivariable analysis, including R-ISS, age, sex, performance status, and renal insufficiency (HR 0.64, 95% CI 0.47-0.86; p=0.004). Subgroup analyses found a consistent PFS benefit for Isa-RVd vs. RVd induction among clinically relevant baseline subgroups (female and male sex, good performance status, ISS stages I, II, and III, normal and elevated LDH, standard risk cytogenetics). Patients with poor performance status (WHO grade >1, HR 1.09, 95% CI 0.47-2.52), and high-risk cytogenetics (HR 1.09, 95% CI 0.63-1.91) did not see benefit at this point. Weighted risk set estimator PFS analyses accounting for second randomization confirmed a significant benefit for Isa-RVd vs. RVd induction followed by lenalidomide maintenance (HR 0.63, 95% CI 0.38-1.07; stratified weighted log-rank p=0.016). Estimated, weighted 3-year PFS rates for Isa-RVd and RVd followed by lenalidomide maintenance were 84% (95% CI 79-89) and 73% (95% CI 67-79). OS was not mature with median OS not reached in either arm, and 3-year OS rates of 88% (95% CI 85-92) and 89% (95% CI 86-93) in the Isa-RVd vs. RVd arm. Conclusions: Addition of Isa to RVd during 18 weeks of induction therapy, followed by ASCT, resulted in a significant and clinically meaningful PFS benefit, regardless of the maintenance therapy strategy. The present analysis of the GMMG-HD7 trial supports the MRD negativity benefit reported previously. The trial is ongoing and will evaluate the addition of Isa to lenalidomide during maintenance after a re-randomization (part 2).

Background A broad spectrum of methods is used for the evaluation of disease activity and minimal residual disease (MRD) in multiple myeloma (MM), including minimally-invasive blood tests and invasive bone marrow analyses to asses residual disease. Mass spectrometry (MS) is a highly sensitive, emerging method to isotype and measure M-protein levels in the peripheral blood, holding the potential for less invasive assessment of therapy response and monitoring of peripheral residual disease (PRD). Herein, we present PRD data from the phase 3 randomized German-speaking Myeloma Multicenter Group (GMMG) HD7 trial (NCT03617731). Methods Serum samples (n = 3154) from 622 patients (pts) at major timepoints (baseline, post induction [IND], post [last] autologous stem cell transplant [ASCT], at 12 months from start of maintenance [MT12], at EOS and [suspected] progressive disease) treated within the GMMG-HD7 trial (Isa-RVd vs. RVd induction followed by randomization into Isa-R vs. R maintenance) were included for analysis, comprising pts with both intact Ig (n = 505) and light chain type (n = 117) MM. The samples were blinded for analysis using the EXENT® Analyzer combining automated IgG/IgA/IgM and total light chains (κ/λ) immune-purification and MALDI-TOF MS analysis to isotype, quantify and track monoclonal immunoglobulins. Results were screened for plausibility, matched to isotype by immunofixation at baseline, and manually reviewed in case of inconsistencies. Landmark analyses were performed post IND, ASCT, and MT12. As MS assessments of light chain type MM were non-inferior to assessments by immunofixation, qualitative assessments of monoclonal light chain persistence were also included in this analysis. Progression free survival (PFS) was measured as the time from the respective landmark until progressive disease or death from any cause, whichever occurred first. For analyses evaluating continued negative MRD (using next generation flow cytometry at a sensitivity of 10-5) from the bone marrow, and continued negative PRD, continued negativity was assessed from IND until ASCT. PFS was estimated using the Kaplan-Meier method, while Hazard ratios and corresponding 95% confidence intervals were obtained using a multivariable Cox regression model adjusted for relevant covariates (treatment arm, age, sex, Revised International Staging System for MM [R-ISS]). Results Post IND, post ASCT, and MT12 22%, 49%, and 79% of pts were PRD-. PRD negativity showed significant prognostic value for PFS (IND HR 0.38, 95% CI 0.23–0.66; p < 0.001 / ASCT HR 0.43, 95% CI 0.29–0.65; p < 0.001 / MT12 HR 0.26, 95% CI 0.15–0.46; p < 0.001). Similar to previously published reports (e.g., Puig et al. 2024; Kubicki et al. 2024; Mai et al. 2023; Claveau et al. 2022), prognostic impact of PRD by MS was most pronounced at later timepoints. When combined with paired bone marrow MRD, the PRD/MRD double-negative pts showed significantly better PFS compared to the double-positive pts (IND HR 0.21, 95% CI 0.11–0.42; p < 0.001; ASCT HR 0.26, 95% CI 0.16–0.43; p < 0.001; MT12 HR 0.09, 95% CI 0.04–0.19; p < 0.001). Compared to double-positive pts, pts with either only PRD- or MRD- status had a similar PFS (e.g., MT12 (PRD+/MRD-): HR 0.11, 95% CI 0.04–0.34; p < 0.001; MT12 (PRD-/MRD+): HR 0.12, 95% CI 0.01–0.97; p = 0.047). Continued PRD- or MRD- status was associated with significantly improved PFS as compared to non-continued PRD- or MRD- status (PRD-/MRD- continued vs. non-continued: HR 0.43/0.33, 95% CI 0.23–0.81/0.21–0.52; p = 0.009/< 0.001). In-depth comparisons of PRD course show significantly improved PFS for continued PRD- vs. PRD+ pts (HR 0.34, 95% CI 0.18–0.65; p = 0.001), and PRD positive-to-negative vs. continued PRD+ pts (HR 0.44, 95% CI 0.27–0.73; p = 0.001). Conclusion The results from the phase 3 GMMG-HD7 trial underscore the significant prognostic value of PRD assessment for newly-diagnosed MM, especially during later timepoints. Association with simultaneous bone marrow MRD assessment demonstrates the utility of PRD as a minimally-invasive option for disease monitoring. Positive PRD results gained significant prognostic value when confirmed by a positive MRD measurement and vice versa. Continued PRD response showed similar prognostic impact as established continued MRD from the bone marrow, highlighting the potential value of MS PRD tracking as an emerging modality for long-term follow-up in pts with newly-diagnosed MM.

Background: Minimal residual disease negativity (MRDneg) in the bone marrow is associated with improved survival outcomes in patients (pts) with newly diagnosed multiple myeloma (NDMM). The randomized, multicenter phase 3 GMMG-HD7 trial (NCT03617731) demonstrated that addition of anti-CD38 monoclonal antibody isatuximab (Isa) to standard of care treatment lenalidomide, bortezomib, and dexamethasone (RVd) in pts with transplant-eligible NDMM significantly increased MRDneg rates after induction therapy (Isa-RVd 50% vs. RVd 36%, OR 1.82, 95% CI 1.33-2.48, p<0.001; Goldschmidt H et al., 2022, Lancet Haematol.). Here we present landmark analyses exploring the impact of MRDneg and continued MRDneg on progression-free survival (PFS). Methods: Pts with transplant-eligible NDMM were stratified by Revised International Staging System (Palumbo A et al., 2015, J Clin Oncol.) and equally randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d po, d1-14 and d22-35; bortezomib 1.3 mg/m2 SC d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d po, d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33). In the Isa-RVd arm, Isa 10 mg/kg IV, cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29 was added. Following induction therapy, pts underwent stem cell collection, high-dose melphalan therapy (200 mg/m2) and autologous hematopoietic stem cell transplant. Pts were then randomized to receive maintenance with either lenalidomide alone (10 mg/d po continuously) or in combination with Isa (10 mg/kg IV., cycle 1: d 1, 8, 15, 22; cycles 2-3: d 1, 15; cycles 4-39: d 1) for up to 36 months. MRDneg from bone marrow samples was assessed by next-generation flow cytometry (sensitivity 10-5) independent of International Myeloma Working Group response rates. Continued MRDneg status was defined as MRDneg persisting from post induction to post intensification. PFS was defined as time from respective landmark to progression or death from any cause, whichever occurred first. Data cut-off for the present analyses was January 31, 2024. Results: Between Oct 2018 and Sep 2020, 662 pts were included in the trial. The intention-to-treat analysis comprised 660 pts (Isa-RVd: 331 and RVd: 329). Baseline characteristics were well balanced. PFS results from first randomization are reported separately. At this respective PFS landmark analyses post induction and post intensification, higher proportions of patients in the Isa-RVd arm vs. RVd arm had improved rates of MRDneg and continued MRDneg. PFS analyses from end of induction therapy comprised 282 MRDneg pts (Isa-RVd: 166/55% and RVd:116/41%) and 304 MRD positive (MRDpos) pts (Isa-RVd: 136/45% and RVd: 168/59%). PFS was significantly longer in pts achieving MRDneg (HR 0.38, 95% CI 0.26-0.55; p<0.001) with 3-year PFS rates from end of induction therapy of 88% (95% CI 85-92) for MRDneg pts and 71% (95% CI 66-77) for MRDpos pts. Among MRDneg pts, PFS was similar in the Isa-RVd and RVd arms (HR 1.12, 95% CI 0.60-2.11, p=0.72). In MRDpos pts, PFS was significantly longer with Isa-RVd vs. RVd (HR 0.64, 95% CI 0.43-0.96; p=0.03). Analyses of the impact of continued MRDneg on PFS from start of maintenance therapy included 227 pts with continued MRDneg (Isa-RVd: 138/53% and RVd:89/38%) and 267 without continued MRDneg (Isa-RVd: 122/47% and RVd: 145/62%). PFS was significantly prolonged in pts with continued MRDneg compared with those without continued MRDneg (HR 0.41, 95% CI 0.25-0.65; p<0.001). 3-year PFS rates from start of maintenance therapy were 90% (95% CI 86-94) in pts with continued MRDneg and 77% (95% CI 72-83) in pts without continued MRDneg. Pts in the Isa-RVd and RVd arm with continued MRDneg had similar PFS (HR 1.13, 95% CI 0.49-2.61; p=0.77). Among pts without continued MRDneg, PFS was longer in the Isa-RVd arm vs. the RVd arm (HR 0.68, 95% CI 0.41-1.13; p=0.14). Multivariable analyses including induction treatment arm, key baseline patient characteristics and disease risk factors confirmed the significant prognostic impact of MRDneg on PFS from end of induction therapy (HR 0.37, 95% CI 0.26-0.55; p<0.001) and continued MRDneg on PFS from start of maintenance therapy (HR 0.44, 95% CI 0.27-0.72; p=0.001). Conclusions: More pts achieved MRDneg and continued MRDneg with Isa-RVd vs. RVd, while the PFS benefit after obtaining MRDneg and continued MRDneg was similar in both arms. For pts who have MRDpos and continued MRDpos, the addition of Isa to RVd is associated with a favorable PFS vs. RVd alone.

Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731) resulted in a significant increase of minimal residual disease negativity (MRD-) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide. We report updated results for part 1 from first random assignment to post-transplant. As of January 31, 2024, MRD- rates continued to deepen after transplant (66% Isa-RVd v 48% RVd). Isa-RVd induction therapy significantly prolonged progression-free survival (PFS) compared with RVd regardless of maintenance therapy (hazard ratio, 0.70 [95% CI, 0.52 to 0.95]; P = .0184). Weighted risk set estimator analysis accounting for second random assignment followed by maintenance with only lenalidomide confirmed a statistically significant benefit for Isa-RVd followed by lenalidomide maintenance versus RVd followed by lenalidomide maintenance (stratified weighted log-rank test P = .016). In conclusion, after 18-week induction therapy followed by transplant without consolidation therapy, adding Isa to RVd resulted in a significant PFS benefit, regardless of maintenance strategy.

Therapy adherence can significantly influence the outcome of cancer patients. The prospective, non-interventional CARO study (NCT02970747) investigated adherence, effectiveness, and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) in the German real-world setting. In total, 359 patients were included at 69 sites. Data on carfilzomib combination regimens were evaluated for three treatment cohorts: carfilzomib with lenalidomide and dexamethasone (KRd), with dexamethasone only (Kd) or with daratumumab and dexamethasone (KdD). Encouragingly, patients maintained levels of treatment adherence >= 95% to carfilzomib across cohorts. The effectiveness outcomes of CARO were in line with previous data. Median PFS (95% CI) was 17.5 months (14.5, 24.7 [KRd]), 13.4 months (7.0, 18.1 [Kd]), and 15.6 months (9.9, NA [KdD]), respectively. Median OS was 38.9 months (31.5, 53.9 [KRd]), 24.2 months (17.3, 36.8 [Kd]), and not reached (KdD). Overall, the CARO study impressively demonstrates efficacy and safety of KRd, Kd, and KdD regimen in real-world.

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.

Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront “novel agents” in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with “conventional” (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to “outdated” treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront “novel agents”.

INTRODUCTION:Survival data reported by randomised controlled trials are collected in a highly selected patient population and can thus only be transferred to a limited extent to real-world patients: the patients in routine care are mostly older, present with more comorbidities and a worse general state of health. This so-called efficacy-effectiveness gap typically results in inferior survival data in routine healthcare. METHODS:Six prospective clinical tumour registries recruited a total of 11,679 patients receiving systemic therapy in haemato-oncological practices in Germany between 2006 and 2020. For these patients with advanced colorectal cancer, breast cancer, lung cancer, pancreatic cancer, renal cell cancer, and lymphatic neoplasms, overall survival was analysed. A comprehensive literature search was performed to identify suitable pivotal randomised controlled trials. RESULTS:Median overall survival of patients treated in German routine care, with advanced colorectal, breast, lung, and pancreatic cancer, as well as with diffuse large B-cell lymphoma and multiple myeloma, is not shorter than the respective survival data reported in trials. Patients with advanced renal cell carcinoma, chronic lymphocytic leukaemia, or indolent non-Hodgkin lymphoma showed slightly lower survival rates compared to clinical trials. CONCLUSIONS:Despite less favourable patient characteristics, survival data from patients with cancer treated in ambulatory routine care in Germany are in range with results from randomised controlled studies.

Treatment regimen an iwCLL and MRD response. The therapeutic armamentarium for chronic lymphocytic leukemia (CLL) has improved dramatically in the recent years: the CD20 antibodies, inhibitors of BTK and Bcl2, as well as their combinations have replaced chemoimmunotherapy in first-line and relapse therapy. Idelalisib, an inhibitor of the δ-isoform of the phosphatidyl-inositol-3-kinase in the B-cell receptor signaling pathway, plays only a minor role in the treatment of CLL because of an increased risk of serious (opportunistic) infections. The CLL2-BCG study is part of a series of phase-II trials conducted by the German CLL Study Group which evaluate a sequential treatment consisting of an optional debulking with bendamustine, followed by an induction and a maintenance with a targeted agent combined with an anti-CD20 antibody. These trials used a measurable residual disease (MRD)-guided discontinuation strategy called "sequential triple-T concept" (tailored, targeted treatment aiming at a total eradication of CLL).1-5 The CLL2-BCG study tested bendamustine, followed by obinutuzumab and idelalisib. The CLL2-BCG trial is a prospective, open-label, multicenter phase-II-trial initiated by the German CLL Study Group with the University of Cologne, Germany, being the legal sponsor (participating sites and recruitment: Table S1 and Figure S1). The sequential treatment started with an optional debulking with 2 cycles bendamustine (recommended for patients with absolute lymphocyte counts ≥25 000/μL or lymph nodes ≥5 cm without contraindications). In the induction (8 months) obinutuzumab was administered 4-weekly and in the maintenance phase (up to 24 months) 12 weekly, while idelalisib was taken continuously from the second cycle onwards. Treatment was stopped in case of a deep response with a complete remission and undetectable MRD in peripheral blood in two assessments within an interval of 3 months (study design: Figure S2). Otherwise this combination was continued for a maximum of 32 months, until unacceptable toxicity, or progression and/or new CLL treatment. Initially, the study recruited an all-comer population of treatment-naive and relapsed/refractory CLL patients irrespective of their physical fitness, comorbidities and high-risk genetic markers. Due to an increased rate of infections in other idelalisib trials, recruitment was later limited to patients with relapsed/refractory CLL with high-risk features such as TP53 deletion/mutation and/or ineligibility for ibrutinib treatment, for whom only few alternative therapies were available (eligibility criteria: Supporting information S1 p2-3). Furthermore, all first-line patients had to discontinue treatment with idelalisib, but were allowed to continue with obinutuzumab according to the treatment schedule if considered reasonable by the treating physician. The primary endpoint was the overall response rate (ORR) at the end of induction. Analyses were performed in a descriptive manner without confirmatory testing as the number of enrolled patients was relevantly lower than initially planned. All analyses are based on the final dataset of the trial as of 1st September 2022 with a median observation time of 37 months (range: 1–51 months). All patients provided written informed consent. The study was approved by the health authorities and the institutional review board of each participating site, was registered with ClinicalTrials.gov number NCT02445131. Between May 2015 and September 2019, a total of 48 patients were enrolled, including 33 (70%) with an unmutated IGHV, 19 (40%) with a TP53 mutation or deletion and 15 (42%) with a complex karyotype with ≥3 aberrations (patient's characteristics: Table S2). Sixteen patients (33%) had treatment-naive CLL and 32 (67%) relapsed/refractory CLL with a median of 2 (range: 1–10) prior therapies, 10 patients had received at least one treatment with a targeted agent (Figure S3a,b). Thirty-eight patients (79%) received bendamustine for debulking, but eight discontinued treatment before the induction due to safety concerns with idelalisib. Forty patients (83%) received at least one dose of induction therapy (efficacy population), 33 completed the six cycles of induction treatment and 27 also continued with maintenance treatment (consort diagram: Figure S4). Nine patients had suboptimal treatment exposure because they discontinued idelalisib due to the novel safety data during or shortly after the induction. The mean dose intensity of the planned dose of idelalisib was 43% in the induction and 5% in the maintenance in the first-line cohort, and 76% in the induction and 58% in the maintenance in the relapsed/refractory cohort. While the mean dose intensity for obinutuzumab in induction and maintenance was 88% and 89% of the planned dose in the first-line and 94% and 78% in the relapsed/refractory patients, respectively (see also Table S3). At the end of induction, 32 of 40 patients responded (ORR 80%, 95% confidence interval 64%–91%), including all 19 patients (100%) from the first-line and 22 of the 30 patients (73%) in the relapsed/refractory cohort (Figure 1A and Table S4a). Nine patients (23%, three patients with previously untreated and six with relapsed/refractory CLL) achieved undetectable MRD (<10−4) in peripheral blood (Figure 1B and Table S4a). After debulking, an iwCLL response was already achieved in 19 of 38 patients (50%) (Table S4b). At the end of maintenance treatment, the ORR was 85% (23 of 27 patients), including three patients with a CR according to iwCLL criteria, another seven were only lacking a CT scan and/or bone marrow examination. Fifteen patients had undetectable MRD in peripheral blood, including 5 in the first-line and 10 in the relapsed/refractory cohort. Five patients with relapsed/refractory CLL also had undetectable MRD in bone marrow, the other 22 patients did not undergo a bone marrow biopsy (Figure 1A,B, Table S4c). Seven of 27 patients improved their MRD level during maintenance treatment, including six with a conversion to undetectable MRD (Table S5). Among the 10 patients who had already received a targeted agent, eight completed the full six cycles of induction treatment and three of them achieved a PR at the final restaging after induction, including one each with an undetectable, intermediate and high MRD level. With continued maintenance treatment, two patients remained in a PR and one patient progressed, the patient with the intermediate MRD level converted to undetectable MRD. The estimated rate of progression-free survival (PFS, defined as the time between registration and first disease progression or death) after 3 years was 69% in the first-line and 41% in the relapsed/refractory cohort (Figure S5). The median PFS from termination of maintenance treatment was not reached for eight patients who stopped treatment early due to a deep remission with undetectable MRD levels, with an estimated PFS rate of 75% after 1 year since treatment discontinuation. Five of them are still in remission after a median time of almost 2 years after end of treatment (Figure S6). The estimated rate of overall survival (OS, defined as the time between registration and death) after 3 years was 90% in the first-line and 78% in relapsed/refractory patients (Figure S7). Of the nine deaths, seven were fatal infections, but three infections were considered unrelated because they occurred either more than half a year after end of treatment or after disease progression/start of subsequent treatment (Table S6). A total of 599 adverse events (AEs) were reported for the entire study duration in 46 of all 48 patients (96%), according to investigator assessment, 315 (53%) were related to study drug and 130 (22%) were serious AEs (Table S7). Sixty-nine AEs (in 30 patients) led to a temporary interruption of one or both study drugs, 22 (in 15 patients) to dose reductions and 19 (in 13 patients) to a permanent discontinuation of one drug or all treatment. During bendamustine debulking, a total of 98 AEs occurred in 30 of 38 patients (79%), most common were infections, cytopenias and gastrointestinal disorders (Table S8). With obinutuzumab and idelalisib, 284 AEs occurred in 39 of 40 patients (98%) in the induction and 150 AEs in 25 of 27 patients (93%) in the maintenance phase. Most common toxicities during induction and maintenance were infections (91 episodes in 35 patients [88%], including 19 patients [48%] with a CTC grade III or higher), followed by cytopenias and gastrointestinal disorders (Table S9). The known relevant, sometimes severe and fatal toxicities of idelalisib were observed also in this trial, but no unexpected or cumulative toxicities occurred with the combination of idelalisib and obinutuzumab and with the prior debulking with bendamustine. The safety measures taken during the conduct of the trial led to a lower than planned treatment intensity. Also, the patient cohort is smaller and a high proportion of patients had adverse risk factors and/or extensive prior therapy. In light of this, the overall response rate at the end of the induction treatment (primary endpoint of the trial) of 80% is in the expected range. However, the rate of undetectable MRD of 23% is relatively low, partly because a relevant proportion of patients (28%) did not undergo MRD testing. The iwCLL and MRD response was improved with maintenance treatment in five and seven patients, respectively. Eight patients were able to stop maintenance treatment early due to a deep remission as defined by protocol and a relevant number of them remained in remission for a clinically meaningful time. The responses among the 10 patients with a prior therapy with targeted agents were disappointing, which underlines the high medical need to develop novel therapeutic approaches for these patients. Thus, this combination should be used with caution and only if all other treatment options are exhausted, that is, covalent BTK inhibitors, venetoclax and novel therapeutic alternatives, for example, the non-covalent BTK inhibitor pirtobrutinib, T-cell-engaging bispecific antibodies (e.g., epcoritamab) or cellular therapies have failed or cannot be used. Paula Cramer, Julia von Tresckow, Barbara Eichhorst and Michael Hallek were responsible for the conception and design of the study; Paula Cramer, Julia von Tresckow, Anna-Maria Fink, Sandra Robrecht, Othman Al-Sawaf, Petra Langerbeins and Kirsten Fischer were responsible for the trial management; Paula Cramer, Julia von Tresckow, Eugen Tausch, Lothar Müller, Wolfgang Knauf, Matthias Zingerle, Othman Al-Sawaf, Petra Langerbeins, Michael Kneba, Clemens-Martin Wendtner, Stephan Stilgenbauer, Barbara Eichhorst and Michael Hallek were responsible for the recruitment and treatment of patients; Paula Cramer, Julia von Tresckow, Anna-Maria Fink, Sandra Robrecht and Adam Giza had access to the raw data; Paula Cramer performed a central review of all clinical data; Eugen Tausch, Karl-Anton Kreuzer, Michael Kneba and Stephan Stilgenbauer performed the laboratory analyses; Sandra Robrecht and Adam Giza performed the statistical analysis. All authors interpreted the data; Paula Cramer wrote the first draft of the manuscript and all authors approved the final manuscript. The authors wish to express their gratitude towards all patients participating in the trial, as well as the physicians and trial staff at the sites (participating sites: Supporting information S1 p1). Also, we thank the study management team with the project managers Tanja Annolleck, Johanna Wesselmann, Miriam Schüler-Aparicio and Angelina Glatt, the safety managers Sabine Frohs, Tanja Annolleck and Berit Falkowski, the data managers Olga Korf, Florian Drey, Viktoria Monar and Irene Preißler-Stodden, the statisticians Jasmin Bahlo, Can Zhang, and Gracia Braun, as well as Dr. Birgit Fath and the monitors from the "competence network malignant lymphoma" ("Kompetenznetz Maligne Lymphome"). The CLL2-BCG trial is an investigator-initiated trial with the University of Cologne being the legal sponsor; financial support and the study drugs were provided by the pharmaceutical companies Gilead and F. Hoffmann-LaRoche. Researchers interested in accessing the de-identified clinical data of this study may submit a formal request to the corresponding author which should include a detailed research proposal, objectives, and an explanation of how the data will be used. Researchers accessing the data will be required to sign a data sharing agreement outlining the terms and conditions of use. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

In IONA-MM first interim analysis, we report comparable baseline characteristics to those seen in ICARIA-MM/IKEMA with few imbalances. Isa-Pd/ Isa-Kd have manageable safety profiles in routine clinical practice. These data provide RWE to support Isa use in RRMM outside clinical trials and in wider populations. Enrollment in IONA-MM is ongoing until sample size n=1,100 is reached.

The COVID-19 pandemic has led to deviations in all sectors of cancer care. We present multidisciplinarily approved recommendations for ethically and empirically based prioritisation of procedures in times of scarce resources for patients with colorectal and pancreatic cancer. The CancerCOVID consortium conducted qualitative and quantitative studies on ethical challenges and psychosocial stress of patients and health care professionals in cancer care. For empirical analyses we obtained data from AOK Plus, the main health insurance in Saxony, AIO (Arbeitsgemeinschaft internistische Onkologie) cancer centers, the institute of Pathology Bochum, the ColoPredict Registry and data of outpatient care from the BNHO (Berufsverband der Hämatologen und Onkologen) and Onkotrakt AG. A selective literature review of international data and guidelines focussing on the effects of the pandemic on cancer care and allocation of resources was conducted. Structured group discussions on justified criteria for prioritisation were held with experts from oncology, ethics, law and health research. Recommendations for prioritisation were formulated as S1 guideline with approval of 9 AWMF Medical Societies, 22 multidisciplinary experts and patient representatives. The main principle for decisions on prioritisation in times of scarce resources is the minimisation of individual and aggregated harm. In case of relevant risk of harm from a possible low priority classification or postponement prioritization decisions should be made individually for the respective patients according to the multiple-eyes principle. Decision making should involve different disciplines and professions depending on local infrastructure. We concretised recommendations for 5 areas in cancer care. Guidelines based on a broad multidisciplinary consensus can give ethically and empirically based support in medical decision making when resources are scarce. This can provide relief for decision-makers and facilitate transparency and trust of patients and population.

BACKGROUND:Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma. METHODS:This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731. FINDINGS:Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related. INTERPRETATION:Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma. FUNDING:Sanofi and Bristol Myers Squibb (Celgene).