Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial.

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).

CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives.

A considerable proportion of non-small-cell lung cancer (NSCLC) patients will develop central nervous system (CNS) metastases throughout the course of their disease and these manifestations cause significant morbidity and mortality. Accordingly, novel therapies with high efficacy and low toxicity are needed for NSCLC-related CNS metastases. In NSCLC patients with activating epidermal growth factor receptor gene (EGFR) mutations EGFR-specific tyrosine kinase inhibitors (TKI) represent effective and well tolerated modes of therapy, however, it has been unclear whether these drugs are also able to cross the blood-brain-barrier (BBB) and cause remission of CNS metastases. Recent studies suggest that this might indeed be the case and intracerebral response rates of 70-80% in molecularly selected patients are considerably higher compared to what would be expected for standard approaches like systemic chemotherapy and whole brain radiation therapy. Limitations in the application of EGFR-TKI may arise from genetic heterogeneity between the primary tumor and CNS metastases. Accordingly, the acquisition of repeated biopsies from all relevant metastatic sites, including the CNS, may be necessary to guide therapeutic decisions. However, even in EGFR-wildtype patients EGFR-TKI seem to represent a valuable second line therapy with response rates of about 10%. Application of EGFR-TKI in a "pulsative" pattern may help to overcome insufficient delivery of TKI to the cerebro-spinal fluid and may further increase response rates and time until progression. In the future, combination of EGFR-TKI with radiation or chemotherapy and/or incorporation of next-generation TKI should be evaluated regarding their potential for further optimizing therapy of NSCLC patients with CNS metastases.

Leukemoid reaction in a patient with adenocarcinoma of the lung: a case report.

INTRODUCTION: Lung cancers are characterized by high incidence, prevalence and mortality. They may be associated with numerous paraneoplastic syndromes. Mild leukocytosis is not rare. The case described here, however, is of a female patient with adenocarcinoma of the lung who developed extreme leukocytosis at over 140,000 cells/µL. Descriptions of such leukemic forms of lung cancer are few and far between in the literature. In our case, the complete hematological diagnostic investigation, which included cytological, immunocytological, cytogenetic, histological and molecular genetic tests of the bone marrow (mutation analyses of BCR-ABL and JAK2), was accompanied for the first time by a molecular genetic workup of the primary tumor for epidermal growth factor receptor and K-RAS gene mutations. CASE PRESENTATION: We present the medical case of a 51-year-old female Caucasian patient, who was diagnosed with a poorly differentiated stage IV (International Union Against Cancer staging) adenocarcinoma of the lung. While undergoing treatment, our patient developed extreme leukocytosis, for which, despite extensive diagnostic tests, no infection-related or hematological cause could be identified. The tumor proved to be highly resistant to treatment. Our patient died only five months after the initial diagnosis. CONCLUSION: A leukemoid course can most likely be interpreted as the paraneoplastic production of hematopoietic growth factors. Despite the absence of a verified primary hematological origin, this possibility should always be investigated in all patients in a comparable situation.

[Complete remission of multiple brain metastases of non-small cell lung cancer induced by gefitinib monotherapy]. / Komplette Remission multifokaler zerebraler Metastasen bei chemotherapierefraktärem NSCLC durch Monotherapie mit Gefitinib.

BACKGROUND: While the activity of tyrosine kinase inhibitors as the first line treatment for primary tumors in patients with stage IV non-small cell lung cancer and a positive EGF receptor mutation is well known, little data on the efficacy in controlling cerebral metastases are available. CASE REPORT AND RESULTS: A 43-year-old woman was diagnosed with non-small cell lung cancer with cerebral and hepatic metastases. Emergency radiation therapy was initiated at the time of diagnosis due to superior vena cava syndrome. However, after she failed to respond to this therapy and in light of a positive EGF receptor mutation, gefitinib was added at a dose of 250 mg/day while continuing radiation to the primary lesion and cervical lymph nodes. She showed a rapid clinical and radiologic response with complete remission of the cerebral metastases 6 weeks after starting gefitinib. No severe toxicity was observed. CONCLUSION: This case demonstrates that gefitinib can be given during radiation treatment without significant toxicity. Furthermore, complete remission of cerebral metastases can be achieved with tyrosine kinase inhibitor monotherapy.

In-patient rehabilitation of lung cancer patients--a prospective study.

PURPOSE: It has not previously been shown whether there is any benefit to multi-morbid patients with lung cancer who participate in complex interdisciplinary rehabilitation programmes after primary therapy. The purpose of this prospective study was to assess changes in exercise capacity and quality of life before and after an in-patient training programme. PATIENTS AND METHODS: Forty-five patients with lung cancer (WHO I-III after surgery and/or radiotherapy and/or chemotherapy) were enrolled in a 28-day in-patient rehabilitation programme that included standardised aerobic training. Functional status and health-related quality of life (QLQ-C30, QLQ-LC13, SF-36, and MFI-20) were examined at the beginning of the study and at day 28. RESULTS: A substantial increase in work performance (bicycle ergometry from 68 +/- 3 to 86 +/- 4 W, p < 0.001, and 6-minute walk test from 322 +/- 11 to 385 +/- 13 m, p < 0.001) was registered. In addition, heart rate at rest was reduced (from 84 +/- 2 to 80 +/- 1 beats per minute, p < 0.05) and heart rate variability (indicator of the efficacy of endurance training) was significantly increased (from 9.7 +/- 1 to 12.9 +/- 1 root mean square of successive differences, p < 0.001). Moreover, there was also a significant improvement in quality of life (48 +/- 3 to 62 +/- 2, p < 0.001) while fatigue was reduced from 66 +/- 3 to 41 +/- 4, p < 0.001. CONCLUSION: A standardised, aerobic endurance training programme as part of the in-patient oncological rehabilitation of patients with lung cancer results in improvements in both physiological and psychological parameters after therapy. A follow-on study in order to determine to what extent this benefit persists over the long-term, particularly, in comparison with patients who have not participated in a rehabilitation programme, is currently being conducted.