Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma.

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) µg/mL for DARA SC and 496 (SD, 231) µg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice. (Clinicaltrials gov. Identifier: NCT03277105.

Age is the most important predictor of survival in diffuse large B-cell lymphoma patients achieving event-free survival at 24 months: a Swedish population-based study.

Routine follow-up for diffuse large B-cell lymphoma have been shortened to 2 years when event-free survival at 24 months (EFS24) emerged as a new milestone. In the present study, we aimed to determine whether the achievement of this milestone affected overall survival (OS). We compared OS to that of an age- and sex-matched population, analysed other factors governing OS, and reviewed the causes of death. Data were collected from the Swedish Cancer Registry and from individual patient's records. We included 1169 adult patients from five counties between the years 2001 and 2014. The median (range) age was 64·6 (18-91) years, 56·6% were men and the median follow-up was 82·3 months. For early stages, the achievement of EFS12 did not improve OS. More than two-thirds of the patients (n = 837, 71·6%) achieved EFS24, of which 190 (22·7%) died during follow-up. Lymphoma (20%), cardiovascular disease (22·4%) and malignancies (16%) contributed to causes of death. Patients aged <60 years had an OS that matched the standard population. In multivariate analysis, only age >60 years significantly affected OS after EFS24 compared with the standard population. We concluded that follow-up beyond EFS24 should be considered for patients aged >60 years.

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. METHODS: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. FINDINGS: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 µg/mL (SD 306) in the subcutaneous group and 522 µg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). INTERPRETATION: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. FUNDING: Janssen Research & Development.

Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome.

Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever. Patients and methods: All adult patients treated 2000-2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records. Results: The number of patients with AID was 106 (17.3%). Thyroid disease dominated (n = 33, 31.1%) followed by rheumatoid arthritis (RA) (n = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) (p = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS (p = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%, p = .034) and those with neutropenic fever had a worse OS (p = .026) in Kaplan-Meier analyses. Conclusion: There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren's syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.

Does the omission of vincristine in patients with diffuse large B cell lymphoma affect treatment outcome?

The standard treatment for diffuse large B cell lymphoma (DLBCL) is rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine (VCR), and prednisone). Maintaining high dose intensity of cytotoxic treatment has been associated with better outcome but little is known about the role of maintaining VCR. This study aimed to answer whether the omission of vincristine due to neurotoxicity affects patient outcome. A Swedish cohort of patients primarily treated with curative intent for DLBCL or high-grade malignant B cell lymphoma was retrospectively analyzed. In total, 541 patients treated between 2000 and 2013 were included. Omission of VCR was decided in 95 (17.6%) patients and was more often decided during the last three cycles (n = 86, 90.5%). The omission of VCR did not affect disease-free or overall survival neither in the whole cohort nor in elderly patients. On the contrary, the relative dose intensity of doxorubicin was associated with overall survival (p = 0.014). Kidney or adrenal involvement (p = 0.014) as well as bulky disease (p = 0.037) was found to be associated with worse overall survival. According to our results, clinicians can safely decide to omit VCR in case of severe neurotoxicity due to VCR but should be aware of the importance of giving adequate doses of doxorubicin during treatment given the growing body of evidence on the role of dose intensity on survival. Considering the association of bulky disease and kidney/adrenal manifestation of lymphoma on survival, further studies should focus on whether the treatment options for these subgroups need to be individualized.

A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family.

UNLABELLED: In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (≥ 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. IN CONCLUSION: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.

OBJECTIVES: Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives. METHODS: Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms. RESULTS: After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P < 0.05) and the VGPR rate higher (P < 0.01) for Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group. CONCLUSIONS: Thalidomide (50-100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients.

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia.

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg-IFN-α2b) 50 µg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.