Ajai Chari

Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.

BACKGROUND New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING Janssen Research & Development.

Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma

The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better.

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma

Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6-80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials.gov as #NCT01432600.

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.

Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971.

State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings

18-Flurodeoxyglucose Positron Emission Tomography with computed tomography (FDG PET/CT) and Magnetic Resonance Imaging (MRI) have higher sensitivity and specificity than whole-body X-ray (WBXR) survey in evaluating disease extent in patients with multiple myeloma (MM). Both modalities are now recommended by the Durie-Salmon Plus classification although the emphasis is more on MRI than PET/CT. The presence of extra-medullary disease (EMD) as evaluated by PET/CT imaging, initial SUVmax and number of focal lesions (FL) are deemed to be strong prognostic parameters at staging. MRI remains the most sensitive technique for the detection of diffuse bone marrow involvement in both the pre and post-therapy setting. Compression fractures are best characterized with MRI signal changes, for determining vertebroplasty candidates. While PET/CT allows for earlier and more specific evaluation of therapeutic efficacy compared to MRI, when signal abnormalities persist years after treatment. PET/CT interpretation, however, can be challenging in the vertebral column and pelvis as well as in cases with post-therapy changes. Hence, a reading approach combining the high sensitivity of MRI and superior specificity of FDG PET/CT would be preferred to increase the diagnostic accuracy. In summary, the established management methods in MM, mainly relying on biological tumor parameters should be complemented with functional imaging data, both at staging and restaging for optimal management of MM.

Proteasome inhibition and its therapeutic potential in multiple myeloma.

Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.

Phase II study of daratumumab (DARA) monotherapy in patients with >= 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).

LBA8512 Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. METHODS MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). RESULTS Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. CONCLUSIONS In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. CLINICAL TRIAL INFORMATION NCT01985126.

Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma.

Introduction Interleukin 6 is a pleiotropic cytokine produced by many cells in response to a variety of stimuli, including infections, trauma, and cancer. It is involved in several physiologic and pathophysiologic functions such as: acute phase protein synthesis, hematopoiesis, leukocyte and osteoclast activation, tumor growth, and cancer cachexia. Interleukin 6 is considered to play a role in the development of many types of malignancies, likely attributable to its influence on the expression of antiapoptotic and cell cycle genes. IL–6-associated malignancies include multiple myeloma, other hematopoietic malignancies and/or disorders (including Castleman’s disease), Kaposi’s sarcoma, and a variety of solid tumors. Interleukin 6 is especially prominent in the pathophysiology of the plasma cell dyscrasia MM. IL-6 is essential for B cell and particularly