Fermand, Jean‐Paul

Abstract Background: In the pivotal FIRST trial, at the pre-specified planned analysis for progression-free survival (PFS), treatment (Tx) with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) improved outcomes for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) compared with melphalan, prednisone, and thalidomide (MPT), as well as Rd for 18 cycles (Rd18; Benboubker, NEJM 2014). Rd18 was added as a third arm to investigate whether Rd continuous Tx would control progression of NDMM longer than Rd18. Here, we present the final analysis of the overall survival (OS) data from the trial. Methods: Transplant-ineligible pts with NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles); both Rd18 and MPT were 72 weeks in duration. The primary endpoint was PFS and the key secondary endpoint was OS; the primary comparison was Rd continuous vs MPT. Other secondary endpoints included time to second therapy (TTST) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Results: At the time of cutoff for the final OS analysis (January 21, 2016), 52 of the 535 pts in the Rd continuous arm and none of the pts in the Rd18 (n = 541) and MPT (n = 547) arms continued to receive Tx. The median follow-up for surviving pts was 67.0 months (range, 0-86.8 months). In the pre-specified final OS analysis for the primary comparison, a statistically significant advantage in OS was shown with Rd continuous over MPT (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92; P = .00234; Table). OS for Rd continuous vs Rd18 was evaluated (HR, 1.02; 95% CI, 0.86-1.20). In this updated analysis, a PFS advantage continued to be seen for Rd continuous vs MPT (HR, 0.69; 95% CI, 0.59-0.79; P < .00001) and vs Rd18 (HR, 0.70; 95% CI, 0.60-0.81). Median TTST was longer for Rd continuous vs MPT (HR, 0.63; 95% CI, 0.54-0.73; Table). More pts in the Rd18 and MPT arms started second-line therapy (n = 377 and 381, respectively) compared with the Rd continuous arm (n = 299). Pts received a variety of Tx at progression, with bortezomib-based regimens the most common in the Rd continuous (n = 179; 59.9%), Rd18 (n = 208; 55.2%), and MPT (n = 170; 44.6%) arms. Pts who received bortezomib after Rd continuous or Rd18 had better outcomes than those who received it after MPT. PFS2 for Rd continuous was improved vs MPT (HR, 0.74; 95% CI, 0.64-0.85). Grade 3/4 adverse events (AEs) occurred in 86.3%, 80.2%, and 88.7% of the 532, 540, and 541 pts in the safety populations of the Rd continuous, Rd18, and MPT arms, respectively; the most common grade 3/4 AEs were neutropenia (29.5%, 26.5%, and 44.9%) and infections (31.6%, 21.9%, and 17.2%), and no new safety signals were seen compared with earlier analyses. Study discontinuation was most commonly due to disease progression and was less common in the Rd continuous vs Rd18 and MPT arms (50.7% vs 66.9% and 61.6%, respectively). Discontinuation due to AEs was similar across the Rd continuous, Rd18, and MPT arms (12.0%, 13.1%, and 13.9%). Solid tumor second primary malignancies (SPMs) occurred in 6.0, 6.9%, and 5.9% of pts, and hematologic malignancies occurred in 0.8%, 0.4%, and 2.6% of pts in the Rd continuous, Rd18, and MPT arms, respectively. Conclusions: Rd continuous significantly prolonged PFS and OS, and improved other secondary endpoints compared with MPT in transplant-ineligible pts with NDMM. Rd continuous also showed a PFS benefit compared with Rd18, delaying the time to next Tx. PFS2 outcomes suggest that Rd does not induce resistant relapses. Few hematologic malignancies occurred in the Rd arms, and the incidence of SPMs was similar between Rd continuous and Rd18. Rd continuous remains a standard of care for transplant-ineligible pts with NDMM. Disclosures Facon: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding. Belch:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Weisel:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Bahlis:BMS: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Geraldes:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. De La Rubia:Amgen, Bristol, Celgene, Janssen: Consultancy, Speakers Bureau. White:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria. Attal:janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; sanofi: Consultancy. Ervin-Haynes:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Houck:Celgene: Employment. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage due to the toxicity of the monoclonal immunoglobulin or to other mechanisms. The latter situation is increasingly observed but still poorly recognized and frequently undertreated, although it often requires rapid specific intervention to preserve involved organ function. To improve early recognition and management of these small B-cell clone–related disorders, we propose to introduce the concept of monoclonal gammopathy of clinical significance (MGCS). This report identifies the spectrum of MGCSs that are classified according to mechanisms of tissue injury. It highlights the diversity of these disorders for which diagnosis and treatment are often challenging in clinical practice and require a multidisciplinary approach. Principles of management, including main diagnostic and therapeutic procedures, are also described. Importantly, efficient control of the underlying B-cell clone usually results in organ improvement. Currently, it relies mainly on chemotherapy and other anti–B-cell/plasma cell agents, which should aim at rapidly producing the best hematological response.

Abstract Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.

AbstractSchnitzler's syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long‐term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzler's syndrome be suspected? How should the diagnosis of Schnitzler's syndrome be established? How should a patient with Schnitzler's syndrome be treated? How should a patient with Schnitzler's syndrome be followed up?. A diagnosis of Schnitzler's syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First‐line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow‐up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.