REFRACTORY GUILLAIN-BARRÉ SYNDROME IN A PATIENT WITH ASYMPTOMATIC MULTIPLE MYELOMA SUCCESSFULLY TREATED WITH LOW-DOSE RITUXIMAB.

Despite being extremely rare, Guillain-Barré syndrome (GBS) has been recognized as a neurological complication of multiple myeloma, with variable responses to plasmapheresis (PEX), intravenous immunoglobulins (IVIG), and anti-myeloma therapies. In this paper, we report a case of a female patient with asymptomatic multiple myeloma (aMM) who initially presented as PEX- and IVIG-refractory GBS. After failure of PEX, IVIG, and anti-myeloma therapy (bortezomib, melphalan, and prednisone), the patient was eventually successfully treated with low-dose rituximab (100 mg/m2 per week in four doses). To the best of our knowledge, this is the first case to report successful treatment of refractory GBS potentially associated to aMM with low-dose rituximab. Additional studies are needed to elucidate the pathophysiological processes and the interplay between the dysregulated immune response, monoclonal immunoglobulin (MG), and neural tissue damage in GBS patients. Also, the potential role of rituximab in the treatment of MG-associated GBS warrants further exploration.

Are we ready to look beyond plasma cells in assessing high-risk smoldering myeloma?

Sklavenitis-Pistofidis et al. report clinical and correlative results of a single-arm phase II trial of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering myeloma. The authors explore the interactions between the genetics of the plasma cell clone and the immune microenvironment as potential biomarkers of treatment susceptibility and efficacy.

Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study.

BACKGROUND: Smoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation. METHODS: The QuiRedex phase 3 trial initiated in 2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363). FINDINGS: After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18-0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96). INTERPRETATION: This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS. FUNDING: Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.

The effect of intervention versus watchful waiting on disease progression and overall survival in smoldering multiple myeloma: a systematic review of randomized controlled trials.

BACKGROUND: Smoldering multiple myeloma (SMM) is an intermediate pre-malignant condition with individuals having a distinct risk of progression to overt myeloma. The optimal management option has remained controversial due to the heterogeneous nature of the condition in which progression to overt diseases is variable. The question of who, when, and what to use for the treatment of SMM remains equivocal. We performed a systematic review of randomized controlled trials and summarized the current evidence supporting the best approach to the management of SMM. METHODS: A comprehensive literature search of Medline/PubMed, PubMed Central, Embase, Scopus, Web of Science, Wiley Cochrane Library, CINAHL, clinicaltrial.gov, and conference proceedings of ASCO, ASH, EHA, and ESMO was performed on October 25, 2020. Synthesis of the result was done using narrative analysis. RESULT: Of the total 1560 identified records, 10 eligible studies involving 1157 patients made up of 580 in the intervention group and 577 in the control group were included in this review. Three early trials of melphalan and prednisone fail to demonstrate any significant impact on disease progression with major toxicities reported. Three trials on bisphosphonate monotherapy show reduced skeletal-related events without any clinical effect on disease progression. Lenalidomide monotherapy or as part of a combination therapy demonstrates superiority in delaying disease progression over observation. Only Lenalidomide and dexamethasone combination demonstrated superior overall survival over observation across the trials. CONCLUSION: Trials of lenalidomide in a less intensive approach has shown promise in delaying disease progression and should be investigated further in clinical trials.

The benefits of early intervention using lenalidomide for high-risk smoldering multiple myeloma: emerging data and its promising clinical impact.

INTRODUCTION: Multiple myeloma is preceded by the early stages: monoclonal gammopathy of unknown significance (M.G.U.S.) and smoldering myeloma (S.M.M.), which are less genomically complex and where patients are overall healthier with preserved quality of life. AREAS COVERED: This review focuses on the current evidence in risk stratification and initial therapy for these patients with the goal to delay progression to and/or cure multiple myeloma. EXPERT OPINION: Advances in the understanding of the factors that contribute to myeloma evolution coupled with new therapeutics that have high efficacy and limited toxicity have revolutionized our approach to early myeloma. Although our current recommendation continues to be to observe S.M.M. outside of clinical trials, the clinical benefit of lenalidomide sets the stage for combinations with immunotherapy, which, in our opinion, will likely lead to regulatory approvals and more widespread treatment of early myeloma.

Persistent challenges with treating multiple myeloma early.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

Changing paradigms in diagnosis and treatment of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).

Multiple myeloma (MM) is a highly heterogenous disease that exists along a continuous disease spectrum starting with premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) that inevitably precede MM. Over the past two decades, significant progress has been made in the genetic characterization and risk stratification of precursor plasma cell disorders. Indeed, the clinical introduction of highly effective and well-tolerated drugs begs the question: would earlier therapeutic intervention with novel therapies in MGUS and SMM patients alter natural history, providing a potential curative option? In this review, we discuss the epidemiology of MGUS and SMM and current models for risk stratification that predict MGUS and SMM progression to MM. We further discuss genetic heterogeneity and clonal evolution in MM and the interplay between tumor cells and the bone marrow (BM) microenvironment. Finally, we provide an overview of the current recommendations for the management of MGUS and SMM and discuss the open controversies in the field in light of promising results from early intervention clinical trials.

Practical approach to the management of smoldering myeloma.

PURPOSE OF REVIEW: The aim of this article is to review the diagnosis and risk stratification of smoldering myeloma (SMM), describe recently published data regarding the early treatment of SMM, and to provide practical strategies on how to manage patients with SMM in the clinic. RECENT FINDINGS: Recently published data from the ECOG E3A06 and GEM-CESAR studies supporting early intervention for certain subsets of high-risk SMM patients will be presented, and the relevance of these findings in relation to real-life application will be explored. SUMMARY: Accurate risk-stratification and standard of care for SMM is evolving, and here we summarize the pertinent clinical data and provide recommendations for clinical management of SMM patients.

Monoclonal antibodies in newly diagnosed and smoldering multiple myeloma: an updated review of current clinical evidence.

Introduction: Monoclonal antibodies (MoAbs) are rapidly changing the therapeutic scenario of multiple myeloma. Most of the available data, however, come from studies performed in patients with relapsed or refractory disease.Area covered: Here, the most recent results from clinical trials that have investigated (or are investigating) efficacy and safety of MoAbs as front-line treatments in both transplant-eligible and not-eligible patients with newly diagnosed multiple myeloma, as well as in smoldering myeloma, are reviewed. PubMed reported articles before 28 March 2020, and abstracts presented at the last ASCO, ASH, EHA, and IMW meetings were considered. Among others, pertinent data regarding daratumumab, isatuximab, elotuzumab, and pembrolizumab will be analyzed.Expert opinion: Introduction of MoAbs as first-line therapy will likely provide a significant improvement in the clinical outcome of patients with multiple myeloma. This will also require an appropriate re-positioning of salvage therapies. The role of MoAbs in smoldering myeloma appears to be promising, but adequate follow-up is needed.

High-risk smoldering myeloma versus early detection of multiple myeloma: Current models, goals of therapy, and clinical implications.

Multiple myeloma, a bone marrow cancer, is preceded by precursor stages called monoclonal gammopathy of unknown significance and smoldering multiple myeloma. Over the past few years, highly effective and safe therapies have been made available to treat multiple myeloma. This represents a major breakthrough and has major therapeutic implications. Treatment for multiple myeloma has evolved to include treatment of precursor stages (early treatment) as these therapies are shown to be safe and effective also in smoldering myeloma. Randomized studies have shown that early treatment can delay the onset of multiple myeloma and even improve overall survival compared to observation in smoldering myeloma. The best therapeutic course and selection of patients with smoldering myeloma to treat is still a matter of debate. In this manuscript, we review the definition, management, clinical implications of smoldering myeloma and early detection of myeloma in the current context and with up-to-date data.

Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma.

PURPOSE: Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma. METHODS: We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression. RESULTS: One hundred eighty-two patients were randomly assigned-92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide. CONCLUSION: Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Therapeutic Advances in the Management of Smoldering Myeloma.

BACKGROUND: The International Myeloma Working Group has defined smoldering multiple myeloma (SMM) as the presence of 10%-60% plasma cells in the bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end-organ damage (an increased calcium level, renal failure, anemia, and destructive bone lesions). AREAS OF UNCERTAINTY: Patients considered to have SMM should not have any myeloma-defining events or amyloidosis. Different risks factors classify SMM into low-, intermediate-, or high-risk categories. The rate of progression from SMM to symptomatic myeloma is ∼10% per year during the first 5 years of diagnosis. SMM requires frequent follow-up ∼every 3 months during the first 5 years as compared to monoclonal gammopathy of undermined significance, which usually requires follow-up every 6-12 months after the first year of diagnosis. DATA SOURCES: A literature search was performed from electronic bibliographic databases: MEDLINE (Ovid SP/PubMed), EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews), and Cochrane Central Register of Controlled Trials and from annual meeting abstracts from inception to May 2017. THERAPEUTIC ADVANCES: This review presents the literature and available data that support or do not support early treatment of high-risk SMM (HR-SMM) and provides evidence-based recommendations for management of SMM patients. Despite emerging data recommending early treatment of HR-SMM, we predict the SMM category may disappear in the near future and patients will be diagnosed with either multiple myeloma or monoclonal gammopathy of undermined significance. CONCLUSIONS: Success with early therapy trials for HR-SMM is largely due to patients meeting current criteria for multiple myeloma that may have been classified as SMM and, therefore, benefitted from therapy. Based on current practices and the literature, SMM should be managed with close follow-up. Based on available data, we suggest SMM to only be treated in clinical trial settings.

Renal and pulmonary thrombotic microangiopathy triggered by proteasome-inhibitor therapy in patient with smoldering myeloma: A renal biopsy and autopsy case report.

RATIONALE: Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common. A more recently described association is with monoclonal gammopathy. Lung involvement by TMA is infrequent, but has been described in Cobalamin C deficiency and post stem-cell transplantation TMA. PATIENT CONCERNS: This is the case of a patient with smoldering myeloma who received proteasome-inhibitor therapy due to retinopathy and developed acute renal failure within one week of therapy initiation. DIAGNOSES: A renal biopsy showed thrombotic microangiopathy. At the time, mild pulmonary hypertension was also noted and presumed to be idiopathic. INTERVENTIONS: Given the known association of proteasome-inhibitor therapy with thrombotic microangiopathy, Bortezomib was discontinued and dialysis was initiated. OUTCOMES: Drug withdrawal failed to prevent disease progression and development of end-stage renal disease, as well as severe pulmonary hypertension that eventually lead to the patient's death. LESSONS: To our knowledge, this is the first reported case of pulmonary involvement by TMA associated with monoclonal gammopathy which appears to have been triggered by proteasome-inhibitor therapy. Clinicians should be aware of this possibility to allow for more prompt recognition of pulmonary hypertension as a potential manifestation of monoclonal gammopathy-associated TMA, especially in patients also receiving proteasome-inhibitors, so that treatment aiming to slow disease progression can be instituted.

Necrobiotic xanthogranuloma associated with smoldering multiple myeloma: satisfactory response to cyclophosphamide, dexamethasone, and thalidomide.

Necrobiotic xanthogranuloma is a rare chronic condition, belonging to the group C non-Langerhans cell histiocytoses, which is relevant due to the possibility of extracutaneous involvement and association with systemic diseases, particularly hematologic malignancies. The case reported here was only diagnosed after nine years of evolution and was associated with plasma cell dyscrasia. After treatment with cyclophosphamide, dexamethasone, and thalidomide, there was a reduction of cutaneous lesions and serum levels of monoclonal protein.

Scleredema associated with immunoglobulin A-κ smoldering myeloma: a case report and review of the literature.

BACKGROUND: Scleredema is a rare sclerodermoid skin condition characterized by diffuse symmetrical thickening of the upper part of the body. Its association with monoclonal gammopathy and myeloma was recently described; very few cases have been reported to date. CASE PRESENTATION: A 66-year-old Sri Lankan woman who had been followed in a dermatology unit for 34 years with diffuse systemic sclerosis presented with an acute exacerbation of the skin disease. Absence of Raynaud's phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibodies test results led to reevaluation for the possibility of scleredema. Skin biopsies from four body sites showed normal epidermis and thickened reticular dermis with swollen collagen bundles separated from one another by clear spaces, resulting in fenestration. The skin appendages were not atrophied or bound down. Alcian blue staining showed interstitial mucin deposition. Serum protein electrophoresis demonstrated an abnormal monoclonal band in the ß-region with a paraprotein level of 8.9 g/dl. Immunofixation showed an abnormal band in the γ-region consisting of immunoglobulin A and κ. Bone marrow biopsy revealed abnormal monoclonal plasma cells (15%) with multinuclearity. There was no evidence of end organ damage, and whole-body magnetic resonance imaging did not reveal any evidence of bone involvement. The patient's diagnosis was revised as scleredema type 2 associated with IgA-κ, and she was referred to a hemato-oncologist for chemotherapy, which led to significant improvement in the skin condition. CONCLUSIONS: Scleredema is a rare disorder that has an enigmatic, rare association with monoclonal gammopathy. Dermatologists should be aware of this rare but important association.

Necrobiotic xanthogranuloma associated with smoldering multiple myeloma: satisfactory response to cyclophosphamide, dexamethasone, and thalidomide

Abstract: Necrobiotic xanthogranuloma is a rare chronic condition, belonging to the group C non-Langerhans cell histiocytoses, which is relevant due to the possibility of extracutaneous involvement and association with systemic diseases, particularly hematologic malignancies. The case reported here was only diagnosed after nine years of evolution and was associated with plasma cell dyscrasia. After treatment with cyclophosphamide, dexamethasone, and thalidomide, there was a reduction of cutaneous lesions and serum levels of monoclonal protein.