Gertz, Morie A

Disease OverviewWaldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.DiagnosisPresence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients.Risk StratificationAge, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.Risk‐Adapted TherapyNot all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients.Management of Refractory DiseaseBortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.

AbstractPositron emission tomography‐computed tomography (PET‐CT) can identify bony lesions, assess disease burden, and detect extramedullary disease (EMD) in patients with multiple myeloma. We retrospectively reviewed records of patients who underwent PET‐CT within 60 days of a new diagnosis (before therapy commenced) to identify the nature and prognostic impact of PET‐CT abnormalities. Patients (N = 313) were seen from April 2005 through June 2017. Of the 234 patients (75%) with focal lesions (FLs), 182 (58%) had at least 3 FLs, 38 (12%) had EMD, and 204 (65%) had documented myelomatous lytic lesions. The median maximum standardized uptake value (SUVmax) for the entire cohort was 5.9 (range 1.5‐48.3). Presence of at least 3 FLs and EMD predicted inferior overall survival (OS); median OS was 57.8 months for patients with 3 or more FLs and 103.6 months for patients with fewer than 3 FLs (P = .003). The median OS was 45.5 and 71.8 months for patients with and without EMD, respectively (P = .004). No clear SUVmax cutoff was predictive of progression‐free survival or OS. PET‐CT is a valuable tool for assessing disease burden and could provide prognostic information about a contemporary cohort of patients with newly diagnosed myeloma who received treatment with novel agents.

AbstractSymptomatic hyperviscosity is a well‐established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity‐related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre‐empt hyperviscosity‐related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate‐analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time‐to‐initial therapy was 6.9 years and only 15% developed hyperviscosity‐related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity‐related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM‐directed therapy.

AbstractDisease OverviewImmunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and “atypical multiple myeloma.”DiagnosisTissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow, salivary gland, or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy.PrognosisN‐terminal pro‐brain natriuretic peptide (NT‐proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months.TherapyAll patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mm Hg, troponin T < 0.06 ng/mL, age < 70 years, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan‐dexamethasone or cyclophosphamide‐bortezomib‐dexamethasone. Daratumumab appears to be highly active in AL amyloidosis. Antibodies designed to dissolve existing amyloid deposits are under study.Future ChallengesDelayed diagnosis remains a major obstacle to initiating effective therapy.Educational ObjectivesUpon completion of this educational activity, participants will be better able to: Master recognition of clinical presentations that should raise suspicion of amyloidosis. Understand simple techniques for confirming the diagnosis and providing material to classify the protein subunit. Recognize that a tissue diagnosis of amyloidosis does not indicate whether the amyloid is systemic or of immunoglobulin light chain origin. Understand the roles of the newly introduced chemotherapeutic and investigational antibody regimens for the therapy of light chain amyloidosis.

AbstractDetection of myeloma progression (PD) relies on serial 24‐h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24‐h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55‐312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24‐h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24‐h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.