Lacy, Martha Q.

Abstract Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

Abstract This spotlight review focuses on the second-generation immunomodulatory drug pomalidomide, which was recently approved by the US Food and Drug Administration. This drug was approved for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. This review focuses on the clinical trial data that led to approval and provides advice for treating physicians who are now prescribing this drug for patients.

Key Points A continued monoclonal protein response after ASCT in the absence of further therapy is prognostic in MM patients.

Key PointsRadiation is appropriate primary therapy in approximately 25% of cases. Radiation provides long-term remissions in more than 50% of patients.

Multiple myeloma is a common plasma cell neoplasm that is incurable with conventional therapy. The treatment paradigm of multiple myeloma is not standardized and is evolving. The advent of novel drugs, including the proteasome inhibitor bortezomib and the immunomodulatory agents, has resulted in increased median survival. Unfortunately, all patients eventually relapse and require further therapy. Pomalidomide is the newest immunomodulatory drug, created by chemical modification of thalidomide with the intention of increasing therapeutic activity while limiting toxicity. Its mechanism of action is incompletely understood but involves anti-angiogenic effects, immunomodulation, an effect on the myeloma tumor microenvironment, and the protein cereblon. It is more potent than thalidomide and lenalidomide. In phase II studies, it has shown significant activity in patients with relapsed and refractory multiple myeloma, including patients who are heavily pretreated, have disease refractory to lenalidomide and bortezomib, and those with high-risk cytogenetic or molecular markers. It is generally well tolerated, with adverse effects including fatigue, neutropenia, neuropathy, and thromboembolic disease. Pomalidomide is a promising new agent in the expanding arsenal of antimyeloma drugs. In this review, we discuss the clinical experience to date with pomalidomide in multiple myeloma.

To clarify the presentation and course of patients with chronic lymphocytic leukemia (CLL) and amyloidosis. Mayo databases were interrogated for patients who carried a diagnosis of amyloidosis and CLL evaluated at Mayo Clinic, Rochester from January 1974 to October 2012. Charts were abstracted and data analyzed. Of the 33 patients identified, 20 (61%) were diagnosed with AL and 13 (39%) with non‐AL. Only four patients had immunoglobulin light chain amyloidosis (AL) that could be solely attributed to the CLL clone; another six had both a plasma cell clone and a CLL clone that shared the same light chain. Median overall survival was 15.6 months for patients with AL and 58.1 months for patients with non‐AL. For patients with AL management involved chemotherapy targeted toward monoclonal plasma cells, lymphocytes or both, and for patients with non‐AL no specific amyloid treatment was administered. AL is a rare complication of CLL, but in this elderly population of patients non‐AL is nearly as common. Distinguishing between these two groups is essential since patients with non‐AL amyloidosis have better outcomes and they do not require cytotoxic chemotherapy to treat their amyloidosis. Am. J. Hematol. 88:375–378, 2013. © 2013 Wiley Periodicals, Inc.

Key Points Thalidomide and prednisone maintenance after transplantation improves progression-free but not overall survival.

AbstractBackgroundCardiac complications following hematopoietic stem cell transplantation (HSCT) are emerging as a significant concern given the increasing utilization of HSCT for a variety of hematologic malignancies.MethodsWe utilized an existing database to determine the frequency of cardiac dysfunction (CD), namely a decrease in left ventricular ejection fraction, following conditioning with high‐dose melphalan (HDM) and autologous HSCT for multiple myeloma (MM) and systemic amyloidosis (AL). We then performed a case–control study to examine variables associated with increased risk of CD in this population.ResultsIn MM patients undergoing HSCT, the rate of CD was 1.6% (17/1050, 95% CI: [0.9, 2.6]). None of the examined pre‐HSCT variables or HDM dose were significantly associated with development of CD in this population. In patients with AL, the rate of CD was 5.6% (24/426, 95% CI: [3.6, 8.3]). On univariate analysis, decision to administer an HDM dose <200 mg/m2 [odds ratio (OR): 4.59 (1.27–16.57) P = 0.02], pretransplant left ventricular ejection fraction <60% [OR: 17.78 (2.29–138.33) P = 0.006], and documented amyloid involvement of ≥3 organs [OR: 4.0 (1.03–15.6) P = 0.046] were associated with the development of CD in the AL population. No other examined peri‐transplant factors were associated with development of CD.ConclusionTo our knowledge, this is the first series to report a significant rate of CD following HDM conditioning and autologous HSCT in patients with AL.

AbstractThe POEMS syndrome (polyradiculoneuropathy, organomegaly, multiple endocrinopathies, monoclonal protein, skin changes) is a rare disease associated with a plasma cell dyscrasia. Patients with disseminated POEMS can be treated with high-dose therapy and autologous stem cell transplantation (ASCT). While clinical improvement is nearly universal in these patients, the long-term outcomes after transplantation are unclear. We therefore assessed the long-term clinical outcomes of 59 POEMS patients treated with ASCT at our institution. With a median follow-up of 45 months, 14 patients have progressed with a progression-free survival of 98% and 75% at 1 and 5 years, respectively. Factors associated with progression have included an IgG-λ monoclonal component (hazard ratio [HR] 7.5; 95% confidence interval [CI], 2.3-28.3; P = .0008), fluorodeoxyglucose-avid lesions on baseline positron emission tomography (HR 6.4; 95% CI, 1.2-120; P = .03), lack of complete hematologic response (HR 5.4; 95% CI, 1.8-16.7; P = .003), and patients aged 50 years or younger at transplantation (HR 4.4; 95% CI, 1.3-20; P = .01). The most common progression events have been radiologic followed by rising VEGF. Symptomatic progression has been rare. Most patients could be salvaged with immunomodulatory drugs or radiation. The 5-year survival is 94%. Herein, we describe a system of monitoring response and progression among patients with POEMS after ASCT.