Ioannis Panagiotidis

Bortezomib‐based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)‐based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib‐treated patients with severe RF (eGFR < 30 ml/min/1.73 m2), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11–724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis‐independent had longer survival than those remaining on dialysis. In conclusion, VD‐based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response. Am. J. Hematol. 91:499–502, 2016.

Evaluation of the Revised International Staging System (R-ISS) in an independent cohort of unselected patients with multiple myeloma

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66–75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma.

Cardiac and renal complications of carfilzomib in patients with multiple myeloma

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m2. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m2) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m2) was associated with a 2‐year progression to dialysis rate of 0% compared to 9% for a ratio of 31‐99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2‐year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib‐based therapy was more effective than lenalidomide‐based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.

Hematologic and renal improvement of monoclonal immunoglobulin deposition disease after treatment with bortezomib-based regimens.

Abstract Monoclonal immunoglobulin deposition disease (MIDD) is characterized by non-organized immunoglobulin-fragments along renal basement membranes with subsequent organ deterioration. Treatment is directed against the immunoglobulin-producing clone. We treated 18 MIDD patients with bortezomib-based regimens (12 received bortezomib-dexamethasone, 6 bortezomib-dexamethasone with cyclophosphamide). Eleven (61%) patients achieved a hematologic response, but only 6 (33.3%) reached to a complete (CR) or very good partial response (VGPR). Regarding renal outcomes 77.8 and 55.6% had ≥30 and ≥50% reduction of proteinuria, respectively, but 33.3% ended up in end-stage renal disease (ESRD). Among patients with CR or VGPR, median eGFR improvement was 7.7 ml/min/1.73 m2 and none progressed to ESRD, but no significant renal recovery was observed in patients achieving a partial response or less, with 50% progressing to dialysis. Pretreatment eGFR seems to influence renal prognosis. Bortezomib-based treatment is considered an effective approach in MIDD and reaching to a deep hematologic response (≥VGPR) conditionally controls further renal declining.

Coexistence of leishmaniasis and multiple myeloma in the era of monoclonal antibody (anti-CD38 or anti-SLAMF7) containing triplets: one shared story of two exceptional cases

Multiple myeloma (MM) patients are considered severely immune-compromised and at high risk of opportunistic infections, independently of the therapeutic approach and the response status. Leishmaniasis seems to behave as such an opportunistic infection; the incubation time of initial infection ranges between 2 and 6 months, while a recurrence of latent infection is possible [1]. It is a rare vector-borne infection that is caused by more than 20 species of an intramacrophage protozoon, which is transmitted to humans by more than 30 different species of phlebotomus sandflies (or less often by contaminated blood products transfusion) [1–3]. Although leishmaniasis is an endemic disease with 90% of cases occurring in tropical and subtropical areas (e.g. Brazil, India but also South and Mediterranean Europe) [2,4], more recently with the growth of international travel, its frequency is also increasing in western countries. This predominantly occurs in immune-compromised patients, including patients with HIV-acquired immunodeficiency [5,6], patients who underwent an organ or hematopoietic stem cell transplantation [4,7–11] and patients with lymphoproliferative disorders who were treated with anti-CD52 and anti-CD20 monoclonal antibodies [12,13]. Recent epidemiological data have shown that novel antimyeloma agents and their combinations have contributed significantly to the increased risk of conventional bacterial and viral infections in MM patients observed in the last decades [14]. However, limited data are available on the incidence of opportunistic fungal and parasitic infections in MM patients who are treated with novel agents. Currently, the approval of monoclonal antibodies (mAbs)-containing triplets, including daratumumab (a human IgGj mAb-targeting surface protein CD38) or elotuzumab (a humanized G1 mAb-targeting surface glycoprotein SLAMF7) in combination with lenalidomide and dexamethasone for relapsed MM has increased the therapeutic options for myeloma patients and has intensified the immune-mediated management [15,16]. In this letter, we present two ‘real-world’ MM patients who developed leishmania infection, which recurred during antimyeloma treatment with a triplet of a mAb with lenalidomide and dexamethasone. In addition, we describe our therapeutic decisions for both diseases and our considerations about the interaction of mAb-triplets and the immune background of underlying leishmania infection.

Inhibition of receptor activator of nuclear factor kappa-B ligand pathway for the management of aggressive osteosarcoma

Receptor activator of nuclear factor kappa-B ligand (RANKL) is a member of the tumor necrosis factor receptor superfamily and is considered the most important factor for osteoclastogenesis. RANKL is encoded by a gene, which is found at chromosome 13q14 and is expressed mainly by osteocytes, activated T-cells and bone marrow stromal cells. Alternative splicing of the RANKL mRNA results either in the expression of a type-II transmembrane glycoprotein or in the expression of a soluble ligand. Soluble RANKL may also be produced from its transmembrane state by the function of metalloproteinases. RANKL acts through its binding to the receptor RANK which is on the surface of mature osteoclasts but also of osteoclast precursors and chondrocytes. The RANKL/RANK binding induces the activity of mature osteoclasts, while it inhibits their apoptosis. Furthermore, the binding of RANKL to RANK enhances the differentiation of osteoclast precursors, their fusion and the formation of mature osteoclasts through the NF-κB, c-fos and Jun N-terminal kinase pathways (1). RANKL is implicated in the pathogenesis of bone loss in several disorders including osteoporosis, malignant disorders (bone metastases of solid tumors and multiple myeloma) as well as metabolic bone diseases (1-3). Osteoprotegerin (OPG) is the decoy receptor of RANKL which is produced mainly by the osteoblasts and is often elevated to balance the RANKL overexpression in several bone malignancies. Among primary bone tumors, RANKL expression and the RANKL/OPG ratio were very high in giant cell tumor of the bone, while high RANKL mRNA expression was observed in cases of osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic cancer (4). More specifically for osteosarcoma, the expression of RANK and RANKL was tested in 91 human osteosarcomas tumor samples. Sixty-three osteosarcomas (69%) expressed RANK, while only 8 cases (9%) expressed RANKL. Interestingly, the expression of RANK was significantly associated with shorter disease-free survival and worse response to chemotherapy, while RANKL expression was more frequent in osteosarcoma of the lower extremity than in any other location (5). These data suggest that inhibiting RANKL seems to be a logical approach for the management of primary bone tumors. To-date, the only inhibitor of RANKL that has entered to clinical development, denosumab, has been licensed not only for the treatment of bone metastases due to solid tumors but also for the management of giant cell tumor of the bone. However, there is no data for the efficacy of denosumab in osteosarcoma patients.