To biopsy or not to biopsy, that is the question in myeloma cast nephropathy

In 2003, the International Myeloma Working Group (IMWG) recognized renal insufficiency [serum creatinine (Scr) > 173 μmol/L) as a myeloma-related organ impairment in their first consensus diagnostic criteria for multiple myeloma (MM) [1]. In 2006, CRAB [hyperCalcemia, Renal impairment (RI), Anemia and Bone lesions] became the official myeloma defining events (MDEs) [2]. Of the four MDEs, RI by far exacts theworse prognosis. Data from a Spanish study showed that patients presenting with RI as their MDE had a much shorter survival than patients who did not. The median overall survival (OS) was 8.6 months for the RI patients versus 34.5 months in patients who presented with other MDEs (P < 0.001) [3]. Similar findings were reported in a Nordic study that found the OS for severe RI (Scr > 2.28 mg/dL), moderate RI (Scr > 1.48 and ≤2.28 mg/dL) and no RI were 13, 18 and 36 months, respectively [4]. The Nordic study was slightly different in that smoldering MM was not excluded. Even more interesting was that the negative impact of RI was not permanent. In both studies, patients who recovered renal function to a Scr of <1.5 mg/dL had OS similar to patients who never developed RI [3, 4]. Lower response to chemotherapy was noted in the RI patients in the Spanish study but only in thosewho died within the first 2 months. No differences in response were noted in the Nordic study when the patients were evaluated at 12 months. In the Nordic study, the hematologic response was not associated with a renal response (P = 0.07). The biggest advancement in the care of MM is the introduction of novel agents (thalidomide, lenalidomide, pomalidomide, bortezomib and carfilzomib) capable of delivering faster and deeper responses with less toxicity. Of the novel agents, bortezomib has shown the greater benefits in RI patients. In the phase III VISTA trial, the addition of bortezomib to melphalan and prednisone significantly improved both the hematologic response, renal recovery and OS without increasing the adverse events in patients with an estimated glomerular filtration rate (eGFR) of <50 mL/min [5]. In a retrospective analysis of MM patients from 1990 to 2005 and beyond, improvement of OS was seen with each successive 5-year period. In patients with severe RI (<30 mL/min/1.73 m), age (> or <65 years) and the class of novel agent were independent risk factors [6]. The largest benefit was seen in younger patients and those treated with bortezomib. Early (<2 months) death was still highest among patients with severe RI (12%) versus moderate RI (7%) and no RI (3%), and the incidence did not change over time. In a subgroup analysis of the randomized HOVON-65/GMMG-HD4 trials, patient treated with a vincristine-based regimen had a 3-year survival of 76% if their presenting Scr was <2 mg/dL versus 34% if the presenting Scr was ≥2 mg/dL [7]. In comparison, the 3-year OS (74%) in the bortezomib-treated patients was not significantly different regardless of their presenting Scr. Bortezomib-treated patients with RI had a hematologic response rate of 75% versus 36% in the vincristine-treated group. Interestingly though, both RI groups still had a significantly higher early mortality regardless of the treatment arm. Thus, while the long-term effects of RI appeared to be reversed, the early mortality remained a challenge. Until recently, RI in MM was mainly defined by the creatinine concentration. The 2010 IMWG definition included the toxic effects of the monoclonal light chains, but the acute kidney injury (AKI) was neither differentiated by the renal lesion nor by the causes such as hypercalcemia or nephrotoxins [5]. There is now a growing body of evidence showing that different renal lesions behave differently in MM. Patients with pure monoclonal immunoglobulin deposition disease (MIDD) have better renal and OS than patients with both MIDD and myeloma cast nephropathy (MCN) [8]. This observation has been confirmed in a larger series of patients with MCN, MIDD or