Leung, Nelson

Abstract Background: Outcome studies for the unique cohort of young patients with multiple myeloma (MM) are sparse. In general, MM is a heterogenous disease with the genetic signature being one of the major determinants of prognosis. We have recently reported on improvement in overall survival (OS) of young patients with the use of novel agents, but the maximal survival gain has been achieved by integrating autologous stem cell transplant (SCT) to our current approach. Herein, we report on outcomes of patients with MM who were 50 years or younger at diagnosis and stratified by fluorescence in situ hybridization (FISH) results. Our study focuses on t(11;14) myeloma as its prognostic impact remains unclear with the use of novel agents upfront. Methods: Out of 1384 patients with MM, evaluated consecutively at Mayo Clinic, Rochester, MN between 1/1/2000 and 12/31/2011, 290 (21%) were 50 years or younger at diagnosis. Interphase FISH, performed within 100 days of diagnosis of MM, was utilized to stratify patients as high-risk [deletion 17p, t(14;16), t(14;20) or t(4;14)] or standard-risk [normal FISH, trisomies, t(11;14), t(6;14) or monosomy13/deletion 13q]. FISH results were available in 125 young patients that comprise the cohort of interest in the current study. OS from diagnosis was estimated by the Kaplan-Meier method. Results: Median age at diagnosis of MM was 47 years (range: 22 to 50 years) and 58% of the patients were male. At the time of data cut-off (7/31/2014), 45 (36%) patients had died with 90% of all known causes of deaths (n=39) being MM related. FISH abnormalities were noted in 114 (91%) patients. At diagnosis, 46%, 30% and 24% patients were categorized as International Staging System (ISS) stage I, II and III, respectively. The estimated median follow up was 60 months (95% CI: 54-67) and the 5-year OS rate was 69% [median 86 months (95% CI: 76-108)]. Standard (n=100; 80%) and high (n=25; 20%) risk patients had a median OS of 89 months (95% CI: 76-108) and 77.6 months (95% CI: 42-130), respectively (p=0.87). In order to further investigate the similar outcomes between these broad risk-groups with typically diverse disease course, we assessed the outcomes based on the common genetic abnormalities (Table 1) within each of the 2 categories. Presence of t(11;14) (n=37; 29%) was associated with a significantly shorter median OS (76 months) compared to patients with trisomic and normal FISH profile (n=46) (91 months, p=0.01; Figure 1). Patients with t(11;14) also had a significantly shorter median OS compared to those with other standard-risk FISH abnormalities (median OS 96 months, p=0.02). Presence of t(11;14) was not associated with higher plasma cell labeling index (PCLI, p=0.29) or worse ISS stage (p=0.99) compared to patients without t(11;14). OS survival of patients with t(11;14) was similar to those with high risk features (median 76.2 vs. 77.6 months, p=0.32). Of 24 (65%) patients with t(11;14) who underwent SCT, 79% had early SCT (within 12 months from diagnosis). Median OS was 79.4 months (95% CI: 36-108) vs. not reached (NR) (95% CI: 27-NR), respectively (p=0.79) in early versus late SCT. Twenty-one (57%) and 13 (35%) patients with t(11;14) received initial immunomodulatory drugs or bortezomib-based therapies, respectively. Those receiving frontline bortezomib had a higher median OS (76.2 months, 95% CI 76-79) compared to 64.8 months (95% CI 32-108) with other initial agents although it did not reach statistical significance (p=0.78). Conclusion: Presence of t(11;14) is associated with an inferior OS compared to patients with normal FISH, trisomies, or other standard risk abnormalities in young patients with MM. Given, the inherent biases associated with a retrospective study from a referral institution, our findings require external validation. However, our data suggest that our current therapeutic approaches in managing young patients with this unique genetic signature are inadequate. Table 1FISHn(%)Median OS in months (95% CI)t(11;14)37(29)76.2 (53.5-107.7)Trisomies35(28)91.3 (76.4-NR)13/del(13q)11(9)NR (32-NR)Normal11(9)95.5 (45.4-95.6)t(4;14)11(9)NR (40.1-NR)del(17p)/-1710(8)42 (19.2-129.6)t(14;16)4(3)77.6 (42.4-NR)Others6(5)NR (11.5-NR) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Both MM specific and patient specific parameters place patients at risk for death. Patient frailty has been delineated primarily by age and ECOG performance score (PS) and secondarily with creatinine, eGFR, and the International Staging System (ISS), which reflect both renal function and disease burden. In an attempt to improve upon these commonly used measures, a frailty score for elderly patients that combines functional status [Activity of Daily Living (ADL) and Instrumental Activity of Daily living scores], comorbidities [Charlson comorbidity index (CCI)] and age has been developed by the IMWG. Incorporation of these tools into a busy clinical practice is challenging due to time constraints. Therefore, the identification of frail patients with an easily applicable, rapid and objective tool remains a challenge and an unmet need. A reliable, non-invasively assessable, biochemical marker of frailty would be an ideal tool to identify patients at higher risk of death. It was our goal to determine the role of NT-proBNP, a well-established cardiovascular risk biomarker, as a marker of frailty in patients with MM and in predicting overall survival (OS). Methods: Patients were elegible for this retrospective study if they were seen at the Mayo Clinic, Rochester, MN within 30 days of their myeloma diagnosis during the interval between 1/1/2007 and 12/31/2011. As part of the Mayo Clinic registration, all patients complete forms containing their past medical history, symptoms, and ADLs. Data from that first visit was abstracted and used to calculate a CCI. We excluded all patients with a concomitant diagnosis of light-chain AL amyloidosis. NT-proBNP concentration was measured in frozen sera collected within 30 days of diagnosis. NT-proBNP assay was run on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). We evaluated the prognostic role of NT-proBNP and these indices on OS using the Kaplan-Meier method. Results: Among the 351 consecutive patients satisfying entry criteria, median age was 65 years (range 22-95), 33% were ≥70 years, and 56% were male. Twenty-eight percent were ISS stage III, 13% had a creatinine ≥2 mg/dL, 19% had PS ≥2, and 11% had ADL score ≥2, and 30% CCI ≥2. The median value of NT-proBNP was 109 ng/L (interquartile range: 30-375 ng/L). NT-proBNP concentrations differed in the three ISS stages (median: 122 ng/L stage I, 190 ng/L stage II and 1822 ng/L stage III, P<0.0001). Median OS was 5.6 years. The best cutoff of NT-proBNP predicting OS at one year was 301 ng/L (sensitivity: 57.88%, specificity: 74.29%; AUC=0.668) and distinguished two groups with different OS (median not reached vs. 35 months, P<0.0001). Variables predictive for OS are shown in the Table and included PS, age, CCI, ISS, NT-proBNP. On multivariate analysis, ISS and NT-proBNP were independent of each other as long as age, PS and/or CCI were excluded from the model. NT-proBNP withstood these clinical variables better than did ISS (data not shown). We built two different models (table). In model 1, NT-proBNP >301 ng/L was an independent predictor of survival while age ≥70 and PS ≥2 and CCI were not significant. However, if we considered ISS stage instead of NT-proBNP in the same model, ISS stage was not significant. Conclusions: In this unselected cohort of patients with newly diagnosed multiple myeloma, NT-proBNP was a useful predictor of survival independent of age and PS. The threshold of 301 ng/L is remarkably similar to the well-established cutoff for heart failure of 300 ng/L. NT-proBNP outperformed the CCI and the ISS as risk factors. NT-proBNP is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple means of determining patient frailty in a busy clinical practice. Table. Results of univariate and multivariate analysis of various prognostic factors (NS, not significant; NI, not included). Univariate Multivariate Multivariate RR (95% CI) P Model 1 P Model 2 P PS ≥2 3.4 (2.4-4.8) <0.0001 2.5 (1.7-3.6) <0.0001 2.8 (1.9-4.0) <0.0001 Age ≥70 2.7 (1.9-3.6) <0.0001 2.1 (1.5-2.9) <0.0001 1.9 (1.3-2.7) 0.0003 CCI >=2 1.9 (1.4-2.6) <0.0001 NS NS 1.5 (1.0-2.0) 0.03 ISS stage 1.1 (1.1-1.8) 0.0004 NI NI NS NS NT-proBNP >301 ng/L 2.3 (1.7-3.2) <0.0001 1.6 (1.1-2.2) 0.007 NI NI Disclosures Merlini: Janssen-Cilag: Honoraria; Prothena: Honoraria; Millennium-Takeda: Honoraria; Pfizer: Honoraria. Kumar:Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria.

Abstract Abstract 599 Purpose: This study was undertaken to develop selection guidelines for transplant centers to determine eligibility for stem cell transplantation in patients with light chain amyloidosis. Patients and Methods: Patients with biopsy-confirmed immunoglobulin light chain amyloidosis who underwent stem cell transplantation between March 8, 1996, and December 31, 2011, were reviewed in 2 cohorts: those who underwent transplantation between March 8, 1996, and June 30, 2009, and those who underwent transplantation between July 1, 2009, and December 31, 2011 (table 1). A second comparison was undertaken among patients who died before posttransplant day 100 to determine features predictive of early death (table 2). Results: A total of 499 patients were identified, 410 in the earlier group and 89 in the later group. After July 1, 2009, significantly fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before posttransplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels higher than 5,000 pg/mL died by 10.3 months (fig 1, left). When the serum troponin T level was > 0.06 ng/mL, 25% died at 3.7 months (fig 2, right). Conclusion: The Mayo staging system is highly predictive for overall survival but not useful for selecting transplant recipients. Patients with serum troponin T levels higher than 0.06 ng/mL or NT-proBNP levels >5,000 pg/mL (not on dialysis) should not be considered acceptable candidates for stem cell transplantation because of unacceptable early mortality. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3992 Little is known about the rare entities of heavy and light chain amyloidosis (AHL) and heavy chain amyloidosis (AH). In this study, we report the renal and hematologic characteristics, pathology, and outcome of 17 patients with renal AH/AHL including 5 with AH (4 IgG and 1 IgA) and 12 with AHL (7 IgGλ, 3 IgAκ, 1 IgAλ, and 1 IgMλ), and compare them with 202 patients with renal AL amyloidosis (AL) diagnosed during the same time period. All cases were diagnosed by kidney biopsy that showed Congo red-positive deposits. Amyloid typing was done by laser microdissection and mass spectrometry (LMD/MS) (12 patients) or by immunofluorescence (5 patients). All patients with renal AH/AHL were Caucasians, with a M:F ratio of 2.4 and a median age at biopsy of 63 years. Compared with patients with renal AL, those with renal AH/AHL had less frequent concurrent cardiac involvement, higher likelihood of having circulating complete monoclonal Ig, lower sensitivity of fat pad biopsy and bone marrow biopsy for detecting amyloid, higher incidence of hematuria, and better patient survival. The hematologic and renal responses to chemotherapy were comparable to renal AL. In 42% of patients, AH/AHL could not have been diagnosed without LMD/MS. In conclusion, renal AH/AHL is an uncommon but under-recognized form of amyloidosis, and its diagnosis is greatly enhanced by the use of LMD/MS for amyloid typing. The accurate histological diagnosis of renal AH/AHL and distinction from AL may have important clinical and prognostic implications. Table 1. Demographics and hematologic characteristics AH/AHL AL p value No. of patients 17 202 Gender: Male/female 12/5 (71%/29%) 126/76 (62%/38%) 0.61 Age, median (range) 63 (50–77) 62 (36–86) 0.73 Additional organ involvement 8 (47%) 126 (62%) 0.3 Cardiac involvement 3 (18%) 100 (50%) 0.01* % of plasma cells in bone marrow, median (IQR) 8 (5–15) 6 (5–10) 0.82 ≥30 plasma cells 4 (24%) 11/198 (6%) 0.02* Positive SPEP/SIF for paraprotein 15 (88%) 158/200 (79%) 0.53 Presence of whole monoclonal protein on SPEP 14 (82%) 108/200 (54%) 0.04* Positive UPEP/UIF for paraprotein 13/16 (81%) 158/189 (84%) 0.73 Presence of whole monoclonal protein on UPEP 10/16 (63%) 61/189 (32%) 0.03* Abnormal serum FLC ratio (<0.26 or >1.65) 9/12 (75%) 150/188 (80%) 0.71 Markedly abnormal FLC ratio (< 0.125 or > 8) 5/12 (42%) 100/188 (53%) 0.55 Positive bone marrow for amyloid 6/16 (38%) 135/183 (74%) 0.004* Positive fat pad biopsy for amyloid 2/14 (14%) 105/145 (72%) <0.001* IQR, interquartile range. Table 2. Renal characteristics at kidney biopsy AH/AHL AL p value No. of patients 17 202 24h urine protein in g, median (IQR) 5.1 (3.2–9.0) 6.0 (3.2–10.0) 0.9 Full nephrotic syndrome 9/16 (56%) 132/197 (67%) 0.42 Serum albumin in g/dl, median (IQR) 2.7 (2.2–3.3) 2.5 (1.9–2.9) 0.29 % albuminuria on UPEP, median (IQR) 68 (61–72) 70 (60–76) 0.47 Serum creatinine in mg/dl, median (IQR) 1.4 (1.1–2.1) 1.2 (0.9–1.8) 0.25 Serum creatinine >1.2 mg/dl 10/16 (63%) 92/201 (46%) 0.3 eGFR, median (IQR) 47 (27–67) 58 (36–75) 0.29 Decreased eGFR 10/16 (63%) 103/201 (51%) 0.44 Microscopic hematuria 9/16 (56%) 44/169 (26%) 0.02* IQR, interquartile range. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 747 Background: Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods: We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results: We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions: The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.

Abstract Abstract 946 Background: The emerging therapies directed at the plasma cell clone have dramatically increased overall survival (OS) for both myeloma and amyloidosis patient populations. As more treatment trials are done in patients (pts) with AL, benchmarks for outcomes among previously treated AL pts are required, especially for those pts who are not candidates for high-dose chemotherapy with peripheral blood stem cell transplantation (ASCT). Inadequate information is available about the number of non-transplant pts who go on to receive second line treatment for AL amyloidosis. Methods: To ascertain the outcomes of pts who did not receive ASCT as primary therapy but who required a second line of therapy, we reviewed the experience of pts seen at Mayo Rochester between 1990 and 2010 according to an IRB approved retrospective review protocol. 1828 pts had their first Mayo visit for AL during this time period. Pts were excluded from this study for the following reasons: 571 had upfront transplant; 907 pts had received only one line of treatment for their amyloid; 91 had longstanding other associated malignancy [Waldenstrom's macroglobulinemia (8), lymphoma (15), CLL (6), multiple myeloma (62)]; and 93 had inadequate follow-up information. One-hundred and sixty-six pts received 2 or more lines of therapy for their AL amyloid and are the subject of these analyses. Statistical analyses were done using JMP statistical software (SAS, Carey, NC). Results: Of the 166 pts, the median age was 64 years (range 34, 84). 49% were male. Baseline organ involvement was as follows: cardiac 84/166 (50%); renal 118/166 (71); liver 23/166 (13.8%); peripheral nerves 19/166 (11.4%); and gastrointestinal 14/166(8.4%). Thirty-one percent (52/16) had both cardiac and renal involvement. Only 73 pts had cardiac biomarkers (NT pro BNP and Troponin T) done at baseline. Of these pts, 26% were stage 1, 49.3% were stage 2, and 24.6% were stage 3 according to original Mayo cardiac biomarker staging system. By inclusion criteria definition, all 166 pts received 1st and 2nd line therapies; 53 (32%) pts received 3rd line of treatment; 20 (12%) received 4th line of treatment; and 10 (6%) received 5th line of treatment. For first line therapy, the most common drugs given either singly or in combination were corticosteroid (147/166; 88.5 %), alkylator (99/166; 59.6%), IMID (34/166; 20.4 %), and bortezomib (19/166; 11.4%). The median time from diagnosis to 2nd line therapy was 10.3 months. Second line regimens received included: corticosteroid, 108/166 (65.1%); alkylator, 76/166 (45.8 %); IMID, 46/166 (27.7%); and bortezomib, 46/166 (27.8%). The median time from diagnosis to 3rd line therapy was 19.8 months. For the 53 pts who received 3rd line treatment, regimens included: corticosteroid, 41/53 (77.3%); IMIDs, 17/53 (32.1%); alkylator, 17/53 (32.1%); bortezomib, 12/53 (22.6%). The median time from diagnosis to 4th line therapy was 31.8 months. For the 20 pts receiving 4th line treatment, regimens included: corticosteroids, 15/20(75%); alkylator, 12/20 (60%), bortezomib, 7/20 (35%); and IMIDs, 4/20(20%). Eighty-three pts have died. The 1 year mortality of our study population was only 8%. The median follow-up of surviving pts was 47.6 months. Figure 1 demonstrates Kaplan-Meier estimates of overall survival (OS) from initiation of each successive therapy. The median OS from initiation of 1st, 2nd, and 3rd lines of treatment were 65, 49.5 and 36.7 months respectively. The median OS after the 4th line of treatment was not reached. The 4 year OS rates from initiation of 1st, 2nd, 3rd and 4th lines of therapy were 58%, 50.8 %, 50 % and 53.4% respectively. Conclusion: Outcomes among relapsed or refractory AL pts are better than what one might expect. Multiple publications have demonstrated that the 1 year mortality of newly diagnosed AL is in the vicinity of 40%. Thereafter, the rate at which pts die dramatically decreases. Our study provides explicit data characterizing the fate of pts unfortunate enough to require additional therapy but fortunate enough to survive past the exceedingly high risk period of death that occurs within 6–12 months of diagnosis. These data provide useful information for benchmarking future trials for treatments of AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Urinary extracellular vesicles (uEVs) have been used as a biomarker tool for detection of low abundance immunoglobulin-based targets in uEVs with heterogeneous high protein mixtures. This protocol outlines a pre-incubation method to minimize non-specific secondary antibody binding. Additionally, we include our approach for standardization of uEV amounts used for sample comparison. We propose that these and knowledge of the detection limit for target proteins are strategies applicable to other laboratories working with complex heterogeneous samples.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Abstract Proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests with chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Acute nephritic syndrome is rare. PGNMID occurs mostly in the sixth decade, but it may affect young adults. Histologically, PGNMID is characterized predominantly by membranoproliferative GN and less frequently by diffuse endocapillary GN, mesangioproliferative GN or atypical membranous GN. Immunofluorescence and electron microscopic studies are the cornerstone of diagnosis, showing granular deposits involving glomeruli only, and composed of monotypic immunoglobulin G (IgG), with a single heavy chain subclass (most commonly IgG3) and light chain (LC) restriction (usually κ), admixed with complement deposits. PGNMID variants with monotypic LC-only, IgA or IgM deposits are uncommon. Ultrastructurally, deposits are amorphous with predominant subendothelial and mesangial distribution. PGNMID should be distinguished from type 1 cryoglobulinemic GN and immunotactoid GN, which share some common pathological features. Contrary to other MGRS lesions, the rate of detection of the nephrotoxic monoclonal Ig in the serum or urine, and of an abnormal bone marrow B-cell clone, is only ∼30%. Renal prognosis is poor, with progression to end-stage renal disease in 25% of patients within 30 months and frequent early recurrence on the renal allograft. The pathophysiology of PGNMID is unclear and its treatment remains challenging. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.