Cyclophosphamide, bortezomib and dexamethasone (CyBorD): a promising regimen for renal light chain deposit disease

Abstract

Renal light chain deposit disease is a rare disease with rapid progression to renal failure when left untreated. There is no standard treatment available. We present a unique case of renal IgA kappa deposit disease who developed severe decline in renal function within a few months of diagnosis. She was started on a single regimen of cyclophosphamide, bortezomib and dexamethasone (CyBorD) followed by maintenance treatment with bortezomib and dexamethasone leading to rapid improvement of renal function. This is the first case to be reported on renal IgA kappa deposit disease who have responded dramatically to CyBorD without the need for any modification of the regimen or stem cell transplant.

Background

Monoclonal immunoglobulin deposition disease (MIDD) is a plasma cell dyscrasia which presents as light chain, heavy chain or a combination deposit disease. Usually, they are associated with a lymphoproliferative disorder like multiple myeloma (MM) but some patients may not have an evident lymphoplasmacytic disorder.^{1 2} Light chain deposit disease (LCDD) can present as deposition of immunoglobin in various organs, especially in the kidneys. Renal failure develops in weeks to months and around 60% cases progress to end-stage renal failure. Five-year patient survival is less than 50% without treatment. Renal LCDD is a rare disease with no standard treatment available.

Literature mentions successful management with two or more successive regimens of chemotherapy or combination of chemotherapy with stem cell transplant (SCT). We present a unique case of renal IgA kappa deposit disease who was treated with single regimen of cyclophosphamide, bortezomib and dexamethasone (CyBorD) with dramatic response thus aborting the need for hemodialysis.

Case presentation

A 63-year-old Caucasian woman with history of hypertension, dyslipidemia, aortoiliac bypass and 30 pack year h/o smoking was initially referred to the Haematology clinic for evaluation for persistent leukocytosis for 9 months. She complained of fatigue and unintentional weight loss of 30 pounds over a 9-month period. She complained of nasal drainage and congestion, productive cough, chronic swelling of b/l legs. Family history is negative for renal disease, father had aortic aneurysm, and mother and maternal grandmother had breast cancer. On examination, vitals were stable, and no lymphadenopathy or pedal oedema was noted. Chest was clear to auscultation; normal heart sounds were heard. Important laboratory values on presentation: WBC range of 13.0–15.0×10³/uL, Absolute neutrophil 7.9–9.7, GFR- 72.4 mL/min/1.73m², creatinine- 0.8 mg/dL (table 1). CML/ALL PCR quantitative mutation and JAK 2 (V617) were negative. As myeloproliferative disorder was low in the list, leukocytosis was presumed to be secondary to chronic sinusitis or bronchitis. On follow-up the next year, she reported microscopic hematuria. She had h/o microscopic hematuria 3 years back when cystoscopy results were unremarkable. CT abdomen was done which showed left renal angiomyolipoma with asymmetric urinary bladder wall thickening. In the next follow-up after 2 years, the patient reported to have persistent hematuria, was found to be anaemic with mild renal dysfunction (GFR- 68 mL/min/1.73m², serum creatinine- 0.89 mg/dL).

Table 1.

Laboratory values throughout disease course

	On first visit	When hematuria was diagnosed	At MGUS diagnosis	IgA kappa nephropathy diagnosis	Starting of treatment with CyBorD	After 10 months of induction regimen	After 28 months of treatment
GFR (mL/min/1.73m2)	72.4	68	50	28	21	42	38.5
Urine protein/creatinine ratio (mg/g)			10 342			978
Serum Cr (mg/dL)	0.8	0.89	1.15	1.83	2.35	1.5	1.4
Serum Kappa (mg/dL)			6.31	7.60	10.50	8.057	4.08
Serum lamda (mg/dL)			3.18	3.30	3.33	3.43	1.60
Serum kappa/lambda ratio			1.984	2.303	3.153	2.349	2.550

Investigations

Monoclonal paraproteinemia was doubted as serum electrophoresis could not exclude artefact from small IgA kappa paraprotein with serum IgG- 396 mg/dL, IgM- 37.8 mg/dL, IgA 185 mg/dL, Kappa −6.31 mg/dL, lambda- 3.18 mg/dL, kappa/lambda ratio- 1.984 with M spike of 0.1 with small IgA 0.12 g%. Renal biopsy showed membranoproliferative pattern of glomerulonephritis with IgA kappa deposits, chronic active tubulointerstitial disease, global and segmental glomerulosclerosis, interstitial fibrosis 70%, tubular atrophy 60%–85%, negative Congo red stain for amyloid, mesangial stain for IgA 2+, kappa light chain 1–2+ with irregular granular staining, trace C3, proximal tubules and tubular cast stain equally for kappa and lambda light chain (figures 1–4).

Figure 1.

High-power view shows kappa light chain deposits by immunofluorescence.

Figure 2.

High-power view shows mesangial and glomerular capillary loop thickening with some capillary loops with double contours (silver stain).

Figure 3.

High-power view shows vessels with minor arterial and arteriolosclerosis (trichrome stain).

Figure 4.

High-power view shows patchy increased cellularity in glomerulus with some mesangial thickening and pas-positive deposits (PAS stain).

Bone marrow biopsy was consistent with MGUS, showed cellularity 30%–50%, 3%–5% plasma cells, adequate maturing erythropoiesis, granulopoiesis, megakaryopoiesis and marrow cytogenetics 47XX. BCR/ABL, JAK2 V617F mutation, MPL515 mutation was negative. Urine immunofixation showed a polyclonal increase in the globulin regions and light chain was detected without any Bence Jones protein. Bone survey was negative for degenerative disease. Thus, the patient was diagnosed with MGUS with renal LCDD. Within the next few weeks, her GFR decreased to 21, serum kappa rose to 10.50 mg/dL, lambda 3.33 mg/dL, ratio 3.153.

Differential diagnosis

For the initial presentation, myeloproliferative disorder was low in the differential list, leukocytosis was presumed to be secondary to chronic sinusitis. Later due to persistent leukocytosis, CML was suspected but was ruled out as CML/ALL PCR quantitative mutation and JAK 2 (V617) were negative and bone marrow showed cellularity of 30%–50% with adequate maturing erythropoiesis, granulopoiesis and megakaryopoiesis. Multiple myeloma was suspected due to the elevated free light chain ratio and worsening renal function. It was ruled out as bone marrow and kidney biopsy results were not consistent. Thus, depending on the serum and urine electrophoresis and kidney biopsy results, MGUS with renal LCDD was diagnosed.

Treatment

Within the next few weeks of diagnosis, her kidney function worsened (table 1) and thus treatment was initiated with CyBorD regimen. She was started on induction therapy with bortezomib SQ 1.3 mg/m², cyclophosphamide 300 mg/m² PO and Decadron 40 mg PO weekly. After around three cycles, cyclophosphamide was changed to IV from oral. After around 10 months of induction therapy, she was started on maintenance therapy with bortezomib 2.4 mg/m² 2 weekly and dexamethasone 20 mg 2 weekly and have responded well. She is currently on maintenance therapy for the last 18 months.

Outcome and follow-up

After around 10 months, she responded well and her GFR increased to 42 mL/min/1.73m², kappa was 8.057 mg/dL, lambda 3.43 mg/dL, kappa/lambda ratio 2.349. Urine protein/creatinine at the time of diagnosis was 10 342 mg/g which trended down to 4985 mg/g and 978 mg/g at 4 and 10 months of treatment, respectively. Due to her upward trend of renal function, she never needed hemodialysis or a change in treatment regimen.

Discussion

Renal MIDD is a rare condition which is characterised by the deposition of monoclonal immunoglobulins in the tubular basement membrane and glomeruli. Usually, these are associated with lymphoproliferative disorder, most commonly MM. Our case was found to have MGUS with slight IgA M spike. It can occur at any decade of life but mostly seen between the ages of 60 and 70 years. Both genders are equally affected. Any organ can be affected but the kidney is the most common where it presents as nephrotic syndrome with severe albuminuria. Renal failure develops in weeks to months and more than 60% cases progress to end-stage renal failure. Five-year patient survival is less than 50% and is influenced by multiple factors like associated multiple myeloma, initial creatinine levels and extrarenal involvement.³ The biopsy usually shows linear staining for monoclonal light chain (kappa or lambda) in the tubules, basement membrane and vessel walls. These were consistent with our patient’s EM findings. Around 80% of renal LCDD is of Kappa isotype. EM shows deposits of punctate granular type which was also noted in our patient. Usually, in around 50% of patients, glomerular deposits produce a nodular mesangial sclerosing pattern but our patient presented with a unique membranoproliferative picture.² Complement deposition may be noted in some cases of heavy chain deposit disease(HCDD) or LCDD which was negative in our case.³ Thickening of the tubular basement membrane is a characteristic feature of LCDD.²

LCDD has been treated with myeloablative doses of melphalan combined with autologous SCT.^{2 3} But without effective treatment, recurrences of LCDD is very common in patients with SCT.³ For LCDD, bortezomib has been successfully used in various combination regimen but mostly requiring a second line of treatment of chemotherapy or SCT (table 2). In a retrospective analysis done at Mayo Clinic between 2007 and 2010, 17 patients with amyloid light chain (AL) with renal and cardiac involvement were treated with 2–6 cycles of CyBorD and after a median follow-up of 21 months, 12 were alive.⁴ Among proteasome inhibitors, bortezomib and carfilzomib have been used as single agents in MGRS, but overall response rate is around 30%–50% depending on the phase of the disease.⁵ In cases with monoclonal IgG (IgA) gammopathy, antimyeloma agents are used but in patients with renal failure, bortezomib, cyclophosphamide and/or Thalidomide regimens are used. Whereas if it is lymphoplasmacytic with a monoclonal IgM, it is treated in the line of Waldenstorm’s macroglobulinemia with rituximab containing regimen.⁶ Since our patient had monoclonal IgA gammopathy with rapidly worsening renal function, a cyclophosphamide-based regimen, CyBorD, was chosen for her treatment plan. ⁷ No treatment guidelines exist so far for effective treatment of renal LCDD. Our case is unique because our patient had IgA kappa LCDD without MM with rapidly progressing myeloproliferative pattern of glomerulopathy which responded dramatically to only CyBorD regimen. As renal LCDD usually progress to ESRD, her rapid response to this combination prevented the need for dialysis. Our patient is still on maintenance treatment with bortezomib and dexamethasone after 18 months of adequate response. Further RCTs are required to prove the effectiveness of this combination and to guide management of LCDD. This case brings hopes that even with a serious decline in renal function in patients with renal LCDD, CyBorD may be a promising regimen.

Table 2.

Summary of the literature

Study	Primary disorder	Treatment	Outcome
Adamu et al 1 (2016)	Kappa LCDD	Cyclophosphamide, bortezomib, dexamethasone (six cycles) ->thalidomide, cyclophosphamide, dexamethasone (six cycles)	Complete remission even after 3 years
Hall et al 2 (2001)	Kappa LCDD with MGUS	Vincristine, adriamycin and dexamethasone (4 months) ->prednisolone and melphalan for 18 months	3 years after, Cr- 1.67 mg/dL (144 mu mo/L), Cr cl- 36 mL/min
Gonzalez et al 7 (2011)	Kappa LCDD	Bortezomib and dexamethasone (six cycles) ->APBSCT (autologous peripheral blood stem cell transplant)	At 5 years, Cr- 2.31 mg/dL, FGR 38 mL/min, Cr Cl- 50 mL/min
Salant et al 3 (2007)	Kappa LCDD	Melphalan (high dose) ->autologous SCT	At five mo, Cr- 3.1 mg/dL, normal serum free light chain k/lamda −1.5)
Our case (2019)	IgA kappa LCDD with MGUS	Cyclophosphamide, bortezomib, dexamethasone (10 months of consolidation) ->bortezomib and dexamethasone (18 months maintenance - ongoing)	At 28 months, GFR- 38.5 mL/min/1.73m2, Cr- 1.4 mg/dL, kappa /lamda - 2.55,

Learning points.

• IgA kappa light chain disease is a rare disorder with serious complications like renal failure within months of diagnosis if left untreated.

• Renal biopsy shows pattern of glomerulonephritis with IgA kappa deposits.

• No treatment guidelines are available until now although combination of multiple chemotherapy regimen or combination of chemotherapy with stem cell transplant has been proven to be beneficial.

• Our case demonstrates that CyBorD is a promising single regimen in the management of IgA kappa renal LCDD.