HaematologyRenal Cases Progress in the treatment of renal failure in multiple myeloma

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Haematology/Renal CasesProgress in the
treatment of renal failure in multiple myeloma

• Dr. Mark Cook
• Consultant Haematologist Honorary Clinical
  Senior Lecturer
• University Hospital Birmingham

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• Background
• Case based presentation covering
• Presentation and management of renal failure in
  myeloma
• The use of novel dialysis techniques
• The use of novel anti-myeloma agents
• Stem cell transplant

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Background

• 50 of MM patients will have renal impairment at
  some stage
• Approximately 10 require dialysis
• Dialysis negatively impacts survival and quality
  of life
• Avoidance of dialysis paramount
• Prompt treatment of dehydration, sepsis,
  hypercalcaemia etc
• Avoidance of nephrotoxic agents e.g. NSAIDs

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Causes of Renal Failure in MM

• Cast nephropathy Hyaline fractured casts,
  degenerated tubular cells
• AL amyloidosis Fibrils Congo red staining
  positive, apple- green birefringence under
  polarized light
• LCDD Deposition of light chains
• Heavy-chain deposition disease Deposition of
  heavy chains
• Tubular disturbance Proximal tubular acidosis
• Hypercalcaemia
• Hyperviscosity
• Membranoproliferative GN Cryoglobulins
• Plasma cell infiltrates
• Rhabdomyolysis Light-chain deposition in the
  muscle
• Pyelonephritis/sepsis Immunodeficiency with
  frequent infections
• Drugs NSAIDs other nephrotoxic drugs

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Plt0.01
MacLennan et al BMJ 1984
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Successful Treatment- What Can the Modern Era
Offer?

• Prompt diagnosis of MM
• Prompt assessment of renal impairment
• Prompt management of renal impairment including
  remedying precipitating factors
• Effective treatment of myeloma and suppression of
  light chain production
• Novel agents
• Thalidomide
• Bortezomib
• Accelerated clearance of free light chains
• Plasma Exchange
• Novel dialysis techniques

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Successful Treatment- What Can the Modern Era
Offer?

• Prompt diagnosis of MM
• Prompt assessment of renal impairment
• Prompt management of renal impairment including
  remedying precipitating factors
• Effective treatment of myeloma and suppression of
  light chain production
• Novel agents
• Thalidomide
• Bortezomib
• Accelerated clearance of free light chains
• Plasma Exchange
• Novel dialysis techniques

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Successful Treatment- What Can the Modern Era
Offer?

• Prompt diagnosis of MM
• Prompt assessment of renal impairment
• Prompt management of renal impairment including
  remedying precipitating factors
• Effective treatment of myeloma and suppression of
  light chain production
• Novel agents
• Thalidomide
• Bortezomib
• Accelerated clearance of free light chains
• Plasma Exchange
• Novel dialysis techniques

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Successful Treatment- What Can the Modern Era
Offer?

• Prompt diagnosis of MM
• Prompt assessment of renal impairment
• Prompt management of renal impairment including
  remedying precipitating factors
• Effective treatment of myeloma and suppression of
  light chain production
• Novel agents
• Thalidomide
• Bortezomib
• Accelerated clearance of free light chains
• Plasma Exchange
• Novel dialysis techniques

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MJ

• Presented to local Hospital with spontaneous
  fracture of left hip
• Referred to specialist centre for bone tumour
  surgery
• Hypotension perioperatively
• ?sepsis post-op received gentamicin and
  furosemide subsequently
• Referred to UHB with ?cast nephropathyas bone
  histology was consistent with plasmacytoma

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MJ- serial results
CTD
(Renal/marrow bx)
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Patient AL

• 8 month history of decreasing exercise tolerance
• Presented with nephrotic syndrome
• Renal biopsy consistent with amyloid
• Further investigations
• Elevated SFL
• Marrow gt30 PC
• Skeletal survey- several lucencies
• Assessed at NAC (RFH)
• Confirmed diagnosis of amyloid secondary to MM
• Also demonstrated cardiac involvement

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CTDx2
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CTDx2
Vel/Dex x8
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JP

• 69yo female
• Presented with vertebral fracture, DVT and
  creatinine 238
• Marrowgt20 PC
• Skeletal survey Vertebral fractures
• Serum free lambda 9000mg/L
• No significant improvement in RF with hydration
• Entered Myeloma IX (intensive pathway)

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JP- serial FLC results
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JP- serial FLC results
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JP- serial FLC results
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Cast Nephropathy

• Intratubular casts
• Tubular cell atrophy
• Giant cell reaction

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Patient DM

• 60yo Afro-Caribbean male diagnosed with MGUS 1999
• Lost to follow up
• Emigrated to Jamaica
• After 1 week, presented to local doctor unwell
• Admitted and diagnosed with dehydration secondary
  to hypercalcaemia and ?myeloma
• Absconded and flew to UK via Miami
• Presented in acute renal failure
• IgG 82g/l Ca gt3.0 Hb lt10 lesions on s. survey
  gt60 PC in marrow
• Consented to enter pilot study of HCO1100
  dialysis membrane

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Dex
Dex
Thal
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Subsequent Course
CTD x3
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Subsequent Course
CTD x3
Autograft
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Subsequent Course
CTD x3
Autograft
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Patient JB

• 56 yo male
• Presented on a Wednesday to his GP feeling unwell
• Bloods showed a creatinine gt1000
• Admitted under renal physicians that night
• Renal biopsy showed cast nephropathy
• Bone marrow performed on Friday
• Transferred to UHB Saturday morning recruited
  into pilot study and commenced therapy

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CTD
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Patient GF

• 53yo male presented with tiredness
• Creatinine 690
• Serum free kappa 42000mg/L
• Renal biopsy confirmed cast nephropathy
• Referred for dialysis using HCO1100 (on pilot
  study)

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Patient GF- Serial SFK
VAD x2 cycles
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Patient BD

• 64 yo male diagnosed with IgG? MM (normal renal
  function)
• Received CTDx2
• Developed ARF with no serological or marrow
  evidence of response
• Renal Bx- cast nephropathy
• Referred for dialysis with HCO1100
• Compassionate use of Bortezomib (Velcade) approved

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Patient BD- PAD Chemotherapy and Dialysis Using
HCO1100
Dex Adriamycin Velcade
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Anti-myeloma Agents in Renal Failure

• Dexamethasone
• Used as a single agent (pulsed dex) or more
  commonly, in combination
• VAD (Vincristine, Adriamycin, Dexamethasone)
• Long-established infusional chemotherapy
• Given continuously for 4 days every 3 weeks
• Safe in renal impairment/dialysis but
  logistically can be a challenge
• ORR 50

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• Thalidomide
• Usually given in combination as an oral regimen
  (in UK with cyclophosphamide and dexamethasone-
  CTD)
• Predictable SEs
• VTE
• Infection
• Neuropathy
• Sedation/constipation
• Rarely, hyperkalaemia
• ORR in region of 70
• Lenalidomide
• Same class as thalidomide
• Renally cleared so significant dose adjustments
  required
• Toxicities include neutropenia and VTE

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• Bortezomib (Velcade)
• Licensed for use at first relapse in myeloma
• Given as an IV bolus in short period of time
  d1,4,8,11 of a 3 week cycle
• Most commonly used in combination (with
  dexamethasone /- adriamycin)
• SEs include
• Neuropathy
• GI toxicity
• Tiredness
• Low platelets
• Response rates high for combinations (70-90) and
  usually occur quickly

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Bortezomib in Renal Failure

• Chanan-Khan et al reported on 24 patients (23 on
  dialysis) treated with bortezomib
• Well-tolerated
• ORR 75 but 80 remained dialysis-dependent
• Ludwig et al reported a phase II study of PAD in
  patients with renal failure
• 75 ORR with 43 showing some improvement in
  renal function
• Toxicities included 3 deaths- doses of
  bortezomib/adriamycin adjusted subsequently

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Autologous Transplant in Renal Failure

• Underlying principle is that autologous
  transplant increases DFS and OS (but not proven
  in a population with renal impairment)
• Non-randomised data suggests that in patients
  that survive the transplant, disease control is
  as good as patients with normal renal function
• Toxicity reportedly much higher (15-24 vs 1-2)
• Requires
• Close liaison with renal team and ITU
• Dose reduction of melphalan
• Absence of other comorbidities
• Expectation of prolonged toxicity

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Summary

• Renal impairment remains the most significant
  comorbidity at presentation in MM

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Summary

• Renal impairment remains the most significant
  comorbidity at presentation in MM
• Still has a negative impact on survival

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Summary

• Renal impairment remains the most significant
  comorbidity at presentation in MM
• Still has a negative impact on survival
• Comprehensive assessment is required at
  presentation to look for reversible causes and to
  treat them

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Summary

• Renal impairment remains the most significant
  comorbidity at presentation in MM
• Still has a negative impact on survival
• Comprehensive assessment is required at
  presentation to look for reversible causes and to
  treat them
• Successful management requires both
• Effective anti-myeloma therapy and
• Some of the novel agents safe and effective

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Summary

• Renal impairment remains the most significant
  comorbidity at presentation in MM
• Still has a negative impact on survival
• Comprehensive assessment is required at
  presentation to look for reversible causes and to
  treat them
• Successful management requires both
• Effective anti-myeloma therapy
• Some of the novel agents safe and effective and
• Accelerated removal of the toxic light chain
• Plasma exchange unproven (MERIT study)
• HCO1100 highly promising