Bendamustine therapy in MM
UKMF Autumn meeting 2015
Dr Karthik Ramasamy
Oxford
Bendamustine use in MM
• Bifunctional agent - combines the alkylating properties of a
mustard group with the activities of a benzimidazole ring,
giving it a unique alkylating activity1
• No cross resistance to melphalan in vitro2
• Safe in MM patients with renal impairment3
• Single agent activity in RRMM4 and shows efficacy in
DRMM5
1.
Ozegowski et al Zentralblatt fur Pharmazie, Pharmakotherapie und Laboratoriumsdiagnostik, 110, 1013–1019.2. Leoni et al Clin Cancer Res
January 1, 2008 14; 309 3. Ramasamy et al Br J Haematol. 2011 Dec;155(5):632-4 4. Michael et al Eur J Med Res 2010;15:13-19 5. Lau et
al Ann Hematol. 2015 Apr;94(4):643-9
Randomised trials in MM
Frontline transplant ineligible1
• n = 131 Benda/Pred vs MP
• ORR – BP (75%) vs MP (69.8%) CR
- BP ( 32 %) vs MP (13%)
RRMM: Dose randomisation trial2
•
•
•
•
•
• TTF - BP ( 14 mo) vs MP ( 10 mo)
• Benda Car Dex NDMM dose
finding trial NCT02002598
1.
Benda/ Thal / Dex 60 vs 100mg/m2
N= 94, with 74 study eligible (
eligibility criteria for platelet and
neutrophil count changed at
interim analysis)
BTD 100mg/m2 – significant
myelosuppression
BTD 60 mg/m2 n= 54 with 61.5%
pre treated with Len and Bort. ORR
46.3%, PFS 7.5 months
BTD60 toxicity: 33% of patients
experienced ≥Grade 3 neutropenia,
31% ≥Grade 3 thrombocytopenia
and 22% ≥Grade 3 anaemia. 21%
discontinued because of toxicity
Ponisch et al J Cancer Res Clin Oncol.2006;132:205-212 2. Schey et al Br J Haematol. 2015 Aug;170(3):336-48
Bendamustine in renal impairment
• Bendamustine is bound to plasma proteins with a mean elimination t1/2 of
approx 30 min. Rapid metabolism via hydrolysis with both faecal and renal
excretion1
• Safe in renal impairment2. Bendamustine is dialysable
• Benda/ Bort/ Pred in NDMM with renal impairment. 18 patients with
eGFR < 35ml/min treated with Bendamustine (60 mg/m2) on days 1 and 2
with prednisone (100 mg) given orally on days 1, 2, 4, 8, and 11, and
bortezomib (1.3 mg/m2). ORR 83% with 4/8 patients ( 50%) dialysis
independent3
• Nine patients who received a combination of benda (120 mg
intravenously, day 1) thalidomide (100 mg/d) and dex (20 mg, days 1, 8,
15, and 22 of a 28-d cycle) in both NDMM and RRMM patients with renal
impairment ( eGFR < 30ml/min). Haematological ORR 55% ( > PR) and
dialysis independence in 3/ 4 ( 75%) patients4
• OPTIMAL trial - BTD vs BBD in NDMM patients with renal impairment.
Coprimary endpoint – haematological and renal response
1.
Gandhi et al Seminars in Oncology, 29, 4–11 2. Preiss et al Onkologie, 26 ( Suppl.5), S131:P717 3. Ponisch et al J
Cancer Res Clin Oncol 2012;138:1405-1412.4. Ramasamy et al Br J Haematol. 2011 Dec;155(5):632-4
Relapsed refractory MM –
Bendamustine combinations
Lau et al Ann Hematol. 2015 Apr;94(4):643-9
Bendamustine therapy in DRMM
• Retrospective audit of Thames Valley & UCL MM patients. DRMM treated
with Benda/ Thal/ Dex ORR( incl MR) 40%.
• Grade 3-4 toxicities ( > 10%): Anaemia, neutropaenia, thrombocytopaenia,
vomiting, infection.
• Bulk of the use in UK will be in the RRMM setting, close monitoring of
counts and supportive therapy is essential
• Trials: Benda + VRD, Benda / Pom/ Dex and Benda/ Liposomal Dox/ Dex
are ongoing
Lau et al Ann Hematol. 2015 Apr;94(4):643-9
Monoclonal gammopathy of
renal significance ( MGRS)
UKMF Autumn meeting 2015
Dr Karthik Ramasamy
Oxford
Monoclonal gammopathy of renal
significance (MGRS) - Definition
• MGRS indicates a causal relationship between the
diagnosed monoclonal gammopathy and the
renal damage1
• Renal impairment does not always associate with
MGUS, also associated with CLL and WM
• Kidney biopsy is essential to characterise renal
damage
• Incidence of MGRS remains unclear
• Outcome of patients with MGRS can be variable
Leung et al Blood 2012 Nov 22;120(22):4292-5
MGRS case studies
On therapy
Conservative management
•
•
•
•
•
38 year old male foot ball coach
Found to be hypertensive by GP with
proteinuria and normal renal function
in Feb’13
•
63 year old male photographer
•
GP noted hypertension, pedal edema and
creatinine 178 umol/l in Oct’2013
IgG lambda PP 4.9 g/l with Lambda LC
35.4 mg/l and k/L ratio 0.54 Albumin
32g/l Hb 13.1 g/dl eGFR > 90ml/min.
Urine 24 hour protein 2.1 g. BM 4% PC
•
IgG Kappa PP 9.2g/l, Kappa LC 25 g/l K/L
ratio 0.94 Albumin 35g/l, Urine 24 hr
protein 3.3g. BM 5% PC
•
Renal biopsy, kappa light chain deposition
disease
•
Started Bort/ Dex x 6 May’15 due to
worsening renal function eGFR 39 ml/min
to 19ml/min – PR
•
ASCT – well tolerated except worsening
renal function eGFR dropped from 19
ml/min ml/min to 8 ml/min
•
Now improved to eGFR 10 ml/min and
stable renal impairment
Well, renal biopsy showed GN with
monoclonal Ig deposits
Managed conservatively. LC, PP &
proteinuria stable, normal renal
function to date
MGRS - Suspicion
• Patients presenting with either chronic or acute renal
impairment with a monoclonal gammopathy
• No alternative causes for renal damage has been
identified. Renal biopsy shows monoclonal
immunoglobulin related changes
• Full haematological work up including BM. Urine
analysis – glycosuria, proteinuria, aminoaciduria.
Serum phosphate, bicarbonate and uric acid to look for
fanconi’s syndrome. Imaging to look for lytic lesions.
• Multi disciplinary working including renal pathologist,
renal physician and haematologist
Bridoux et al Kidney Int April;87(4):698-711
MGRS - Diagnosis
• Renal biopsy should be examined by an experienced renal
pathologist – Biopsy examined by Immunohistochemistry,
Immunofluorescence and Electron microscopy methods
• Often BM shows evidence of MGUS with no skeletal abnormalities
on imaging or hypercalcaemia
Leung et al Blood 2012 Nov 22;120(22):4292-5
Yadav et al Kidney Int April 2015; 87)4):692-7
MGRS - Management
• Early and accurate diagnosis is crucial1
• Early therapy is proposed by consensus group in patients
where salvaging renal function or limiting further renal
damage is required2. Patients with renal impairment and/
or excessive proteinuria.
• Choice of therapy currently follows myeloma treatment
pathway2,3
• ASCT can be performed in eligible patients4
• Establishing a prospective registry can help define
epidemiology and outcomes in patients
• Once patients benefiting from therapy defined, a
prospective trial would help define management in this
group of patients
1. Leung et al Blood 2012 Nov 22;120(22):4292-5 2. Fermand JP et al Blood 2013 Nov 21;122(22):3583-90,
3. Cohen et a Kidney Int Jul 15 epub 4. Hassoun H et al Bone Marrow Transplantation (2008) 42, 405–412.
Management of Solitary
Plasmacytoma
UKMF Autumn meeting 2015
Dr Karthik Ramasamy
Oxford
Solitary Plasmacytoma definition1
Categories
Definition
Progression
rate to MM
Solitary
Biopsy-proven solitary lesion of bone or soft tissue with
10% within 3
plasmacytoma evidence of clonal plasma cells
years 2-5
Normal BM with no clonal PCs
Normal skeletal survey and MRI (or CT) of spine and pelvis
(except for the primary solitary lesion)
Absence of CRAB that can be attributed to a
lymphoplasma cell proliferative disorder
Solitary
As above except Clonal plasma cells < 10%
plasmacytoma
with marrow
involvement
60% (bone)
or 20%
(soft tissue)
within
3 years 3-5
1.Rajkumar et al Lancet Oncol 2014; 15: e538–48 2. Dimopoulos MA, et al Sol. Hematol Oncol Clin North Am 1999; 13:
1249–57. 3. Hill QA, et al.. Blood 2014; 124: 1296–99. 4. Paiva B, et al. Blood 2014; 124: 1300–03. 5. Warsame R, et al. Am J
Hematol 2012; 87: 647–51.
Plasmacytoma work up
• Full blood count
• Biochemical screen including electrolytes and corrected
calcium
• Serum immunoglobulin levels & Serum free light chains
• Serum and urine protein electrophoresis and
immunofixation
• Full skeletal survey, including standard x-rays of the
skeleton including lateral and anteroposterior cervical,
thoracic and lumbar spine, skull, chest, pelvis, humeri and
femora*
• Whole body imaging – MRI or FDG PET/CT
• Bone marrow aspirate with flow cytometry and trephine
* Could be avoided if whole body imaging is performed
Stratification – Higher Risk of
progression to myeloma
• BM involvement, by morphology and aberrant
phenotype by Flow cytometry ( 72% vs 12.5% at
3.7 years fu)1
• Abnormal sFLC ratio ( 44% vs 26% at 5 years)2
• Size (>5 cm) of plasmacytoma 3,6
• Persistence of paraprotein following
radiotherapy4
• PET positive lesions2,5
• Age > 60 years6
1. Hill QA, et al.. Blood 2014; 124: 1296–99 24. 2. Warsame R, et al. Am J Hematol 2012; 87: 647–51.
3. Tsang et al. Int J Radiat Oncol Biol Phys 2001; 50: 113-20. 4. Wilder RB et al Cancer 2002; 94: 1532-7.
5. Fouquet G et al Clin Cancer Res 2014 Jun 15;20(12):3254-60 6. Knobel D BMC Cancer 2006;6:118
Plasmacytoma management algorithm
Thames Valley Plasmacytoma guideline adapted from BCSH Plasmacytoma guidelines 2009
Trials and unanswered questions
• 1. Increase cure rate in patients with solitary
plasmacytoma, precise diagnosis is essential
• 2. Identify further factors at risk of progression to
myeloma ( currently 50% at 3 years)
• 3. Therapeutic intervention in high risk patients – IDRIS
trial exploring adjuvant Lenalidomide &
Dexamethasone
• 4. Systemic therapy following radiotherapy:
Randomised trial – Ixa/ Len / Dex / Zol vs Zol in SBP
(NCT02516423)
• 5. Genetic changes ( chromosomal aberrations and
GEP) in plasmacytoma vs MM and plasmacytoma to
MM progressors vs non progressors