Bendamustine therapy in MM

UKMF Autumn meeting 2015Dr 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 MMFrontline transplant ineligible1

• n = 131 Benda/Pred vs MP• ORR – BP (75%) vs MP (69.8%)

CR - BP ( 32 %) vs MP (13%)

• TTF - BP ( 14 mo) vs MP ( 10 mo)• Benda Car Dex NDMM dose

finding trial NCT02002598

RRMM: Dose randomisation trial2

• 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

1. 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 2015Dr 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 studiesConservative

management• 38 year old male foot ball coach• Found to be hypertensive by GP with

proteinuria and normal renal function in Feb’13

• 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

• Well, renal biopsy showed GN with monoclonal Ig deposits

• Managed conservatively. LC, PP & proteinuria stable, normal renal function to date

On therapy• 63 year old male photographer

• GP noted hypertension, pedal edema and creatinine 178 umol/l in Oct’2013

• 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

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):4292-5Yadav 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 2015Dr Karthik Ramasamy

Oxford

Solitary Plasmacytoma definition1

Categories Definition Progression rate to MM

Solitary plasmacytoma

Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cellsNormal BM with no clonal PCsNormal 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

10% within 3 years 2-5

Solitary plasmacytoma with marrow involvement

As above except Clonal plasma cells < 10% 60% (bone) or 20%(soft tissue) within3 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