Multiple Myeloma in HUSM. Dr Azlan Husin HUSM

Multiple Myeloma in HUSM Dr Azlan Husin HUSM

Outline Overview Presenting features Progress in myeloma Global HUSM

Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, associated organ dysfunction

MGUS Smouldering - MM

Pathology of Myeloma Skeletal destruction Hypercalcaemia Spinal cord compression Fractures Marrow Infiltration Anaemia Thrombocytopenia Neutropenia Myeloma protein Renal damage Hyperviscosity Bleeding Amyloidosis Malignant proliferation of plasma cells Immune paresis Recurrent infections Poor humoral immunity

Criteria for Diagnosis of MM MM* (all 3 criteria required) Monoclonal plasma cells in bone marrow 10% and/or presence of biopsy-proven plasmacytoma Monoclonal protein present in serum and/or urine Myeloma-related organ dysfunction (1 or more) (C) Calcium elevation in blood (serum calcium >2.88 mmol/l or ULN) (R) Renal insufficiency (secr > 177 µmol/l) (A) Anemia (hemoglobin <10 g/dl or 2g <normal) (B) Lytic bone lesions or osteoporosis ** *Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smoldering or indolent myeloma; If no monoclonal protein is detected (non-secretory disease), then 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required; A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related; **If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are sole defining criteria, then 30% plasma cells are required in BM Durie BGM et al. Hematol J. 2003;4:379 [published correction in Hematol J. 2004;5:285] Kyle RA et al. Mayo Clin Proc. 2003;78:21

Durie-Salmon Staging Stage Criteria Myeloma Cell Mass ( 10 12 cells/m 2 ) I All of the following: Hemoglobin >10 g/dl Serum calcium level <10.5 mg/dl (normal) Normal bone or solitary plasmacytoma on X ray Low M-component production rate: IgG <5 g/dl; IgA <3 g/dl Bence Jones protein <4 g/24 hr Median OS (months) <0.6 (low) 82 II Not fitting stage I or III 0.6 1.2 (intermediate) 68 III One or more of the following: Hemoglobin <8.5 g/dl Serum calcium level >12 mg/dl Advanced lytic bone lesions on X ray High M-component production rate: IgG >7 g/dl; IgA >5 g/dl Bence Jones protein >12 g/24hr >1.2 (high) 50 Subclassification A B Criteria Normal renal function (serum creatinine level <177 micmol/l) Abnormal renal function (serum creatinine level 177 micmol/l) Durie BG, Salmon SE. Cancer. 1975;36:842 Multiple Myeloma Research Foundation. Available at: http://www.multiplemyeloma.org

International Staging System Stage Criteria Median OS I Serum 2 M <3.5 mg/l Serum albumin 3.5 g/dl 62 mo II Serum 2 M <3.5 mg/l 44 mo Serum albumin <3.5 g/dl OR Serum 2 M 3.5 to <5.5 mg/l* III Serum 2 M 5.5 mg/l 29 mo *Irrespective of serum albumin level Greipp PR et al. J Clin Oncol. 2005;23:3412

Prognostic markers Clinical Durie-Salmon IIIB ISS stage I vs III LDH Normal vs high β2-m Low/normal vs high Cytogenetic Conventional del 13 hypodiploidy FISH t(11;14) t(4;14) del 17p13

Percentage ISS: Survival 100 80 Median Deaths/N in Months Stage I 606/1111 62 (58,65) Stage II 1054/1505 44 (42,45) Stage III 968/1305 29 (26,32) 60 40 20 0 24 48 72 96 120 144 168 192 216 Months From Initial Chemotherapy Treatment Greipp PR et al. J Clin Oncol. 2005;23:3412

PROGRESS IN TREATMENT

Principal management To eradicate myeloma cells? Cure Induction Consolidation High dose chemo + auto SCT Maintenance Supportive therapy Bone disease: Pain, fracture management, bisphosphonate, surgery, radiotherapy, analgesics Anemia: Transfusion, erythropoietin Renal support Infection prevention Thrombosis prevention

Treatment Options in Multiple Myeloma 1990s Supportive care (AB, Vaccination, Erythropoetin) 1962 Melphalan/ Prednisone 1999 Thalidomide 2002 modif. allo-sct 2006 Lenalidomide Melphalan Since 1990s Myeloablation + ASCT 2000s Tandem ASCT 2003/2004 Bortezomib

Thalidomide & Lenalidomide 1950 s 1970 s 1960 s

Thalidomide & Lenalidomide Proposed MOA Inhibit IL-6 production Activation of apoptotic pathways Activation of T cells to produce IL-2 augmenting the activity of NKdependent cytotoxicity. Side effect Sedation, peripheral neuropathy, constipation, DVT, marrow suppression More potent than thalidomide No or minimal neuropathy More incidence marrow suppression than thalidomide Others s/e same: DVT, teratogenicity

Proteosome inhibition

Induction / Consolidation / Maintenance CTD CyBORD Thalidomide TD VMP Lenalidomide VTD MPT Velcade VMP VAD VT VD ESHAP RD or Rd dvd RVD PAD MPR VMPT MP DT-PACE VcTD

Soup of abbreviated alphabets

Treatment approach: Old Paradigm Induction Chemotherapy Transplant Nonalkylating Agent No Transplant Alkylating Agent Induction chemotherapy choice depends on transplant status Transplant candidates induced with nonalkylating agents Nontransplant candidates treated with alkylating agents Depth of response to induction therapy Not critical in transplant CR, PR, or SD acceptable Kyle RA, et al. N Engl J Med. 2004;351:1860-1873.

Induction Therapy :Traditional Study N Regimen CR/ ncr CR + PR Stem Cell Harvest Rajkumar 100 Dex 0% 50% Yes Goldschmidt 203 VAD 3% 63% Yes Rifkin 97 DVd 3% 43% Yes IFM90 100 VMCP/ BVAP 5% 52% Yes/No Palumbo 126 MP 7% 48% No Ref JCO 2006 ASH 2005 Cancer 2006 NEJM 1996 ASH 2005 DVd, liposomal doxorubicin, vincristine, dexamethasone; VMCP/BVAP, vincristine, melphalan, cyclophosphamide, prednisone, carmustine, and doxorubicin.

Treatment approach: New Paradigm Induction Novel Agents Transplant No Transplant Start induction therapy with novel agents Aim for CR or PR May improve efficacy in nontransplant candidates May make stem cell transplant optional May allow transplant decision to be deferred If indicated, may optimize stem cell transplantation

Treatment strategy in myeloma

IMWG uniform criteria

IMWG uniform criteria

Treatment strategy in myeloma

AK Stewart, PG Richardson and JF San-Miguel, Blood 2009

IMWG uniform criteria for survival PFS: Progression Free Survival PFS is the time from start of the treatment to disease progression or death. This encompasses all patients and has been considered a surrogate marker for overall survival duration. EFS: Event-free survival The definition depends on how event is defined. In some studies, this can be the same as PFS. EFS can also include additional events that are considered to be of importance besides death, including serious drug toxicity. EFS is not recommended for general use unless specifically defined, as confusion can arise about the details of additional events

IMWG uniform criteria for survival TTP: Time to Progression time from start of treatment to disease progression with deaths owing to causes other than progression not counted, but censored. This is a helpful method to assess the durability of treatment benefit. DFS: Disease-free survival applies to patients in CR, and is measured from the start of CR to the time of relapse from CR. limited value in myeloma at present. OS: Overall survival Over 5 years of follow-up are required to assess benefit. Initial response and TTP may or may not translate into overall survival benefit.

IMWG uniform criteria for survival DOR: Duration of Response applies to patients achieving at least PR by and is measured from start of achieving PR (first observation of PR before confirmation) to the time of disease progression, with deaths owing to causes other than progression not counted, but censored. for consideration in the assessment of new agents and/or new comprehensive treatment strategies

Treatment strategy in myeloma

Maintenance Rx in elderly?

Novel agents Good side Can be treated as outpatient / daycare Remarkable efficacy esp in combination Response after induction Improved response after HSCT Improved in PFS, TFS Trend towards improving OS Bad side Peripheral neuropathy Thalidomide Bortezomib Thrombotic events Thalidomide, Lenalidomide Myelosupression Lenalidomide, thalidomide Bortezomib (mild, plt) Infection Lenalidomide, thalidomide Bortezomib (mild, plt) Others GI upset, sedation

Most important complication 21 caps, 25 mg, 26 thousand RM!

Most important complication 1 vial, 3.5 mg, 3 thousand++ RM! Need 4 vials / cycle

Most important complication 1 box, 100 mg, 28 tablets, 2 hundreds RM! Need 4 vials / cycle

WHY HIGH DOSE CHEMO & AUTO SCT?

Principle of HD chemo & auto SCT Giving myoablative chemotherapy / radiotherapy Followed by re-infusion of patient s hemopoietic stem cells (as rescue) That was collected via apharesis technique Stored in nitrogen storage

Auto SCT in HUSM First patient started in November 2007 Offered for upfront Rx for myeloma patient age 70 or less Upfront Rx for selected high risk aggressive NHL / HL Consolidation Rx for patient with relapse NHL/HL?? Patients so far No TRM

Preparation for transplant Patient has to undergo induction Rx to achieve CR or VGPR Hemopoieitic stem cell mobilization High dose cylophosphamide + GCSF Hemopoieitic stem cell collection BM harvest Peripheral Blood Stem Cell Collection

Treatment strategy in myeloma

Lower relapse rate following exposure to drugs

Auto SCT in HUSM

Supportive / adjunct therapy Myeloma bone disease Bisphosphonate (Pamidronate / Zolendronate) Pain Caution in renal impairment, infusion rate Osteonecrosis of the jaw (dental team) Good analgesic : opioid based constipation/dizzy/stigma Fracture Cord compression Radiation therapy Spine team : surgery / vetebroplasty / kyphoplasty

Osteonecrosis of the jaw

Supportive / adjunct therapy Anemia Blood transfusion Look for other cause: GIB Erythropoietin Selected patient, target of Hb Concerns Renal support Hydration / Hemodialysis / Plasmapharesis Avoid nephrotoxic (ACE-I, ARB, NSAIDs)

Supportive / adjunct therapy Infection: Disease + treatment associated IV IgG support 0.4g/kg/dose every 3-4 weeks Antimicrobial prophylaxis Bactrim, Acyclovir, +/- fluconazole

Supportive / adjunct therapy Prevention of thrombotic event According to risk profile: mobility, treatment use Non pharmacological measure Hydration Elastic stocking Physiotherapy Aspirin / warfarin / LMWH / pentasaccharide (fondaparinux)

PROGRESS IN SURVIVAL

10-year relative survival (%) Improvements in survival of younger patients Period estimates of 10-yr survival by major age groups in defined calendar periods 50 45 40 35 30 25 20 15 10 5 0 1984 1986 1987 1989 1990 1993 1992 1995 Calendar period 1996 1998 1999 2001 2002 2004 <50 50 59 60 69 70 79 80+ Brenner et al. Blood 2008

Myeloma patients treated in HUSM Presenting Sx Duration of Sx Treatment Survival Total 58 Bone pain 39/53 (73.6%) Cord / nerve compression 8/40 (20%) Anemia 28/41 (68.3%) Renal impairment 14/41 (34.1%) Hyper Ca 17/35 (48.6%) Recurr infection 8/43 (18.6%) Mass 10/43 (23.2%) Analyzable= 50 Before 2005 VAD MP Dex Pred Analyzable = 35 pt > 3 mo = 62.5% Median = 22 mo After 2005 TD Td VD VTD RVD 2 years = 29.30% 3 years = 24.13% Current status 24 / 52 alive

Consideration Treatment efficacy Treatment toxicity

THANK YOU Audience Committee members MOs & supporting staffs in Hemato/ Onco wards HUSM AVA & security staffs Department of Medicine, SMS USM IMS- USM Roche (M)

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