Reviewed by Dr. Michelle Geddes (Staff Hematologist, University of Calgary) and Dr. Matt Cheung (Staff Hematologist, University of Toronto)

Transcription

1 MULTIPLE MYELOMA Updated March 2017 by Doreen Ezeife, PGY-5 resident, University of Calgary Reviewed by Dr. Michelle Geddes (Staff Hematologist, University of Calgary) and Dr. Matt Cheung (Staff Hematologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: accounts for <1% of all cancers. In 2011, incidence in Canada 5 in 100,000 people. - Mortality: In 2011, total number of deaths estimates at 1,350 RISK FACTORS - Environmental/Chemical/Infections: Radiation, benzene, organic solvents, herbicides, insecticides - Genetic: Genetic predisposition, older age, immunosuppression, gender (male > female), ethnicity (African American) PREVENTION & SCREENING: Patients with myeloma likely had an MGUS preceding myeloma diagnosis. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS (CRAB= calcium elevated, renal failure, anemia and bone lesions) - Common Symptoms: Anemia, bone pain, fatigue/general weakness, weight loss - Common Signs: Elevated creatinine, hypercalcemia, normocytic anemia - Common Presentations: Radiculopathy, pathologic fracture, cord compression INVESTIGATIONS - Laboratory: CBC, albumin, total protein, Calcium, Creatinine, B2microglobulin, LDH, calcium, LFT, SPEP with immunofixation, Free Light Chain assay (kappa, lambda, FLC ratio), 24hr UPEP, NT-proBNP, troponin - Diagnostic Imaging: Skeletal survey, MRI (to rule out cord compression if back pain or neurologic symptoms) echo/cardiac MRI (if suspicion of cardiac amyloidosis) - Diagnostic Procedures: Bone marrow biopsy and aspirate (for morphology, flow cytometry, and cytogenetics). If suspect amyloidosis perform Congo red staining, fat pad biopsy or organ specific biopsy. PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: o Peripheral Blood Smear: rouleaux, normocytic anemia, circulating plasma cells o Bone marrow aspirate: mature plasma cells with immunohistochemistry positive for CD79a, CD138, CD38 - Relevant Cytogenetics: FISH for prognosis o Poor prognosis: t(14;16), t(4;14), del17p, hypodiploidy o Standard prognosis: t(11;14), hyperdiploidy

2 CLASSIFICATION International Myeloma Working Group (IMWG) diagnostic criteria for MM and related plasma cell disorders Disorder Non-IgM MGUS IgM MGUS Light Chain MGUS Smoldering MM (SMM) MM Solitary Plasmacytoma Disease Definition All 3 criteria must be met: - Serum M protein (non-igm type) <3g/dL - Clonal bone marrow plasma cells <10% - Absence of end-organ damage, such as CRAB, that can be attributed to the plasma cell proliferative disorder - Ca (corrected) > 0.25mmol/L - Ca (corrected)>0.25mmol/l upper limit of normal or >2.75mmol/L Renal impairment: Creatinine>176μmol/L Anemia:Hemoglobin < 100g/L or 20g/L below lower limit of normal Bone lesions: lytic lesions or osteoporosis with compression fractures Others: symptomatic hyper-viscosity, amyloidosis, recurrent bacterial infections (>2/year) All 3 criteria must be met: - Serum IgM monoclonal protein <3g/dL - Bone marrow lymphoplasmacytic infiltration <10% - No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder All criteria must be met: - Abnormal FLC ratio (<0.26 or >1.65) - Increased level of the appropriate involved light chain - No immunoglobulin heavy chain expression on immunofixation - Absence of end organ damage that can be attributed to the plasma cell proliferative disorder - Clonal bone marrow plasma cells <10% - Urinary monoclonal protein <500mg/24hr Both criteria must be met: - Serum M protein (IgG or IgA) 3g/dL, or urinary monoclonal protein 500mg/24hr and/or clonal bone marrow plasma cells 10-60% - Absence of myeloma defining events (CRAB) or amyloidosis Both criteria must be met: 1. Clonal bone marrow plasma cells 10% or biopsy proven bony or extramedullary plasmacytoma 2. Any one or more of the following myeloma defining events: - Hypercalcemia: serum Ca >0.25mmol/L higher than upper limit of normal or >2.75mmol/L - Renal insufficiency: CrCl <40mL/min or Scr>177umol/L - Anemia: Hb >2g/dL below lower limit of normal or Hb <10g/dL - Bone lesions: one or more osteolytic lesions on skeletal survey, CT, or PET-CT - Clonal bone marrow plasma cell 60% - Involved:uninvolved serum FLC ratio focal lesions on MRI studies (at least 5mm) - t(4;14) or p53 deletion All 4 criteria must be met: - Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells - Normal bone marrow with no evidence of clonal plasma cells - Normal skeletal survey and MRI (or CT) of spine and pelvis (except

3 Solitary Plasmacytoma with minimal marrow involvement for the primary solitary lesion) - Absence of end organ damage such as CRAB that can be attributed to a lympho-plasma cell proliferative disorder All 4 criteria must be met: - Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells - Clonal bone marrow plasma cells <10% - Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) - Absence of end organ damage such as CRAB that can be attributed to a lympho-plasma cell proliferative disorder STAGING - International Staging System (ISS): Stage B2M (mg/l) Albumin (g/l) Median Survival (months) I < 3.5 And II 3.5 to <5.5 And/or <35 44 III β2m Durie-Salmon Staging: Stage Myeloma Cell Mass (X10 12 cells/m 2 ) I All of the following: Hb >100, normal Calcium, no lytic bone <0.6 lesions, IgG<50g/L, IgA <30 g/l, Urine M-protein <4 g/24h II Neither I nor III III One of more of the following: Hb<85, Ca >3mmol/L, IgG>70g/L, IgA>50g/L, Urine M-protein >12g/24h >1.2 IMWG RESPONSE CRITERIA Classification Stringent Complete Response (scr) Complete Response (CR) Very Good Partial Response (VGPR) Partial Response (PR) Stable Disease (SD) CR as defined below Normal FLC ratio Absence of clonal cells in BM by IHC or immunofluorescence Negative immunofixation on the serum and urine Disappearance of any soft tissue plasmacytomas 5% plasma cells in BM Normal FLC ratio of 0.26 to 1.65 on 2 consecutive assessments Serum/urine M protein detectable by IF but no on electrophoresis 90% decrease in serum M protein plus urine M protein level <100mg/24h 90% decrease in the difference between involved and uninvolved FLC 50% reduction of serum M protein and reduction in 24h urinary M protein by 90% or to <200mg/24h If serum and urine M protein are unmeasurable a 50% decrease in the difference between involved and uninvolved FLC required If serum and urine FLC unmeasurable, 50% reduction in plasma cells required In addition to above, if present at baseline, a 50% reduction in size of soft tissue plasmacytoma Not meeting criteria for CR, VGPR, PR or progressive disease

4 C) TREATMENT: TRANSPLANT ELIGIBLE (age 65yo) Reference: ASH SAP Bottom Line General Approach: o Induction: Pre-transplant induction with a triple drug regimen that includes a novel agent such as bortezomib or lenalidomide. Triple drug regimen such as CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) or VRD (Bortezomib, Lenalidomide, Dexamethasone). o VRD is an option for high-risk disease (17p deletion of t(4;14)). o ASCT: High dose melphalan +/- bortezomib followed by autologous stem cell transplantation o Consolidation: Post transplant consolidation (ie) VRD, bortezomib not standard practice, not usually funded in Canada o Maintenance: Maintenance until disease progression with lenalidomide or bortezomib - Important Phase III Clinical Trials: 1. Phase III trials incorporating novel agent-based INDUCTION prior to ASCT Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase III study. GIMEMA MM-BO2005 Cavo et al. Lancet 2010; 376(9758):

5 Regimen VTD vs TD VTD (bortezomib, thalidomide, dexamethasone) X3 ASCT X2 VTD X2 TD (thalidomide, dexamethasone) X3 ASCT X2 TD X2 Mechanism of Bortezomib: proteasome inhibitor Action of Experimental Drug Primary Endpoint Postinduction CR/nCR rate Eligible for auto-sct Size (N) 480 patients Postinduction CR/nCR VTD vs TD: 31% vs 11% (p<0.001) Post HSCT CR VTD vs TD: 42% vs 30% 3yr PFS and OS VTD vs TD PFS: 68% vs 56% VTD vs TD OS: 86% vs 84% Toxicity VTD: higher occurrence of peripheral neuropathy VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. IFM Moreau et al. Blood 2011;118 (22): Regimen VD vs vtd VD (bortezomib, dexamethasone) X4 ASCT Versus dose reduced vtd X4 - ASCT Primary Endpoint Postinduction CR, eligible for auto-sct Size (N) 199 patients Postinduction CR, CR plus VGPR CR vtd vs VD: 13% vs 12%, p=0.74 VGPR vtd vs VD: 49% vs 36%, p=0.05) Post HSCT CR plus VGPR vtd vs VD: 74% vs 58%, p=0.02 Median PFS vtd vs VD: 26mo vs 30mo Toxicity vtd vs VD - reduced incidence of peripheral neuropathy (14% vs 34%) vtd yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before ASCT

6 Bortezomib Induction and Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma: of the Randomized Phase III HOVON-65/GMMG-HD4 Trial Sonneveld et al. JCO 2012; 30(24): Regimen VAD vs PAD VAD (Vincristine, doxorubicin, dexamethasone) ASCT maintenance Thalidomide X 2yrs Vs PAD (Bortezomib, doxorubicin, dexamethasone) ASCT maintenance bortezomib X 2yrs Eligible for auto-sct Size (N) 827 patients Other Postinduction CR/nCR VAD vs PAD: 15% vs 31%, p<0.001 CT/nCR after Maintenance VAD vs PAD: 34% vs 49%, p<0.001 PFS, 5yr OS PFS VAD vs PAD: 28mo vs 35mo, p=0.002 OS VAD vs PAD: 55% vs 61% Benefit observed in patients with del17p in bortezomib arm (median PFS 12 vs 22mo, median OS 24 mo not reached at 54 mo) Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS 2. Phase III trials incorporating novel agent-based CONSOLIDATION following ASCT Bortezomib-Thalidomide-Dexamethasone is superior to Thalidomide-Dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma Cavo et al. Blood 2012;120(1):9-19 Regimen VTD vs TD Consolidation VTD (bortezomib, thalidomide, dexamethasone) X3 ASCT X2 VTD consolidation X2 Versus TD (thalidomide, dexamethasone) X3 ASCTX2 TDX2 Primary Endpoint Efficacy and safety of consolidation with VTD or TD Eligible for auto-sct, age 18-65yo Size (N) 480 patients Toxicity Postconsolidation CR, CR/nCR CR VTD vs TD: 60.6% vs 46.6% CR/nCR VTD vs TD: 73.1% vs 60.9% 3yr PFS VTD vs TD: 60% vs 48% Grade 2 or 3 peripheral neuropathy more frequent with VTD (8.1% vs 2.4%) VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study.

7 Bortezomib consolidation after autologous stem cell transplantion in multiple myeloma: a Nordic Myeloma Study Group randomized phase III trial Mellqvist et al. Blood 2013;121(23): Regimen 20 doses bortezomib during 21wks versus no consolidation Eligible for auto-sct, age 18-65yo Bortezomib naïve patients Size (N) 370 patients PFS: Bortezomib vs Placebo (27mo vs 20mo, p=0.05) OS: no difference in OS Toxicity Increased reports of fatigue among bortezomib arm in self reported quality of life questionnaires. No other major differences in QoL Consolidation with bortezomib after ASCT in bortezomib naïve patients improves PFS without interfering with QoL 3. Phase III trials incorporating novel agent-based MAINTENANCE following ASCT Lenalidomide Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma Attal et al. NJEM 2012; 366: Regimen Post ASCT randomized to maintenance treatment with lenalidomide (10mg/d for 1 st 3 months, increased to 15mg if tolerated) versus placebo until relapse Inclusion/Exclusion <65yo who had nonprogressive disease after first-line transplantation Size (N) 614 patients PFS Len vs placebo: 41mo vs 23mo, p< yr OS Len vs placebo: >70% in both groups Median EFS Len vs placebo: 40mo vs 23mo, p<0.001 Toxicity Grade ¾ peripheral neuropathy similar in both arms Incidence of second primary cancers 3.1 per 100patient-years (lenalidomide arm) vs 1.2 per 100 patient years (placebo arm) p=0.002 Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups.

8 Bortezomib Bortezomib Induction and Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma: of the Randomized Phase III HOVON-65/GMMG-HD4 Trial Sonneveld et al. JCO 2012; 30(24): Regimen VAD vs PAD VAD (Vincristine, doxorubicin, dexamethasone) ASCT maintenance Thalidomide X 2yrs Vs PAD (Bortezomib, doxorubicin, dexamethasone) ASCT maintenance bortezomib X 2yrs Eligible for auto-sct Size (N) 827 patients Other Postinduction CR/nCR VAD vs PAD: 15% vs 31%, p<0.001 CT/nCR after Maintenance VAD vs PAD: 34% vs 49%, p<0.001 PFS, 5yr OS PFS VAD vs PAD: 28mo vs 35mo, p=0.002 OS VAD vs PAD: 55% vs 61% Benefit observed in patients with del17p in bortezomib arm (median PFS 12 vs 22mo, median OS 24 mo not reached at 54 mo) Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS D) TRANSPLANT INELIGIBLE (Age >65yo) - Bottom Line General Approach: o Combination chemotherapy (ie) Cyclophosphamide/Bortezomib/Dexamethasone (CyBorD) for 9-12 cycles, or Bortezomib/Melphalan/Prednisone (VMP) for 9 cycles followed by maintenance therapy (ie) Lenalidomide or Bortezomib, until disease progression o Alternatively, Lenalidomide plus Dexamethasone until disease progression - Important Phase III Clinical Trials: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. VISTA trial investigators Miguel et al. NEJM 2008;359(9): Regimen Nine 6wk cycles VMP (bortezomib, melphalan, prednisone) Versus MP (Melphalan, prednisone) Primary Endpoint Time to Disease Progression Inclusion/Exclusion Transplant ineligible patients with MM, previously untreated Size (N) 682 patients Median TTP 24mo VMP vs 16.6mo MP, p<0.001 Mean response duration 19.9mo VMP vs 13.1mo MP OS median f/u of 16.3mo not reached in either group VMP was superior to MP alone in pts with newly diagnosed MM who were ineligible for high dose therapy

9 Continuous lenalidomide treatment for newly diagnosed MM. MM-015 Investigators Palumbo et al. NEJM 2012;366(19): Regimen MPR-R (melphalan, prednisone, lenalidomide X4 à Len maintenance until disease progression Vs MPR (melphalan, prednisone, lenalidomide) Vs MP (melphalan, prednisone) Ineligible for auto-sct, age >65 Size (N) 459 patients Toxicity PFS MPR-R 31mo vs MPR 14mo vs MP 13mo PFS benefit with MPR-R noted in 65-65yo, but not in those >75 Response Rates MPR-R 77% vs MPR 68% vs MP 50% Most frequent AE grade 4 neutropenia in 35%, 32%, 8% in MPR-R, MPR, MP groups respecitively 3yr rate 2 nd primary cancers 7% MPR-R, 7% MPR, 3% MP MPR-R significantly prolongs PFS in pts with newly diagnosed MM who were ineligible for ASCT with the greatest benefit seen in pts 65-75yo Lenalidomide and Dexamethasone in transplant-ineligible patients with myeloma. FIRST Trial Team Benboubker et al. NEJM 2014:371(10): Regimen RD (lenalidomide, dexamethasone) 28d cycle until disease progression vs RD for 72weeks (18 cycles) vs MPT (melphalan, pred, thalidomide) for 72 weeks Ineligible for auto-sct, age >65 Size (N) 1623 patients Median PFS 25.5mo RD-continuous, 20.7mo RD, 21.2mo MPT 4yr OS 59% RD-continuous, 56% RD, 51% MPT Toxicity Grade ¾ AE less frequent with RD-cont than MPT (70% vs 78%) As compared with MPT, RD-cont had fewer heme/neuro events, a moderate increase in infections, and fewer 2 nd primary heme cancers E) RELAPSED/REFRACTORY - General Considerations: As compared with MPT, RD-continuous until disease progression was associated with significant improvement in PFS, with an OS benefit at interim analysis among pts with newly diagnosed MM who were ineligible for ASCT o Always consider for clinical trial *** o Components of initial therapy: Novel agents? ASCT? o Degree and duration of response to primary therapy: PR, VGPR, CR? >6mo, >1yr? o Previous toxicities: myelosuppression, peripheral neuropathy, renal insufficiency o Type of relapse: aggressive, indolent

10 o o o Age and performance status: elderly, frail Comorbidities Patient Preference - Definitions o Refractory: Nonresponsive while on primary or salvage therapy OR progresses within 60days of last therapy o Relapsed: Disease recurrence in absence of current therapy after response established (25% rise in M protein, new plasmacytoma, or hypercalcemia) o Relapsed & Refractory: Nonresponsive while on salvage therapy OR progresses within 60days of last therapy in those who have achieved response at some point - Newer Generations of Antimyeloma Drugs Mechanism/Target Drugs Proteasome Inhibitors Carfilzomib, Ixazomib Immunomodulatory Drugs Pomalidomide PIeK/AKT/mTOR Inhibitors Temsirolimus, Everolimus Histone Deacetylase Inhibitors Panobinostat, Vorinostat Alkylating plus purine analog Bendamustine Monoclonal Antibodies Daratumumab (anti CD38), Elotuzumab (SLAMF7 inhibitor) - for Daratumumab, see POLLUX and CASTOR NEJM 2016 trials in Dropbox - for Elotuzumab, see ELOQUENT trial NEJM 2015 in Dropbox - for Ixazomib, see NEJM 2016 trial in Dropbox - for Pomalidomide, see MM-003 Lancet Oncol 2013 trial in Dropbox F) OTHER TREATMENT CONSIDERATIONS 1. Anemia a. Rule out Iron deficiency b. Transfusion support c. Consider Erythropoietin 2. Pain a. Tylenol, hydromorphone, fentanyl patch, radiation, kyphoplasty, bisphosphonates b. Avoid NSAID (renal insufficiency) 3. Neuropathy a. Mild: reduce dose b. Severe affecting ADLS: stop treatment c. Consider duloxetine, pregabalin, gabapentin 4. Infection a. Septra (1 st 3months post chemotherapy or after ASCT) b. Acyclovir (bortezomib, ASCT) c. Vaccinate (influenza, pneumococcal, no live vaccines) d. IVIG if low IgG 5. Bone a. Bisphosphonates reduce bone complications and inhibit bone resportion by suppression of osteoclast activity. Monthly Pamidronate or Zoledronic acid for 2 years in all patients b. Pretreatment dental evaluation, yearly dental checkups, avoid dental extractions à risk of Osteonecrosis of the jaw 6. Thromboprophylaxis a. Thrombosis common with Immune Modulators (lenalidamide, thalidomide) and concurrent use of steroids b. Risk factors: Obesity, previous VTE, Immobilization, Surgery, EPO, Hyperviscosity, comorbidities (Cardiac, CKD, DM, acute infection) c. High Risk: 2 or more risk factors, treat with LMWH or warfarin d. Low Risk: No or 1 risk factor, treat with ASA 81mg

11 D) REFERENCES - Alberta Health Services Guidelines - UptoDate - Canadian Cancer Society - Odette Cancer Centre Guidelines - Blade et al. How I Treat Relapsed Multiple Myeloma. Blood 2015; 125(10) - Moreau et al. Blood Review Series: Frontline therapy of multiple myeloma. Blood 2015; 125(20)