Reesident talk 4 12 17 anderson pcd final[2]
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Transcript of Reesident talk 4 12 17 anderson pcd final[2]
Myeloma andPlasma Cell Disorders
4/12/2017Larry Anderson, MD, PhD
Director, Myeloma, Waldenstrom’s, and Amyloidosis Program
Plasma Cell Disorder Spectrum Monoclonal Gammopathy of Undetermined
Significance (MGUS) Smoldering/Asymptomatic Myeloma (SMM) Symptomatic Multiple Myeloma Solitary Plasmacytoma (Bone vs Extramedullary) Waldenström’s Macroglobulinemia (WM) Primary Light Chain Amyloidosis (AL)
MGUS62% (803)
Myeloma15% (193)
Amyloidosis(AL) 8% (130)
Lymphoproliferative2.5% (31)
SMM 3.5% (44)
Solitary or extramedullary,1.5% (20)WM, 3% (41)
Other, 2.5% (34)
n=1296
Distribution of Monoclonal Gammopathies
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
Initial Diagnostic Workup CBC Chem panel Calcium/
albumin Quant Ig
(IgG,A,M) Immunofixatio
n Electrophoresis (not just SPEP which can miss small spikes)
Serum Light Chains
Bone Marrow Biopsy
24-hour urine UPEP/immunofix
Beta2-microglobulin
Skeletal survey If skel survey
neg but symptoms get MRI and/or PET/CT
Dispenzieri A, Gertz MA, et al. Mayo Clin Proc 2001;76:476-87
61% Liver disease
22% CTD
6% Chronic infxn
Immunofixation (IFE)
Criteria for Diagnosis of Myeloma
MGUS <3 g/dL M spike <10% PC
AND
Smoldering MM
3 g M spike OR 10% PC
SymptomaticMyeloma10% PC
+/- M-spike AND
NO CRAB ≥ 1 CRAB:Calcium elevation, Renal dysfunction Anemia (Hgb <10)Bone lesions
Ultra High Risk SMM = Active Myeloma
Not CRAB but now SLiM CRAB• S (60% PCs)• Li (Light chains I/U Ratio >100)• M (MRI >1 focal lesion)• C (calcium elevation)• R (renal insufficiency)• A (anemia)• B (bone disease) Lancet Oncology
11/2014
Risk Factors for Progression of MGUS to MM
• M-spike > 1.5 g/dL• Non-IgG Subtype (IgA or IgM)• Abnormal Serum Free Light Chain Ratio
Any of these 3 factors (or CRAB) warrants a BM Bx, imaging, and closer follow-up
IgG 1% per year, IgM MGUS 1.5% per year
Rajkumar et al., Blood 2005 and Blood Reviews 2007.
Risk Factors for Progression of SM to MM• M-spike > 3 g/dL• PCs >10%• Abnormal Serum Free Light Chain Ratio
Probability of Progression to Active/Symptomatic MM in pts with Smoldering MM or MGUS
Kyle RA et al. N Engl J Med 2007;356:2582-2590
These patients DO NOT require treatment!! (unless the progress to Symptomatic MM).
Many NEVER require treatment!
Management of MGUS and SMM MGUS:
– Avg 1% per year progression to MM– If NO risk factors, repeat labs in 6 mo and
then q 1-2 years– If any risk factor, repeat labs q 6 mo x 1 yr
and then yearly Smoldering MM (Stage I):
– Avg 10% per year prog to Sx MM– Repeat labs q 3-4 months– Skeletal survey yearly
Multiple Myeloma Classic Triad
M-Spike
>10% Malignant Clonal Plasma Cells in Bone Marrow
Lytic Bone Lesions
Durie-Salmon Staging System for MyelomaStage Criteria
I All of the following:Hemoglobin >10 g/dLSerum calcium level normalNormal bones or solitary plasmacytoma on X-RayLow M component production rate: IgG <5 g/dL; IgA <3 g/dL Bence Jones protein <4 g/24 hr(Smoldering Myeloma – does not need treatment)
II Not fitting stage I or IIIIII One or more of the following:
Hemoglobin <8.5 g/dLSerum calcium level >12 mg/dLLytic bone lesions on x-rayHigh M-component production rate: IgG >7 g/dL; IgA >5 g/dL Bence Jones protein >12 g/24 hr
Durie B, Salmon S. Cancer. 1975;36:842; Multiple Myeloma Research Foundation.
Subclassification Criteria A Normal renal function (serum creatinine level <2.0 mg/dL) B Abnormal renal function (serum creatinine level 2.0 mg/dL)
Greipp PR, et al. Blood 2005
INTERNATIONAL STAGING SYSTEM
REVISED INTERNATIONAL STAGING SYSTEMR-ISS
Multiple Myeloma Facts 2nd most common Hematologic Malignancy
~30,330 people Dx with MM in 2016 in US
65,000 people in the US living with myeloma
12,650 MM patients die each year in US
Median age at Dx 65-68 years (only 4% <45)
Incidence twice as high in African Americans
More frequent in men (1.3:1) bone/back pain, fatigue/anemia or infections This disease remains incurable in most
patients Median survival with older therapies 3yrs,
with transplant 5-7 years, and with novel therapies + transplant probably 8-10 years (see graph)
M protein seen in 99% of cases in serum and/or urine, IgG > 50%, IgA 20-25%, IgE/IgD 1-3%, light chain only 5-10%, 1% nonsecretory
Multiple Myeloma Facts
Management of Active/Sympotomatic MM
Those patients with CRAB (Stage II or III Disease) need treatment
Even Active MM outcomes can vary widely, and there are many treatment options – Need to stratify prognosis based on risk
factors and whether or not the pt is a stem cell transplant candidate
– mSmart System
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART):
Year Milestone Notes
1962 Melphalan-prednisone (MP)
Introduction of melphalan in the 1960s associated with improved survival. More intense chemotherapy regimens increased response rates, but no improvement in survival compared to MP
1996 Autologous SCTSeveral randomized trials demonstrated a survival advantage for ASCT compared to conventional chemotherapy (CCT).
1999 Thalidomide (Thalomid)
First IMID: Improved response rates and PFS compared to dexamethasone alone. When added to MP, it improves survival compared to MP alone
2003 Bortezomib (Velcade)
First Proteasome Inhibitor (PI): improves survival compared to high-dose Dex in relpased MM, and VMP improves survival in newly Dx pts compared to MP
2006 Lenalidomide (Revlimid)
2nd Gen IMID: Given with weekly dex, improved survival compared with dex in relapsed myeloma
2012 Carfilzomib (Kyprolis)
2nd Gen PI: 22% Response rate if refractory to both Vel and Rev. Also KRd better than Rd, updated approval in 2015
2013 Pomalidomide (Pomalyst)
3rd Gen IMID: 30% Response rate if refractory to both Vel and Rev (Only works if given with weekly Dex)
MAJOR MILESTONES IN MYELOMA THERAPY
Year Milestone Notes
2015 Panobinostat (Farydak)
Pan Histone Deacytylase Inhibitor. Approved in combination with Velcade for Relapsed MM
2015 Ixazomib (Ninlaro)First Oral Proteasome Inhibitor: Given once weekly days 1/8/15 along with Rev and Dex for relapse. Much less neuropathy risk.
2015 Daratumumab (Darzalex)
Anti-CD38 Monoclonal Antibody. 29% Response rate alone. (Also can be combined with Rev or Pom per ASH data and Vel per ASCO data). Initially Required 3 prior Lines of Therapy
2015 Elotuzumab (Empliciti)
Anti-SLAMF7 (CS1) Monoclonal Antibody. Must be given along with IMID such as Revlimid for activity. Requires only 1 prior line of therapy
2015 Carfilzomib (Kyprolis) updates
Approved as triple therapy with KRd (superior outcomes in Aspire vs Rd) and also as high dose 56 mg/m2 (superior outcomes in Endeavor vs Vd)
2016 Daratumumab updates
Approved as triple therapy with Len/dex and Vel/dex for 2nd line therapy
2017 Lenalidmide Maintenance Approved
MAJOR MILESTONES IN MYELOMA THERAPY
Therapeutic algorithms for newly diagnosed patients with plasma cell
myeloma
Induction Consolidation
Front line treatment
Maintenance
Maintenance
Salvage
Relapsed
Rev/Dex, Vel/Dex RVD, VCD
CTD, VTD, VDD, MPT, MPV, MPR
Auto-SCT
NoneRev
ThalidomidePrednisone
VelcadeClinical Trial
Whatever worked before or
haven’t tried
International Myeloma Working Group Uniform Response Criteria
Durie BGM, et al. Leukemia. 2006;20:1467-1473.
PR: ≥ 50% reduction in serum M-protein
VGPR: > 90% reduction in M-protein
Near CR: Negative SPEP/UPEP but POSITIVE Immunofixation (Faint monoclonal band but too small to quantitate)
CR: Negative SPEP AND Negative Immunofixation (serum and urine)
Stringent CR: CR + Normalization of free light chain ratio (serum free light chain assay), <1% plasma cells (NOW proposing new criteria for absence of aberrant cells on flow cytometry due to better survival in these pts)
Anything VGPR or better considered a “Deep Remission”
Autologous peripheral blood stem cells collected by apheresis, frozen, later used as a “rescue” from marrow ablative effect of high dose chemo
Introduced in the 1980’s, several randomized trials in the 1990’s and early 2000’s using high dose melphalan and ASCT showed improved PFS and Overall Survival
Generally see 1-2 year survival increase compared to conventional chemotherapy
SOC since the 1990’s and remains todayAttal M, et al. N Engl J Med 1996;335:91-7. Child JA, et al. N Engl J Med 2003:1875-83.
High Dose Chemotherapy with Autologous Stem Cell Transplantation (ASCT)
54
42
Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883.
15 30 45 60
25
50
75
100
OS
(%)
00
High dose (ASCT)
Conventional dose
Mos20 40 60 80
25
50
75
100
Surv
ival
(%)
00
High Dose (Auto SCT)
Standard therapy
Mos
P = .03
ASCT vs Conventional Chemotherapy
At our transplant center we transplant Myeloma patients up to age 75, depending on comorbidities
Generally done after 3-6 cycles of induction therapy but also possible to store stem cells and hold off on transplant until later relapse
Tandem ASCT subgroup analysis shows benefit only in pts not achieving VGPR after first SCT
Allogeneic SCT may “cure” small subset of patients but very toxic due to GVHD and no clear benefit over Auto
Attal M, et al. N Engl J Med 2003;349:2495-502
ASCT, cont’d
NOVEL THERAPIES• Not traditional chemotherapy
(which kills both cancer and healthy cells by attacking cell division)
• These drugs target the cancer cells by attacking other pathways besides cell division and are more cancer specific, often less toxic
Thalidomide (Thalomid) First “Novel Agent” (non-chemo) routinely used for
therapy of myeloma (other than steroids) (ORAL!) Several Mechanisms:
Stimulation of T-cells and natural killer cells (Hence the term “Immunomodulatory” agent = IMiD)
Anti-angiogenesis properties (decreased VEGF) Suppress Myeloma growth factors: IL-6, TNF-alpha Inhibits myeloma cell adhesion to stroma
Side Effects: Teratogenic!! Peripheral Neuropathy!!! DVT/PE (requires full anticoag), Constipation, and Sedation
MECHANISM OF IMIDS
Teo SK.. AAPS Journal. 2005
Bortezomib (Velcade) First-in-class proteasome inhibitor, approved 2003 (IV) Potentiates sensitivity of myeloma to both
conventional and novel therapeutic agents (IV or SQ) Mechanism of action
– Reversible inhibitor of 26S proteasome– Inhibition of proteasome prevents proteolysis of ubiquitinated
proteins– disrupts homeostasis, leads to apoptosis– Overcomes t(4;14) and del 13q (now intermediate) but not 17p
Side Effects:• Peripheral Neuropathy!
• Decreased by SQ or q weekDecreased Plt or WBCZoster due to IC
Armand J et al. The Oncologist 2007;12:281-290
PROTEASOME INHIBITION BY BORTEZOMIB.
Lenalidomide (Revlimid) FDA approved in 2005 More “potent” immunomodulator than thalidomide Up to 50,000 times more potent inhibitor of TNF Fewer side effects compared to thalidomide:
no neuropathy, less constipation, less VTE (ASA prophylaxis), and sedation; more myelosuppression/cytopenias
May be teratogenic so same safety precautions Oral (d1-21, 1 wk off)
Schey SA et al. J Clin Oncol. 2004;22:16 Richardson P, Anderson K. J Clin Oncol. 2004;22:16
Novel Agents + ASCT
ASCT
VAD TD RD VTD CVD RVD CVRD
Combinations of Novel Agents 3 Drug Regimens (especially those that have 2
novel agents) improves response rates and chances of deep remission
VRD and CyBorD (VCD) are very well tolerated and 97% response rates
Adding a 4th drug (VRCD, VMPT) may slightly increase response rate but increases toxicity and not yet shown to have survival benefit
All patients will eventually relapse
Lenalidomide Maintenance Effect on PFS
Lenalidomide Maintenance Effect on OS
Only gave 2 years and stopped, while American study gave
Until PD
Relapse Therapy
Tetrapeptide epoxyketone Novel proteasome inhibitor
– Binds irreversibly, given by IV infusion (2 d/wk)
Active in 22% of MM pts refractory to Velcade and Revlimid (and may be more powerful than velcade in up-front therapy but studies ongoing)
Mainly Hematologic toxicity, Peripheral Neuropathy RARE (despite being similar to Velcade)
FDA Approved July 2012 (only for those that are relapsing after prior velcade and revlimid)
2015 approved in combo with Rev/dex
Carfilzomib (Kyprolis)
1. Kuhn DJ, et al. Blood. 2007;110:3281-3290. 2. O’Connor OA, et al. Clin Cancer Res. 2009;15:7085-7091. 3. Vij R, et al. Blood. 2012;[Epub ahead of print].
Carfilzomib
O O O O
O O ON N
HNH
HN
HN
New IMiDs (more potent, less toxic)Pomalidomide - 30% Response in Rev and
Vel-Refractory pts (FDA approved 2/2013)
3 Recently approved TherapiesNew Proteosome Inhibitors (ORAL)
Ixazomib (Ninlaro) – weekly pill combined with Rev/Dex in relapsed pts (Triple Oral Therapy without neuropathy!!!)
Monoclonal Antibodies targeting PCsDaratumumab (monoclonal antibody
targeting CD38), single agent responses 29%, combined with Imid OR Velcade 83-93% (initially 4th line but now 2nd line therapy!)
Elotuzumab (Anti-CS1/SLAMF7) ~ 80% Response in Relapsed pts combined with Rev/dex but not alone (activates NK cells)
Supportive Care Don’t Forget: Bisphosphonates
Monthly 1st year, then q 3 months 2nd year
– Dental eval before starting to avoid needing dental extractions and risk of ONJ
Surgery (repair impending hip fractures) Kyphoplasty/Vertebroplasty for
compression Fx Acyclovir with Velcade Dialysis Collect stem cells before too much
myelotoxic therapy (Avoid Mel or >4 cycles of Rev)
Conclusions Between the 60’s and 90’s there was nothing better than
MP for Myeloma and survival was dismal
Survival improved with high dose chemo and ASCT
No new MM drugs approved for 4 decades from the 60’s until 2003 but now we have 4 highly active Novel agents approved over the past 9 years
Survival is Improving in Myeloma with combinations of Novel Agents and Auto SCT over the past decade
Although we have effective therapies, all MM pts relapse and become refractory to all therapies so we need more
Not known if combinations of these new drugs will make myeloma curable vs a chronic disease
Topics if time allows:Plasmacytoma
Amyloidosis
Waldenstrom’s and POEMS
PLASMACYTOMA Can be solitary or multifocal
Can arise in bone or soft tissue (Extramedullary)
Most common EM location is the upper resp tract (80%), 10yr DFS 70-80%. (10-15% develop MM)
Bone plasmacytomas higher risk of progression to MM (10yr DFS 25-50%)(50-60% develop MM)
Treatment of solitary is local radiation +/- surgery (The only curable plasma cell disorder)
Multifocal plasmacytomas treated like myeloma.
AL Amyloidosis Deposition of fibrillar light chains in tissues that is
detected by Congo red staining (green birefringence)
Median age at presentation 65yrs, med survival 13mo
Can be localized or systemic (primary systemic amyloidosis)
Range of presentation: nephrotic syndrome, cardiomyopathy, macroglossia, neuropathy, skin lesions
Dx based on biopsy and presence of M spike in serum or urine and Mass Spec at Mayo for subtyping.
No systemic treatment needed for localized deposits, only symptom relief
Systemic disease treated similar to myeloma (Auto PBSCT or novel agents like Velcade).
Worse prognosis if elevated BNP, troponin, septal thickness >13mm, multiple organ dysfxn
Combined Bone Marrow and Fat Pad: 89%
- 94% response rate, 71% complete hematologic response, 24% partial response- Time to Light Chain response was 2 months but organ response 6 months. - 3 pts originally not eligible for ASCT became eligible .- 50% had a 50% decrease in proteinuria. - Of the 7 pts monitored for cardiac biomarkers, 5 improved (with 3 normalized)
Characteristic combination of :
Monoclonal IgM protein (Immunoglobulin) secretion
Infiltration of the bone marrow with clonal lymphoplasmacytic Lymphoma (LPL) cells
90% have mutation in MyD88 gene in the LPL cells
1% are Non-IgM and called LPL but not WM
Cause Unknown but can run in families in 20%
Diagnosis of Waldenström’s Macroglobulinemia (WM) aka Lymphoplasmacytic Lymphoma (LPL):
Signs/Symptoms of WM/LPL
Low blood counts (Marrow replacement)
• Anemia (Hgb <10) or Low platelets (Plt <100)
Hyperviscosity (Sludging due to very high IgM)
• Dizziness, blurry vision, nose bleeds (Medical Emergency)
Enlargement of spleen, liver or bulky lymph nodes (>5cm)
4% with Neuropathy (anti-MAG, Sulfatide, GM1, etc)
Cold Agglutinins or Cryoglobulins (monoclonal)
Fevers/Night Sweats/Weight Loss
Systemic Amyloidosis
Therapy for Symptomatic Waldenström’s Macroglobulinemia
No treatment for Smoldering WM (Risk of progression similar to SMM 4-10% per year)
Plasmapheresis for temporary control of hyperviscosity
First-line treatment options in WM– Alkylating agents, rituximab, proteasome inhibitor,
steroids Best response w/ combination
Bendamustine/Rituximab, Cytoxan/Rituxaimab, Bortezomib/Rituximab/Dex
Single agent Rituxan VERY effective and minimally toxic
Avoid single agent Rituxan if IgM >5000 due to >50% risk of IgM “Flare”
Ibrutinib (btk inhiitor) approved 2012 (oral tki) and the ONLY FDA approved therapy for WM
POEMS SYNDROME(aka: Osteosclerotic Myeloma)
PolyneuropathyOrganomegalyEndocrinopathyMonoclonal protein (usually IgA)Skin changes
Criteria for the diagnosis of POEMS syndrome
Mandatory major criteria (both required) Polyneuropathy Monoclonal plasma cell proliferative disorder (95% are lambda)
Other major criteria (one required) Sclerotic bone lesions Castleman's disease Elevated levels of vascular endothelial growth factor (VEGF)*
Minor criteria (one required) Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (edema, pleural effusion, or ascites) Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic, DM)• Skin changes (hyperpigmentation, hypertrichosis, hemangiomata, plethora, acrocyanosis, flushing, white nails) Papilledema Thrombocytosis/polycythemia
The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the three other major criteria, and one of the six minor criteria are present. • In order to consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes or hypothyroidism is required since these two disorders are common in the general population.
• VEGF mediated in part (not the paraprotein)
• Both sensory and motor symptoms are distal, symmetric, progressive
• Severe weakness in >50%, chronic inflammatory demyelinating polyneuropathy.
• Sural nerve Bx usually shows both axonal degeneration and demyelination
• Response to therapy based on (IFE, light chains, VEGF level), imaging studies (if PET avid mass), and later symptom improvement.
• Neuropathy takes ~3 months to stabilize, 6 mo to begin to improve, 2-3 yrs for max improvement after SCT
POEMS syndrome
Case #1 55 y/o WF with h/o early Breast Cancer
2001 (lumpectomy/radiation, aromatase), early Uterine Cancer 1999 (TAH/BSO), hypothyroid, on routine f/u late 2008 noted to have elevated total protein 8.9, globulin 4.9 (actually stable)
Further workup showed M-spike 2.4 IgM Kappa, Total IgM 3630, Free Kappa 93.1mg/L, K/L 50.9, Viscosity 1.9, Beta 2 Micro 2.6, Hgb 12.4, Plt 339
Bone Marrow Bx done 1/2/09: LPL involving 50% of cellularity, aspirate diff shows 31% Lymphs + 8% PCs, Flow shows clonal Kappa Restricted LPL
What Treatment would you start??
Case #1, cont’d No Splenomegaly, bulky adenopathy,
Cytopenias, B-Symptoms, hyperviscosity, Neuropathy, skeletal survey neg, CT C/A/P neg
Therefore “Smoldering WM” and NO need for treatment
Watch and wait with repeat labs and checkup every 3 months the 1st year, q4 months the 2nd year, then at least every 6 months if stable with no progression
Graph of IgM and M-spike …….
Case Scenario #1, cont’dIgM Over Past 7 Years (Observation Only)
Case #2 80 y/o WF with increasing back pain,
osteoporosis, compression fractures but no lytic lesions. Workup showed anemia w/ Hgb 9.5, elevated total protein, M-spike > 3 g/dL
Referred for Treatment of “Multiple Myeloma”
Case #2 Don’t forget to do the immunofixation and
quantitative immunogloblins: IgM 6380, M-spike 3.6 g/dL IgM Lambda,
Hgb 9.1, viscosity 2.3, Beta 2 Micro 4.74, Lambda 60
BMBx showed similar findings to the previous case with 54% Lymphoplasmacytic Infiltrate. Imaging confirmed several compression fractures and osteoporosis but NO lytic lesions
Case #2, cont’d IgM >5000 but elderly, no
hyperviscosity, tried the oral cytoxan in combination with Rituxan (DRC) but had terrible nausea with one dose of oral cytoxan so changed to single agent Rituxan and did well without flare
4 weekly doses followed by another 4 weekly doses 3 months later (weeks 12-15)
Graph of IgM …….
Case #2IgM Over Past 6 Years
Rituximab 4 wkly doses repeated at 3 months apart(2/09, 5/09 followed by 3 year remission, then 2/12, 5/12
now 1 dose q 3 mo Maintenance)
IgM Continued to Improve on Maintenance
Q 3 month dosing, off maintenance 3 years and
IgM 120 now (normal 230)
Case #3 62 y/o WF (Daughter of Case #2) Was seeing PCP at UTSW for back pain and URI,
found to have elevated total protein 1/6/14: Returned to PCP for results of SPEP: M-spike
2.27 g/dL. She called me and I saw her for new pt consult same day expecting to see WM!
Kappa FLC 174, IgM 5686, BMBx showed 30-40% PCs, Kappa restricted, IgM+, Cyclin D1+, FISH showed t(11;14)
Xrays: subcortical lucency of the left hip greater trochanter, 1.5cm lytic lesion of L1 on PET/CT so Stage IIA IgM Myeloma
Failed Rev/dex, 92% VGPR to VRD, stable VGPR s/p SCT for 2 years, then failed Ninlaro, Pom, now responding to Dara/Pom/Dex combo