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

Questions ?