Multiple myelomaNovember 24, 2017 at Vientiane, Laos

Teeraya Puavilai, M.D.

Division of Hematology, Department of Medicine

Faculty of Medicine Ramathibodi, Mahidol University, Thailand

Multiple myeloma

• Neoplastic plasma cell disorder • Clonal proliferation of malignant plasma cells in the bone marrow microenvironment

• Monoclonal protein in blood or urine

• Organ dysfunction

• 1% of neoplastic diseases

• 13% of hematologic cancers

• In western countries, the annual age-adjusted incidence is 5.6 cases per 100,000 persons

• In recent years, the introduction of autologous stem cell transplantation & the availability of agents such as thalidomide, bortezomib and lenalidomide have changed the management of myeloma and extended overall survival.

• Patients < 60 years, 10 year survival is approximately 30%

N Engl J Med 2011;364:1046-60

Epidemiology of Thai MM patients

Retrospective data collection for 10 years, multicenter study in 2008▪ Median age = 62 years (20-96)▪ Total case 1,100 cases▪ Gender

▪ Male 52.6%▪ Female 47.4%

Pathogenesis of Multiple Myeloma

Hideshima T, et al. Nature Reviews Cancer 7, 585-598 (August 2007)

The proliferation and survival of multiple myeloma cells within the tumor microenvironment is, therefore, dependent on their interaction with the BMSC and the ECM.

1. During progression→ focal amplifications of 1q21.2(43 72%), amplification & translocation of c-myc/bcl2→ increasing resistance to anti-MM therapy

2. Increase of coding mutations during therapy(46↑)

3. Acquiring new subclones/changes in the clonal composition under therapy

Multistep pathogenesis of MM

Increasing genetic instability / new genetic alterations during the progression of MM

Chesi M and Bergsagel PL et al. ASH education 2011

Risk factors for newly diagnosed MM

Host Plasma cell genetics Other

Advanced age, frailty Deletion (17p) High S phase, high LDH

Performance status t(4;14), t(14;16), t(14;20) Circulating PC’s

Comorbidities (renal failure, low albumin, high β2M)

Deletion (1p); addition (1q) High serum FLC; high β2M

Medical community Deletion (13q) by metaphase cytogenetics

Extramedullary disease

Drug discovery/ availability Hypodiploidy Reduced polyclonal BMPC’s

Rational regimen design High-risk GEP signatures Early relapse; absence of response

Clinical presentation of MM

▪ Bone marrow failure

▪ Bone pain due to osteoporosis or compression fracture of spine

▪ Neurological symptoms eg. Polyneuropathy, mononeuropathy multiplex or autonomic neuropathy from paraprotein8 or systemic amyloidosis

▪ Paraproteinemia

▪ Metabolic : renal failure, hypercalcemia, tumor cachectic syndrome

▪ Cardiovascular : high output heart failure, restrictive cardiomyopathy due to cardiac amyloidosis

▪ Systemic amyloidosis

▪ POEMS syndrome

CRAB: end organ damage

Hypercalcemia Serum Calcium > 11 mg/dL

Renal insufficiency Serum Creatinine > 1.9 mg/dL

Anemia Hemoglobin < 10 g/dL

Bony lesions Lytic bone lesions, or osteoporosis with compression fractures

Other associated findings

Symptomatic hyperviscosity, amyloidosis, recurring bacterial infections ( >2 episodes in 12 months)

Multiple myeloma (MM)

PBS: Rouleaux formation BM smear: immature plasma cell

Multiple myeloma (MM)

Serum protein electrophoresis Urine protein electrophoresis

Multiple myeloma

Osteolytic bone lesions

Multiple myeloma: CD 138

Am. J. Clin. Pathol. 121 (2): 254–63

Diagnostic criteria for MMBoth criteria must be met:

1. Clonal BM plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma

2. Any ≥1 of the following myeloma defining events:• Evidence of end organ damage that can be attributed to the underlying plasma cell

proliferative disorder, specifically: 1) Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or

>2.75 mmol/L (>11 mg/dL)2) Renal insufficiency: CCr <40 mL per minute or serum creatinine >177 lmol/L (>2 mg/dL)3) Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or Hb <10 g/dL4) Bone lesions: ≥ 1 osteolytic lesions on skeletal radiography, CT or PET-CT

• Clonal BM plasma cell ≥ 60%• Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level

must be ≥100 mg/L)• >1 focal lesions on MRI (at least 5 mm in size)

Rajkumar et al., Lancet Oncol, 2014, 15, e538-e548

Monoclonal gammopathy of undetermined significance (MGUS)• “Asymptomatic premalignant stage”

• Rate of progression from MGUS to MM = 0.5%-1%

• 3%-4% of population of the age > 50 years

Lancet Oncol 2014; 15: e538–48

Smouldering multiple myeloma (SMM)

• “Intermediate stage between MGUS and MM”

• Progression rate to MM in first 5 years after diagnosis = 10% per year

• 14% of all plasma cell dyscrasias

• 2 subsets• Patients with biologically premalignancy

• Patients with CRAB negative malignancy

• Need study for prognostic factor identification

Lancet Oncol 2014; 15: e538–48

Multiple myeloma (MM)

• 80% originate from non-IgM MGUS : IgA, IgD, IgE, IgG

• 20% originate from light chain MGUS : kappa, lambda

• IgM MGUS usually evolves Waldenstorm macroglobulinemia• Rare for progression from IgM MGUS to MM

Lancet Oncol 2014; 15: e538–48

Comparison of Clinical Features MM, SMM, or MGUS

Characteristics MM SMM MGUS

Marrow plasma cells ≥ 10% ≥ 10% < 10%

Serum M-spike ≥ 3 g/dL ≥ 3 g/dL < 3 g/dL

Bence-Jones protein ≥ 1 g/24 hrs < 1 g/24 hrs < 1 g/24 hrs

Anemia Usually present May be present absent

Hypercalcemia, renal insufficiency

May be present absent absent

Lytic bone lesions Usually present absent absent

Revised IMWG criteria

MGUS SMM MM

• <10% BMPC and• <3 gm/dL protein and • No MDE

• ≥10-60% BMPC or• ≥3 gm/dL S. M protein or• ≥500 mg/24hr Ur. M

protein and• No MDE

• PCPD, and• 1 or more MDE• CRAB• ≥60% BMPC• ≥100 PLC ratio• >1 MRI focal lesion

Rajkumar SV, Dimopoulos M, Palumbo A, et al. Lancet Oncol. 2014;15(12):e538-e548

International Staging System

Gripp PR et al. JCO 2005;23:3412-20

Cytogenetic risk groups (by FISH) for MM

Risk group Cytogenetic findings Disease characteristics Median survival

Good risk • hyperdiploidy• t(11;14) by FISH• t(6;14) by FISH

Most often• Express IgG kappa• Lytic bone lesions

8-10 years

Intermediate risk

• t(4;14) by FISH • Often IgA lambda• Less bone disease

5 years

High risk • del 17p by FISH• t(14;16) by FISH• cytogenetic del 13 • hypodiploidy• 1q gain• plasma cell leukemia

• Often express IgA lambda• Skeletal-related complications

(less often)

< 2 years

Cytogenetic risk groups (by FISH) for MM

Risk group Cytogenetic findings Disease characteristics Median survival

Good risk • hyperdiploidy• t(11;14) by FISH• t(6;14) by FISH

Most often• Express IgG kappa• Lytic bone lesions

8-10 years

Intermediate risk

• t(4;14) by FISH✓ cytogenetic del 13

• Often IgA lambda• Less bone disease

5 years

High risk • del 17p by FISH• t(14;16) by FISH• cytogenetic del 13 • hypodiploidy• 1q gain• plasma cell leukemia

• Often express IgA lambda• Skeletal-related complications

(less often)

< 2 years

ISS and Revised-ISS for MM

Stage International Staging System (ISS) Revised-ISS (R-ISS)

I Serum β2 microglobulin < 3.5 mg/Lor Serum albumin ≥ 3.5 mg/L

ISS stage I and standard risk chromosome abnosmalities by FISHand Serum LDH < the upper limit of normal

II Not ISS stage I or III Not R-ISS stage I or III

III Serum β2 microglobulin ≥ 5.5 mg/L

ISS stage III and either high risk chromosome abnosmalities by FISHorSerum LDH > the upper limit of normal

Revised International Staging System for Myeloma

R-ISS for MM 5 year survival rate (%)*

Stage I→ All of the following: • Serum albumin 3.5 gm/dL

• Serum beta-2-microglobulin <3.5 mg/L

• No high-risk cytogenetics

• Normal serum LDH

82

Stage II→ Not fitting Stage I or III 62

Stage III→ Both of the following:• Serum beta-2-microglobulin >5.5 mg/L

• High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] or Elevated serum LDH

40

Revised International Staging System (R-ISS)

Palumbo et al. JCO 2015;33:2863-9

Goals of initial therapy

• High response rate: rapid response

• Depth of response

• Improve performance status and QOL

• PBSC mobilization (for younger patients)

Treatment paradigm for NMM

Transplant eligible patients

Induction therapy

Autologous stem cell

transplantation

ConsolidationMaintenance Treatment of

relapsed disease

Transplant ineligible patients

Initial therapy/ maintenance

Supportive care

Medications for MM in Thailand

• Chemotherapy : VAD, Cy-dex, MP, DCEP, DVD, Melphalan IV for ASCT

• Target therapy• Immunomodulatory drug: Thalidomide, Lenalidomide, Pomalidomide• Proteosome inhibitor: Bortezomib IV & SC, Carfilzomib• Anti-CD 38: Daratumomab• Clinical trial drug: Ixazomib (oral PI) • Bisphophonate: Pamidronate, Zolindronic acid, Alendronate

• Mobilization for ASCT• G-CSF• Cyclophosphamide high dose + G-CSF• Plerixafor (CXCR4 antagonist) + G-CSF

Should we tailor therapy?

• By genetic risk category• Proteosome inhibitors improve but not overcome poor prognosis of high risk

genetics

• By age with comorbidities• Dose modification and intensity modulation

• For severe renal impairment• Choose Bortezomib, Thalidomide, Pomalidomide, Cyclophosphamide,

Dexamethasone

Newly diagnosed transplant candidate MMAge ≤ 65

Induction therapy 4-6 cycles

Response ≥ VGPR Response < VGPR

Autologous stem cell transplantation Salvage therapy until response ≥ VGPR

Consider consolidation/maintenance

Thailand

Thai guideline 2017Primary therapy for transplant candidatesThalidomide-based therapy

• Cyclophosphamide/thalidomide/dexamethasone (ก๒/+)

• Thalidomide/doxorubicin/dexamethasone (ก๒/+)

• Thalidomide/dexamethasone (ข๒/+)

Bortezomib-based therapy

• Bortezomib/dexamethasone (ก๒/+)

• Bortezomib/doxorubicin/dexamethasone + bortezomib maintenance (ก๒/+ & ก๒/++ for high risk)

• Bortezomib/thalidomide/dexamethasone (ก๒/+)

• Cyclophosphamide/bortezomib/dexamethasone (ข๒/++)

Thai guideline Primary therapy for transplant candidatesLenalidomide-based therapy

• Lenalidomide/dexamethasone (ข๒/+/-)

• Bortezomib/lenalidomide/dexamethasone (ข๒/-)

Chemotherapy therapy

• Cyclophosphamide /dexamethasone

• VAD

• DCEP

• DVD

Thai guideline Primary therapy for transplant candidates• MM + Peripheral neuropathy → caution if use thalidomide or

bortezomib (ข๒/++)

• MM + Hx or risk of thromboembolism → avoid thalidomide and lenalidomide (ข๒/++)

• MM + Severe renal abnormality → avoid lenalidomide (ข๒/++)

• MM + high risk + renal abnormality → early use bortezomib (ข๒/++)

Thai guideline Primary therapy for transplant candidates

• MM with age ≤ 65 years & good performance status & good end organ function → upfront ASCT (ก๒/++)

• Tandem ASCT : ↑Response rate but ↑TRM (ก๒/-)

• Allogeneic SCT → only research (ก๒/+)

Phase 3 trials evaluating novel agent-based maintenance therapy after ASCT

Study Regimen Comparator Increased PFS? Increased OS?

Lenalidomide • Attal et al• McCarthy et al• Palumbo et al

LENLENLEN

PlaceboPlacebo

No maintenance

Yes Yes (TTP and EFS)

Yes

No YesNo

Thalidomide • Attal et al• Barlogie et al• Spencer et al• Lokhorst et al• Morgan et al• Stewart et al

THAL + PAMTHAL + IFNa + DEX

THAL + predTHAL THAL

THAL + pred

PAM or no maintenanceIFNa + DEX

PredIFNa

No maintenanceNo maintenance

Yes (EFS)Yes (EFS)

YesYes (EFS)

YesYes

NoYesYesNoNoNo

Bortezomib • Sonneveld et al• Rosinol et al

PAD → BORTBORT + THAL

VAD → THAL THAL or IFNa

YesYes

NoNo

Facon T. Hematology 2015;279-85

Treatment paradigm for NMM

Transplant eligible patients

Induction therapy

Autologous stem cell

transplantation

ConsolidationMaintenance Treatment of

relapsed disease

Transplant ineligible patients

Initial therapy/ maintenance

Supportive care

NCCN version 3.2016Non-Transplant candidate for MM

Transplantation ineligible

Transplant Ineligible

High Risk

MPT 12 cycles or consider bortezomibcontaining regimen to max response

If not in CR consider Thal-Pred to max response if no prior thalidomide

Standard Risk

MPT 12 cycles

Observation

Selected nontransplant trials for NMMPhase Trial Arm N PFS* HR ORR ≥ VGPR ≥ CR

3 FIRST MPTRd 18

Rd cont.

547541535

21.220.725.5 0.72#

62%73%75%

28%43%44%

9%14%15%

3 SWOG S0777 VRdRd

264261

4330

0.712 81.5%71.5%

43.5%31.8%

15.7%8.4%

2 RVD lite RVd 50 90%@ 60% 25%

3B UPFRONT VdVTdVMP

168167167

14.715.417.3

73%80%70%

37%51%41%

3%4%4%

3 GEM2005 VMPVTP

130130

3425

80%81%

20%28%

3 MAIA Rd-daraRd

Ongoing

3 TOURMALINE-MM2

IRdRd

Closed to accrual

* Median PFS in months# HR of Rd continuous vs MPT@ Response rates are after 4 cycles of treatment in 40 patients

Effect of patient fitness on myeloma treatment outcomes

Palumbo A et al. Blood 2015;125:2068-74

CR correlate with long term survival in elderly patients treated with novel agents

Gay F et al. Blood 2011;117:3025-31

Cure: Use aggressive multidrug strategy targeting CRControl: Sequential disease control approach that emphasizes QOL as well as OS

Active myeloma

Asymptomatic

2

5

10

Refractoryrelapse

MGUS or smouldering

myeloma Plateau

remission

Symptomatic

Relapse

M p

rote

in (

g/d

L)

Time

Durie BGM. 2011. Concise review of the disease and treatment options. Multiple myeloma. North Hollywood, CA: International Myeloma Foundation. Available from: http://myeloma.org/pdfs/PH2010-Eng_l2.pdf. Accessed November 2012.

Thank you for your attention