Ekarat Rattarittamrong, MD Division of Hematology ...

Ekarat Rattarittamrong, MD Division of Hematology

Department of Internal Medicine Faculty of Medicine

Chiang Mai University

Multiple myeloma (MM) Systemic AL amyloidosis Monoclonal gammopathy of renal

significance (MGRS) POEMS syndrome



Clonal plasma cell disorder with evidence of specific end-organ damage

HyperCalcemia Renal failure Anemia Bone lesions

Rajkumar SV. Am J Hematol 2016;91:90–100.

CRAB features

Palumbo A. N Engl J Med 2011;364:1046-60.

Ghobrial IM. Blood 2014;124:3380-8.


Clonal BM plasma cells ≥10% or plasmacytoma and any one or more of the following myeloma defining events (MDE):

Rajkumar SV. Lancet Oncol 2014;15:e538–48.

Evidence of end organ damage: Hypercalcemia: serum calcium > 1 mg/dL higher than UNL or > 11 mg/dL Renal insufficiency: CrCl < 40 mL/min or Cr > 2 mg/dL Anemia: Hb > 2 g/dL below LNL or < 10 g/dL Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Biomarkers of malignancy: Clonal bone marrow plasma cell percentage ≥ 60% Involved : uninvolved serum free light chain ratio ≥ 100 > 1 focal lesions on MRI studies

BM plasma cells Abnormal FLC ratio

Kastritis E. Leukemia 2013;27:947–53.

Hillengass J. Leuk Lymphoma 2013;54:1355–63.

Presenter

Presentation Notes

Magnetic resonance imaging can demonstrate patterns of bone marrow involvement that are generally described as normal, focal, diffuse (homogeneous or heterogeneous), variegated (also known as salt and pepper) or a combination of these. Normal or variegated marrow patterns have been associated with lower disease burden, whereas focal or diffuse marrow patterns have been associated with higher disease burden. A focal or diffuse pattern of bone marrow involvement is not unique to myeloma and may be present in other haematological malignancies and in metastatic disease.

Not reached 13 months

Hillengass J. J Clin Oncol 2010;28:1606–10.

Monoclonal gammopathy of undetermined significance (MGUS) ◦ Serum monoclonal protein < 30 g/L or abnormal free light

chain ratio ◦ Clonal bone marrow plasma cells < 10% ◦ Absence of end-organ damage (CRAB) or amyloidosis

that can be attributed to the plasma cell proliferative disorder

Progression to MM, solitary plasmacytoma, or light chain amyloidosis 1% per year


Go RS. Blood 2018;131:163-73.

Kyle RA. N Engl J Med 2018;378:241-9.

Go RS. Blood 2018;131:163-73.

Go RS. Blood 2018;131:163-73.

Go RS. Blood 2018;131:163-73.

Go RS. Blood 2018;131:163-73.

Go RS. Blood 2018;131:163-73.

Smoldering multiple myeloma Intermediate clinical stage between MGUS and MM ◦ Serum monoclonal protein > 30 g/L and/or clonal bone

marrow plasma cells 10-60% ◦ Absence of end organ damage ◦ No myeloma-defining biomarkers

Risk of progression to malignant disease 10% per year in the first 5 years


Ghobrial IM. Blood 2014;124:3380-8.

Solitary plasmacytoma ◦ 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 for the primary solitary lesion) ◦ Absence of end-organ damage (CRAB) that can be

attributed to a lymphoplasma cell proliferative disorder Progression to MM 10% in 3 years


CBC and blood smear ◦ Anemia 40-73% ◦ Rouleaux formation if hyperglobulinemia

Blood chemistry ◦ BUN, Cr ◦ Serum calcium ◦ LFT : hyperglobulinemia normal alkaline phosphatase

Detection of monoclonal protein ◦ Serum and urine protein electrophoresis

(SPEP, UPEP) ◦ Urine Bence Jones protein ◦ Serum immunofixation ◦ Serum free light chain

Bone marrow aspiration and biopsy ◦ Increase plasma cells (>10%)

Serum protein electrophoresis (SPEP)

Presenter

Presentation Notes

Serum protein electrophoresis (SPEP or SPE) is a laboratory test that examines specific proteins in the blood called globulins. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum (the fluid portion of the blood after the blood has clotted) is placed into a gel, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta globulins, and gamma globulins IFE The method detects by precipitation: when a soluble antigen (Ag) is brought in contact with the corresponding antibody, precipitation occurs, which may be visible with the naked eye or microscope. It consists in depositing the serum (or urine which has been previously concentrated in) on a gel. After application of an electric current that allows the separation of proteins according to their size, antibodies specific for each type of immunoglobulin were laid upon the gel. It thus appears the more or less narrow bands on the gel, which are at different immunoglobulins. Immunofixation as immunoelectrophoresis, takes place in two steps: The first step is identical for both techniques. It consists in depositing the immunoglobulins contained in the serum or urine on a gel and then separating the immunoglobulins according to their electrophoretic mobility by making migrate under the effect of an electric field. This migration depends on the mass and charge of the antigen. Once separated immunoglobulins, we can move to the next step. The second step is based on the technique used. Immunofixation requires to migrate serum tested several times. For this anti-immunoglobulin are not placed in a channel, as in electrophoresis, but they are added individually to each migration lane. The presence of a monoclonal immunoglobulin results in the appearance of a narrow band after staining complex precipitates. For example, in the case of an IgG lambda, there will be a narrow band, both on the track on which was deposited anti-G and on which has been deposited that the anti-lambda. Immunofixation identifies (antibodies) in a mixture in function of their specific electrophoretic mobility. For the identification antigens are used that are specific for the targeted antibody

Dispenzieri A. Leukemia 2009;23:215–24.

Normal kappa : lambda ratio 0.26-1.65

Kumar S. Lancet Oncol 2016; 17:e328–46.

Lahuerta JJ. J Clin Oncol 2017;35:2900-10.

Imaging study Conventional X-ray: IMWG guideline A complete conventional radiographic status is

recommended for each newly diagnosed patient ◦ Skull in 2 views ◦ Spine (cervical/thoracic/lumbar) in 2 views ◦ Chest AP ◦ Pelvis AP ◦ Long proximal bones AP

80% have radiological evidence of involvement

Dimopoulos M. Leukemia 2009;23:1545-56.

Hillengass J. Leuk Lymphoma 2013;54:1355–63.

Hillengass J. Lancet Oncol 2019; 20:e302–12.

Hillengass J. Lancet Oncol 2019; 20:e302–12.

Revised ISS for MM Overall survival

Palumbo A. J Clin Oncol 2015;33:2863-9.

Kumar S. Lancet Oncol 2016;17:e328–46.

Kumar S. Lancet Oncol 2016;17:e328–46.

**Clinical relapse: for use in clinical practice

Dejoie T. Leukemia 2019;33:313–8.

Newly diagnosed patients with MM

Transplant-eligible patients Transplant-ineligible patients

Induction chemotherapy

Autologous stem cell transplantation (ASCT)

Induction chemotherapy

Adapted from Palumbo A. N Engl J Med 2011;364:1046-60.

Many choices of induction therapy Transplant-eligible patients Depth of response correlated with long-term outcome Combination with novel agents (usually with

corticosteriod) Proteasome inhibitors: bortezomib Immunomodulatory drugs: thalidomide, lenalidomide Non melphalan-based regimen

Transplant-ineligible patients ◦ Balance efficacy and toxicity


Long term follow up after high-dose therapy with autologous transplantation 10 year survival rate is 20% 10% of patients seem to remain in continuous CR

Martinez-Lopez J. Blood 2011;118:529-34.

Kyle RA. N Engl J Med 2004;351:1860-73.

Moreau P. Ann Oncol 2017;28 (Suppl 4):iv52–iv61.

Stewart AW. Blood 2009;114:5436-43.

1 Palumbo A. J Clin Oncol 2014;32:587-600. 2 Larocca A. Blood 2015;126:2179-85.

For frail patients: palliative care, reduced-dose corticosteroids, MP, Cy-dex2

Newly diagnosed elderly or younger patients with MM not eligible for high dose treatment (MEL 200)

Assessment of patient status Presence of comorbidities and/or limits in mental or mobility functions

Specific index and scores can be used

Very Fit Fit Unfit

Reduced-intensity ASCT (MEL 100)

MPT BMP/BMPT-BT

BCD/BRD MPR-R/Rd

Low-dose MPT/BMP

Bd/Rd

Presenter

Presentation Notes

Oral treatment, neuropathy: Rd Rapid disease control, renal dysfunction: Vd

Progression/ Relapsed

Indication of treatment

Clinical relapsed √ √ Biochemical relapsed 25% increase

from baseline Doubling in 2-3 months

Serum M-protein AI > 0.5 g/dL AI ≥ 1 g/dL Urine M-protein AI > 200 mg/day AI ≥ 500 mg/day Percentage of BM plasma cells AI > 10% - Difference between involved FLC and uninvolved FLC

AI > 10 mg/dL AI ≥ 20 mg/dL + abnormal ratio or 25% increase

Sonneveld P. Haematologica 2016;101:396–406. Laubach J. Leukemia 2016;30:1005-17.

AI: absolute increase

Clinical relapse ◦ Development of new soft-tissue plasmacytomas or

bone lesions ◦ Definite increase (≥ 50%) in size of existing

plasmacytomas or bone lesions ◦ Hypercalcemia (≥ 11.5 mg/dL) ◦ Decrease in hemoglobin of ≥ 2 g/dL, or to < 10 g/dL ◦ Rise in serum creatinine by ≥ 2 mg/dL or more ◦ Hyperviscosity requiring therapeutic intervention

Sonneveld P. Haematologica 2016;101:396–406.

Patient factors Disease factors Previous treatment

Chim CS. Leukemia 2018;32:252–62. Moreau P. Ann Oncol 2017;28 (Suppl 4):iv52–iv61.

Laubach J. Leukemia 2016;30:1005-17.




Age (still eligible for a second ASCT?)

Co-morbid illnesses Performance status Patient’s preference “Goal of therapy”




High-risk karyotypic aberrations such as del(17p)

Aggressiveness Organ function Extramedullary

disease

Adverse cytogenetic abnormalities: hypodiploidy, t(4;14), del(17p), amp(1q21)

High B2M (> 5.5 mg/L) or low albumin (< 3.5 mg/dL) The presence of extramedullary disease Short duration of response to prior therapy or progression

while on current therapy Aggressive clinical features including ◦ Rapid onset of clinical symptoms ◦ Extensive disease at relapse based on laboratory, pathology, or

radiographic findings ◦ Disease-associated organ dysfunction at relapse including renal failure,

hypercalcemia, or bone event such as fracture High LDH Circulating plasma cells





Duration of response to prior induction or ASCT

Progression on therapy

Side-effects from prior treatments

Moreau P. Ann Oncol 2017;28 (Suppl 4):iv52–iv61.

New proteasome inhibitor ◦ Carfilzomib ◦ Ixazomib

New immunomodulatory agents ◦ Pomalidomide

Monoclonal antibodies ◦ Anti-CD38: daratumumab ◦ Anti-SLAMF7: elotuzumab

Histone deacetylase inhibitor ◦ Panobinostat

van de Donk NW. Immunol Rev 2016;270:95–112.

Lonial S. J Clin Oncol 2015;33 [abstract 8508].

SLAMF7: signaling lymphocytic activation molecule F7

Presenter

Presentation Notes

The SLAM family is a subgroup of the immunoglobulin superfamily of receptors Elotuzumab exerts a dual effect by directly activating natural killer cells and mediating antibody-dependent cell-mediated cytotoxicity through the CD16 pathway. SLAMF7 mediates activating signals in natural killer cells (lack CD16) by coupling with its adapter protein EAT-2. In myeloma cells, SLAMF7 signaling is compromised owing in part to the lack of EAT-2 expression; therefore, elotuzumab does not induce the proliferation of myeloma cells. ERd: 10 mg of intravenous elotuzumab per kilogram of body weight on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 starting with the third cycle

Trial and Regimen CR (%)

Median PFS (mo)

HR for Disease Progression or Death (95% CI)

P Value

Lenalidomide-based regimen

TOURMALINE-MM1 Lenalidomide–dexamethasone Ixazomib-Lenalidomide–dexamethasone

7 12

14.7 20.6

0.74 (0.59-0.94) 0.01

ELOQUENT-2 Lenalidomide–dexamethasone Elotuzumab–lenalidomide–dexamethasone

7 4

14.9 19.4

0.70 (0.57-0.85) <0.001

ASPIRE Lenalidomide–dexamethasone Carfilzomib–lenalidomide–dexamethasone

14 32

17.6 26.3

0.69 (0.57-0.83) <0.001

POLLUX Lenalidomide–dexamethasone Daratumumab–lenalidomide–dexamethasone

19 43

18.4 NR

0.37 (0.27-0.52) <0.001

Bortezomib-based regimen PANORAMA Bortezomib–dexamethasone Panobinostat–bortezomib–dexamethasone

6 11

8.1 12

0.63 (0.52-0.76) <0.001

CASTOR Bortezomib–dexamethasone Daratumumab–bortezomib–dexamethasone

9 19

7.2 NR

0.39 (0.28-0.53)

<0.001

Rajkumar SV. N Engl J Med 2016;375:1390-2.

Indications to initiate BMA Situation Management

MM patients with lytic disease or compression fracture

IV pamidronate 90 mg or zoledronic acid 4 mg q 3 to 4 wks Alternative treatment: denosumab

MM patients without lytic disease

The Expert Panel supports starting intravenous bisphosphonates

Solitary plasmacytoma or smoldering myeloma or MGUS with osteopenia

Bisphosphonates is not recommended

Anderson K. J Clin Oncol 2018;36:812-8.

All patients receiving MM therapy should be given ◦ Bisphosphonates (category 1) or ◦ Denosumab: preferred in patients with renal

insufficiency Baseline dental exam Monitor ◦ Renal dysfunction (bisphosphonate therapy) ◦ Osteonecrosis of the jaw

NCCN Guideline version 2.2019.



Merlini G. N Engl J Med 2003;349:583-96.

Presenter

Presentation Notes

The three-dimensional structures of lysozyme, transthyretin, apolipoprotein A-I and immunoglobulin k light are shown on the left. As shown in the middle panel, all these polypeptide chains converge into a cross-beta super-secondary structure that has been well characterized by x-ray diffraction, with prototypical interstrand and intersheet distances of 4.7 and 10 to 13 Angstrom, respectively. The original conformation of the precursor protein can no longer be distinguished at this stage. Contiguous b-sheet polypeptide chains constitute a protofilament. As shown on the right, several (four to six) protofilaments are wound around one another to form an amyloid fibril, with a distinct diameter of 7.5 to 10 nm visible on transmission electron microscopy (ฌ100,000). This ultrastructure of the fibril allows the regular intercalation of Congo red dye, conferring a diagnostic optical property to amyloid such as apple-green birefringence under polarized light microscopy


Presenter

Presentation Notes

AL amyloidosis occurs in only 12 to 15 percent of patients with myeloma The gold standard in the applications of proteomics for amyloid typing today is laser microdissection followed by mass spectrometry (LMD-MS)


Presenter

Presentation Notes

Only one quarter of the patients had involvement of a single organ at presentation; the remaining patients had involvement of two organs (36 percent) or three or more organs (39 percent). The heart mass can be markedly increased, and the interventricular septum is thickened. Involvement of the gastrointestinal tract may cause life-threatening bleeding. Shown is one example of peripheral nervous system involvement: infiltration of the carpal tunnel by amyloid, which may damage the median nerve, with consequent marked hypotrophy of the hand muscles. Soft tissues that may be infiltrated by amyloid include the tongue and the submandibular regions; bruising is typical and is caused by vascular fragility resulting from the infiltration of the vessel walls by amyloid

Nondiabetic nephrotic syndrome Nonischemic cardiomyopathy with “hypertrophy”

on echocardiography Hepatomegaly or increased alkaline phosphatase

value with no imaging abnormalities of the liver Chronic inflammatory demyelinating

polyneuropathy with a monoclonal protein

Gertz MA. Am J Hematol 2014;89:1133–40.

Presence of an amyloid-related systemic syndrome ◦ Renal, liver, heart, GI tract, or peripheral nerve

Positive amyloid staining by Congo red in tissue ◦ Fat aspirate, bone marrow, or organ biopsy

Evidence that amyloid is light-chain-related ◦ Direct examination of amyloid using mass spectrometry-

based proteomic analysis, or immunoelectronmicroscopy Evidence of a monoclonal plasma cell proliferative

disorder ◦ Serum or urine monoclonal protein, abnormal free light-chain

ratio, or clonal plasma cells in BM


Clinical suspicion of amyloidosis

Tissue biopsy (Congo red staining of abdominal fat or other tissue*)

Immunohistochemical Staining of biopsy Identify Diagnosis

Kappa or lambda light chain

More invasive biopsy of other affected organ +

Monoclonal protein in serum or urine Plasma cell dyscrasia in BM

-

+

- No further work-up

AL amyloidosis (screening for cardiac, renal, hepatic, autonomic involvement, FX deficiency)

* Abdominal fat pad + BM biopsy identify 85% Harrison’s Principle of Internal Medicine, 18th edition.

Rajkumar SV. N Engl J Med 2007;356:2413-5.

Chemotherapy ◦ Melphalan-dexamethasone (Mel-dex) ◦ Novel agent based therapy Bortezomib – dexamethasone +/- cyclophosphamide or

melphalan Thalidomide – dexamethasone +/- cyclophosphamide Lenalidomide – dexamethasone +/- cyclophosphamide

Autologous stem cell transplantation (ASCT)

Comenzo RL. Blood 2009;114:3147-57. Gertz MA. Am J Hematol 2014;89:1133–40.

Gertz MA. Amyloid 2010;17(s1):48.

Jaccard A. N Engl J Med 2007;357:1083-93.

56.9 months 22.2 months

Presenter

Presentation Notes

Mel-dex : monthly courses of oral melphalan (10 mg/m2 on days 1 to 4) plus high-dose oral dexamethasone (40 mg per day on days 1 to 4) 22 of the 50 patients assigned to SCT (44%) were not evaluable for response or long-term survival, including 13 who never received SCT due to death or progression and nine who died peri-SCT

Organ response Mel-Dex ASCT P value At least one organ response

39% (17/44) 45% (13/29) 0.60

Renal 11/44 8/29 Hepatic 3/44 5/29 Cardiac 3/44 4/29 Neurologic 2/44 1/29

Jaccard A. N Engl J Med 2007;357:1083-93.

Staging is defined by NT-proBNP and troponin T thresholds of 332 pg/mL and 0.035 ng/mL, respectively.

Dispenzieri A. Blood 2004;104:1881-7.

Jaccard A, et al. 2007 Cibeira MT, et al. 2011

Median OS 22.2 months Median OS 76 months

1 Jaccard A. N Engl J Med 2007;357:1083-93. 2 Cibeira MT. Blood 2011;118:4346-52.



Heart failure ◦ Salt restriction and weight monitoring ◦ Diuretics: do not reduce intravascular volume ◦ ACE inhibitors: should be used at the lowest dose with

caution due to hypotension ◦ Left ventricular assist devices: might be used as a

bridge for candidates for heart transplantation Hypotension ◦ Elastic leotards ◦ Midodrine

Gavriatopoulou M. Leukemia 2018;32:1883–98.

Arrhythmias ◦ Pacemaker for patients with recurrent syncope due to

arrhythmia/ICD use remains controversial ◦ Amiodarone: avoid digoxin

Nutritional support Diarrhea: octreotide Neuropathic pain: gabapentin or pregabalin Organ transplant for patients with end-organ

damage who achieve CR

Gavriatopoulou M. Leukemia 2018;32:1883–98.



Organized

Non-organized (granular)

Crystals Fibrillar Microtubular Myeloma cast nephropathy Light chain

amyloidosis Type I and type II cryoglobulinemic GN

Light chain proximal tubulopathy (with or without Fanconi syndrome)

Nonamyloid Immunotactoid GN

Crystal-storing histocytosis Fibrillary GN GOMMID

MIDD (Randall type) Other LCDD Proliferative GN with monoclonal Ig deposits

LHCDD Waldenström macroglobulinemia

HCDD

GOMMID, glomerulonephritis with organized microtubular monoclonal Ig deposits; MIDD, monoclonal immunoglobulin deposition disease; LCDD, light-chain deposition disease; LHCDD, light and heavy-chain deposition disease; HCDD, heavy-chain deposition disease

Leung N. Blood 2012;120:4292-5.

Dimopoulos MA. J Clin Oncol 2016;34:1544-57.

Fava A. Clin Kidney J 2018;11:777–85.





Paraneoplastic syndrome due to an underlying plasma cell neoplasm ◦ Polyneuropathy ◦ Organomegaly ◦ Endocrinopathy ◦ Monoclonal plasma cell disorder (M protein) ◦ Skin changes

Other important features: PEST ◦ Papilledema, Extravascular volume overload, Sclerotic

bone lesions, Thrombocytosis/erythrocytosis

Dispenzieri A. Am J Hematol 2017;92:814–29.

Both mandatory criteria + One major criteria + One minor criteria




Slide from Lunn M. MRC Centre for neuromuscular disease.


Systemic therapy e.g. melphalan-dexamethasone, corticosteriods, bortezomib, thalidomide, lenalidomide, ASCT

Spectrum of plasma cell disorders from MGUS, smoldering MM to MM ◦ MM: CRAB symptoms or biomarker of

malignancy Other organ involvement from monoclonal

immunoglobulin ◦ AL amyloidosis: nephrotic syndrome, cardiac

involvement, neuropathy, skin, GI ◦ MGRS: nephrotic-nephritis, renal failure ◦ POEMS: polyneuropathy (↑ VEGF)

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Ekarat Rattarittamrong, MD Division of Hematology ...

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