Multiple Myeloma & Myelodysplastic Syndrome- Heemer

What are the risk factors of Multiple Myeloma (MM)?

• genetics

• environmental

  • radiation exposure

  • chemical exposure

MM might be preceded by what 2 diseases?

• monoclonal gammopathy of undetermined significance (MGUS)

• smoldering MM

What is multiple myeloma? What is it characterized by?

• rachy’s definition: a type of blood cancer that affects plasma cells, which are a kind of white blood cell found in your bone marrow. Plasma cells normally make antibodies to help fight infections, but in multiple myeloma, they grow out of control and cause problems in your body.

• Heemer: accumulation of malignant plasma cells in bone marrow

• Heemer: characterized by clonal proliferation and accumulation of monoclonal Ig secreted from the plasma cell that can be measured in the plasma or urine

Why is multiple myeloma called multiple myeloma?

(don’t memorize, I just added for understanding)

bc it mainly affects the bone marrow (the soft tissue inside your bones), causing issues in multiple bones—hence the name "multiple" myeloma.

____________ is a malignant plasma cell involved in unregulated productions of a monoclonal antibody.

M-protein

Multiple Myeloma cells grow in the supportive bone marrow that promotes the expansion of myeloma clones including:

• ______

• ______

• ______

• ______

• IL-6

• VEGF

• IGF-1

• NF-kB

What is the most important mutation you might find in multiple myeloma?

Del (17p)

WHAT ACRONYM describes the CLINICAL PRESENTATION OF MULTIPLE MYELOMA (MM)? Explain what each letter means.

• “CRAB”

• Hypercalcemia

• Renal Insufficiency

• Anemia

• Bone Lesions

How is multiple myeloma staged? How many stages are included?

revised international staging system (R-ISS)—> ONLY 3 STAGES

What does the R-ISS include?

• serum B2-microglobulin

• albumin

• LACTATE DEHYDROGENASE LEVELS

• high-risk chromosomal abnormalities

Elevated LDH= __________ prognosis

a. better

b. worse

b

What is the general approach to multiple myeloma tx?

• start tx only if experiencing symptoms

• primary therapy

  or

• if transplant eligible—> transplant then maintenance (± primary therapy)

What 3 DRUG REGIMEN is used for INITIAL therapy for MM?

Include the drugs from the specific class that are the standard of care as well!!!!

1. dexamethasone

2. immunomodulatory drug- LENALIDOMIDE

3. proteasome inhibitor- BORTEZOMIB

If candidates for autologous HSCT:

• receive __ - __ months of therapy before hematopoietic stem cell collection

• need to harvest enough stem cells for ___ transplants

(idk how imp)

• receive 4 - 6 months of therapy before hematopoietic stem cell collection

• need to harvest enough stem cells for 2 transplants

What are the risks of dexamethasone?

• higher risk of infection

• CNS toxicity

What are the 3 Immunomodulatory Drugs (IMiDs) used in MM tx?

• Thalidomide

• Lenalidomide

• Pomalidomide

The exact MOA of IMiDs are not understood, but is thought to do what?

• decrease cytokines and growth factors

• inhibit NF-kB

WHAT IS THE MAJOR SIDE EFFECTS AND TOXICITIES with IMiDs? Which requires a REMs program?

• VTE

• severe birth defects and fetal death—→ REMS PROGRAM

What drugs are used for VTE prophylaxis because of IMiDs like Lenalidomide?

• aspirin (low risk)

• warfarin, LMWH, DOAC (high risk)

What are the 3 proteasome inhibitors (PIs) are used in MM tx? What is their ROA?

• Bortezomib- IV

• Carfilzomib- IV

• Ixazomib- PO

MOA of proteasome inhibitors?

inhibit proteasomes and NF-kB activation

There is less neurotoxicity with what administration of Bortezomib?

SQ

What are the main side effects with each Proteasome Inhibitors?

• Bortezomib

• Carfilzomib

• Ixazomib

(Idk how important)

• Bortezomib- GI tox, neuropathy

• Carfilzomib- less neuropathy then Bortezomib, CV tox, Pulmonary tox

• Ixazomib- BMS, neuropathy, GI, CV tox less than Carflizomib

What monoclonal antibodies are used in MM tx? What do they target?

(reminder: these drugs are outside the 3-drug regimen for MM but still can be used)

• Daratumumab: CD38

• Isatuximab-irfc: CD38

• Elotuzumab: SLAMF7 (signaling lymphocyte activation molecule family 7)

• Belantamab: BCMA (B cell maturation antigen)

What REMS program is required for Belantamab?

OCULAR TOXICITY —> must get eye exam prior to each dose

What is Panobinostat? What is the ROA, MOA, and main toxicity?

(reminder: this drug is outside the 3-drug regimen for MM but still can be used)

• Panobinostat—> ORAL INHIBITOR of histone deacetylase enzymes

• ADR: cardiac toxicity (QTc prolongation)

What is Selinexor? What is the MOA and main toxicity?

(reminder: this drug is outside the 3-drug regimen for MM but still can be used)

• Selinexor—> inhibits tumor suppressor proteins (TSPs) and Exportin 1 (XPO1)

• ADR: BMS

In 2021, the FDA-approved ______________ for the tx of relapsed or refractory MM.

idecabtagene vicleucal

What is idecabtagene vicleucel?

(i have a hunch she will ask something about this drug)

• IT IS A CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY!!!!!!!

  • aka CAR T-cell Therapy

  • basically the pts. T-cells are collected and genetically modified to target malignant cells

Mutliple CAR T-cell products (directed at CD19) are also FDA approved for the tx of ______________________.

B-cell malignancies (BCMA)

For supportive care in MM, we use bone-modifying therapies. What are some of these therapies used? What is the main toxicity with these?

• bisphosphonates (zoledronic acid, pamidronate)

• Denosumab (a mAb that inhibits RANK-L)

• main toxicity: Osteonecrosis of the jaw

What is myelodysplastic syndrome (MDS)?

• heterogeneous group of myeloid stem cell disorders

• characterized by ineffective hematopoiesis w/ morphologic dysplasia in hematopoietic cells and peripheral cytopenia

What is the cause of myelodysplastic syndrome (MDS)?

• exact cause not known

• aging?

What happens to hematopoietic stem cells as we age?

reduced self-renewal, become more clonal

What are the risk factors for MDS?

• environmental

• ionizing radiation (dose-dependent)

• occupational exposures (hair dye, cereal dust, gases, fuels, etc.)

• therapy-related myeloid neoplasms (TR-MN)

  • 2 types—> therapy-related MDS or AML

What are therapy-related myeloid neoplasms?

basically it’s MDS or acute leukemia that is caused by cancer therapies (radiation, chemo, etc.)

(FYI: 10-20% cases of MDS and acute leukemias are attributed to this)

In about 45% of pts. with de novo MDS they have chromosome abnormalities. They are the strongest determinants of prognosis. What 2 scoring systems are used that analyze chromosome abnormalities and assess prognosis?

• IPSS (internation prognostic scoring system)

  • (FYI: 5q, 20q, 7)

• IPSS-R (revised version)

  • (FYI: 5q, 20q, 7, 8, 19, 12p, 11q)

MDS with ____ deletions are a subtype of MDS, have a FAVORABLE PROGNOSIS, and likely response to lenalidomide.

5q

True or False: MDS benefits the bone marrow microenvironment and helps regulate the immune system.

false—> the opposite

Why is a goal of MDS tx to reduce the # of red blood cell transfusions?

bc blood contains iron and can cause iron overload

Tx for MDS can be divided into what 2 groups? What is the goal for each?

1. lower-risk MDS pts.—> hematologic improvement (basically increase components of a CBC)

2. high-risk MDS pts.—> delay disease progression

What are the tx options for lower-risk MDS patients?

Name the drug within the class that is the PRIMARY drug used?

• immunomodulating agents (IMiDs)

  • LENALIDOMIDE PRIMARY DRUG USED

  • Thalidomide

• growth factors

  • GCSF

• immunosuppressive therapy

  • ATG, cyclosporine, steroids

• hypomethylating agents

  • azacitidine, decatabine

What is the MOA of IMiDs like Thalidomide and Lanalidomide?

suppress 5q deletion clones (by inducing ubiquitination of heplodeficient casein kinase 1A1)

Growth Factors are usually used based on…

EPO level

What are examples of growth-colony stimulating factors used in treatment for lower-risk MDS?

• filgrastim

• Luspatercept

• Eltrombopag

What is the tx for HIGHER-risk MDS?

• DNA hypomethylating agents

• Allogeneic HSCT—> only “curative” option

  • remember for higher-risk, not recom. for lower risk

• immunomodulating agents

  • Lenalidomide (for MDS with 5q deletion)

• if chemo—> anthracycline + cytarabine

  • can be used to bridge HSCT to reduce tumor burden and control disease

What DNA hypomethylating agents are used in higher-risk MDS? Name the agents they can also be combined with.

• Azacitidine

• Azacitidine and Venetoclax

• Decitabine

• Decitabine with Cedazuridine

For higher-risk MDS: What hypomethylating agent was FDA-approved in 2020 and with what?

ORAL decitabine with cedazuridine

(FYI: cedazuridine inhibits cytidine deaminase)

PRACTICE:

Which of the following is not recommended for TREATMENT in higher-risk MDS?

a. Lenalidomide

b. Decitabine

c. Allogeneic HSCT

d. Azacitidine

e. Bortezomib

e

What are the main complications MDS pts. are at risk for?

anemia, infection

What can be used for supportive care for higher risk MDS?

(idk how important…)

• rbc transfusions

• same growth factors used for lower-risk tx

  • stimulate WBC production

  • used for infections