An MM Expert Shares New Developments
Hear Dr Sikander Ailawadhi, Hematologist-Oncologist, discuss multiple myeloma, including unmet need and targets under investigation.
DISEASE STATE
Multiple myeloma (MM) originates in the bone marrow and secondary lymphoid organs, where B cells undergo differentiation before transforming into plasma cells.1 Mutations occur when B cells differentiate and lead to the formation of malignant plasma cells that produce an abnormal amount of nonfunctional antibodies (M-protein).1,2
Learn about MM, including changes to the treatment landscape.
Multiple myeloma prevalence3,4
Multiple myeloma is the third most common hematologic cancer. In 2023, it is estimated that there will be 35,730 new cases and 12,590 deaths in the U.S.
Multiple myeloma is most frequently diagnosed among patients aged 65-74 years.
Median age
at diagnosis is
69 years
Higher incidences in Black and male patients
Diagnostic criteria in multiple myeloma
IMWG CONSIDERS CLONAL BONE MARROW PLASMA CELLS ≥10% OR BIOPSY-PROVEN BONY OR EXTRAMEDULLARY PLASMACYTOMA* AND ANY 1 OR MORE OF THE FOLLOWING MYELOMA-DEFINING EVENTS5†
CRAB
- C = Hypercalcemia
- R = Renal insufficiency
- A = Anemia
- B = Bone/skeletal-related events (pathological fractures)
SLiM
- S = Clonal plasma cells in bone marrow ≥60%*
- Li = Involved vs uninvolved serum free light chain ratio ≥100‡
- M = >1 MRI focal lesion§
*Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
†The International Myeloma Working Group (IMWG) recommends using both CRAB symptoms and SLiM biomarkers for diagnosis.
‡These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L.
§Each focal lesion must be 5 mm or more in size.
Multiple myeloma is a genetically complex disease and includes both asymptomatic (monoclonal gammopathy of undetermined significance [MGUS], smoldering multiple myeloma [SMM]) and symptomatic (active myeloma) stages.6-9
Common mutations in multiple myeloma include6:
- Translocations
- Hyperdiploidy
- Deletions and amplifications of chromosome arms
- Ras mutations
As Multiple Myeloma progresses, the potential for mutations increases.6
Unmet Need
Multiple myeloma remains an incurable disease, with nearly all patients relapsing and requiring subsequent therapy1,10-17
- With each subsequent relapse, fewer treatment options remain18,19
- Each remission is typically shorter than the previous one1
PATIENTS FACE A REDUCTION IN TREATMENT RESPONSE WITH SUBSEQUENT LINES OF THERAPY20
The MAMMOTH study was a multicenter, retrospective study conducted from January 2017 to June 2018, which included 275 patients with MM. Study objective was to investigate the natural history and outcomes of patients with MM refractory to CD38 monoclonal antibodies.
In the study, patients progressed on multiple lines of treatment (including proteasome inhibitors, immunomodulatory agents, or high-dose alkylating chemotherapy) and were refractory to CD38 monoclonal antibodies.
- For triple- and quad-refractory patients on the next line of therapy, overall response rate (ORR) was 29%
- At their fifth line of therapy or further, ORR declined to 18%
SURVIVAL RATES CAN DECLINE AS PATIENTS BECOME REFRACTORY TO MORE THERAPIES20
In the MAMMOTH study, median overall survival (mOS) in triple/quad refractory was <10 months20
- Not triple-refractory (N=57) mOS=11.2 months (95% CI: 5.4-17.1)
- Triple- and quad-refractory (N=148) mOS=9.2 months (95% CI: 7.1-11.2)
- Penta-refractory (N=70) mOS=5.6 months (95% CI: 3.5-7.8)
Current Treatment Classes
There are currently three primary classes of treatment in multiple myeloma18,21,22
Inhibitors
Agents
Monoclonal
Antibodies
OTHER APPROVED CLASSES INCLUDE: ANTI-SLAMF7, SINE, AND ANTI-BCMAs23-28
Many surface proteins are differentially expressed on multiple myeloma cells compared to healthy cells.22,29-34
Investigational Targets
There are also several surface protein treatment targets under investigation in multiple myeloma, including CD138, FcRH5, CD19, GPRC5D, κ-light chain, and CD7029,31-34
Two protein targets that are furthest along in their investigation35,36:
GPRC5D37,38
- GPRC5D, a transmembrane receptor protein with a short extracellular domain40-42
- Highly expressed on multiple myeloma cells, but minimal expression in healthy tissues40-42
- Expressed in a broad range of patients with MM (low- and high-risk)43
GPRC5D has CAR-T and bispecific antibody constructs under investigation40,44
FcRH537-39
- FcRH5 is a cell surface antigen belonging to the immunoglobulin superfamily (IgSF)29,34
- Highly expressed on multiple myeloma cells compared to normal plasma cells29,34
- Expression reported in several B cell malignancies, suggesting broader applicability in hematological malignancies34,45
FcRH5 has ADC and bispecific antibody constructs under investigation29,40,46
ADC, antibody-drug conjugate; BCMA, B cell maturation antigen; CAR-T, chimeric antigen receptor T; CD, cluster of differentiation; CI, confidence interval; CRAB, hypercalcemia, renal insufficiency, anemia, bone/skeletal-related events; FcRH5, Fc receptor-homolog 5; GPRC5D, G-protein coupled receptor family C group 5 member D; MM, multiple myeloma; MOD, mechanism of disease; MRI, magnetic resonance imaging; NKG2D, natural killer group 2D; Ras, rat sarcoma virus; SINE, selective inhibitors of nuclear export; SLAMF7, signaling lymphocytic activation molecule family; SLiM, sixty percent or more clonal bone marrow plasma cells, light chains, MRI.
Extending the time between remissions and delaying disease progression remain important unmet needs in relapsed or refractory multiple myeloma. This cycle of relapse and remission highlights the constant need to explore new targets.18
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