What are the different phases of multiple myeloma?

Different Phases of Multiple Myeloma

Multiple myeloma progresses through distinct phases including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and symptomatic multiple myeloma, with relapsed/refractory multiple myeloma representing the final phase of disease progression.

Precursor Conditions

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Asymptomatic precursor condition characterized by:
  • Small burden of clonal plasma cells (<10% in bone marrow)
  • Low levels of monoclonal protein
  • No end-organ damage
  • Risk of progression to MM is approximately 1% per year 1
  • Requires observation only, no active treatment

Smoldering Multiple Myeloma (SMM)

• Intermediate phase between MGUS and symptomatic MM characterized by:
  • Higher burden of malignant plasma cells (≥10% but typically <60%)
  • Higher levels of monoclonal proteins than MGUS
  • No end-organ damage or myeloma-defining events
  • Risk of progression to symptomatic myeloma is 10% per year in the first 5 years 1
  • Heterogeneous condition where approximately one-third have biological malignancy 2
  • High-risk SMM patients may benefit from early intervention with lenalidomide or lenalidomide plus dexamethasone 2

Active Multiple Myeloma

Newly Diagnosed Symptomatic Multiple Myeloma

• Requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more multiple myeloma defining events 3:
  • CRAB features (hypercalcemia, renal failure, anemia, or lytic bone lesions)
  • Bone marrow clonal plasmacytosis ≥60%
  • Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC is ≥100 mg/L)

  • 1 focal lesion on MRI

• Risk stratification is essential using the Revised International Staging System (R-ISS) 1:
  • R-ISS I: ISS stage I (β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL) with normal LDH and standard-risk cytogenetics
  • R-ISS II: Neither stage I nor III
  • R-ISS III: ISS stage III (β2-microglobulin ≥5.5 mg/L) with either high LDH or high-risk cytogenetics

Durie-Salmon Staging System

The traditional staging system based on clinical parameters 1:

Parameter	Stage I	Stage II	Stage III
Hemoglobin	>10 g/dl	8.5–10.0 g/dl	<8.5 g/l
Calcium	<3.0 mmol/l	3.0 mmol/l	>3.0 mmol/l
M-protein IgA	<30 g/l	30–50 g/l	>50 g/l
IgG	<50 g/l	50–70 g/l	>70 g/l
Urine light chain	<4 g per 24 h	4–12 g per 24 h	>12 g per 24 h
Bone X-ray	Normal bone structure	Minor bone lesions	Advanced bone lesion

With subclassification:

• Stage A: Serum creatinine <177 μmol/l
• Stage B: Serum creatinine ≥177 μmol/l

High-Risk Multiple Myeloma

• Defined by specific cytogenetic abnormalities 3:
  • del(17p)
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • gain 1q
  • del 1p
  • p53 mutation
• Double-hit myeloma: presence of any two high-risk factors
• Triple-hit myeloma: presence of three or more high-risk factors

Advanced Disease Phases

Plateau Phase

• Period of stable disease after initial treatment response
• Characterized by stable M-protein levels
• Maintenance therapy is often administered during this phase 1

Relapsed Multiple Myeloma

• Disease progression after a period of response to previous treatment
• Typically requires change in therapy
• Response durations tend to become shorter with successive relapses 4

Refractory Multiple Myeloma

• Disease that is non-responsive to current therapy
• Defined as disease progression during therapy or within 60 days of last treatment 4
• Median survival ranges from 6-9 months in patients with relapsed/refractory disease 4

Relapsed and Refractory Multiple Myeloma

• Disease that has become resistant to multiple lines of therapy
• Characterized by more aggressive tumor phenotype, higher proliferative fraction, and lower apoptotic rates 4
• Often requires novel therapeutic approaches or clinical trials

Clinical Considerations

• Risk assessment should be performed at diagnosis and repeated at relapse 1
• Bone marrow examination with FISH for myeloma abnormalities is essential at relapse to detect new high-risk abnormalities such as 17p deletion and 1q amplification 1
• Treatment approaches differ based on:
  • Transplant eligibility
  • Risk stratification
  • Previous therapies and response
  • Disease biology at relapse

Understanding these distinct phases of multiple myeloma is crucial for appropriate risk stratification, treatment selection, and prognostication of patients with this heterogeneous disease.