The spectrum

• Single plasma cell \(\rightarrow\) mutation \(\rightarrow\) proliferative advantage \(\rightarrow\) increase in clonal cell numbers
• Continuum of disease state and culminates in death

Disease state has been discretised into different stages (MGUS, Myeloma)

Patients are caught at different stages

Malignant plasma cell is immortal

Evolution to Myeloma (low disease load)

NEJM, 2018; https://doi.org/10.1056/NEJMoa1709974

Evolution to Myeloma (high disease load)

NEJM, 2007; https://doi.org/10.1056/NEJMoa070389

Evolution into Myeloma

Explanation: https://sumprain.netlify.com/post/evolution_to_myeloma/

Ill effects of Gammaglobulinemia

• Can be any of the heavy Chains, light chains, full or truncated Ig, insoluble form or amyloid form

• Usually causes no symptoms

• Antibody related complications (neuropathy, RA, glomerulonephritis, hematological)

• Deposition related complications (LCDD, Amyloidosis)

• Hyperviscosity related complications

Presence of ill effects excludes diagnosis of MGUS/SMM

Ill effects of Myeloma

• Symptomatic myeloma is characterised by complications attributed to interaction of malignant plasma cells with bone marrow niche in form of C R A B

• Complications can be devastating: AKI \(\rightarrow\) ESRD, vertebral fracture \(\rightarrow\) paraplegia with bladder involvement

Emerging goal of myeloma treatment is to prevent devastating myeloma related complications

Stage in between MGUS and Myeloma

High Risk for progression

• Increased tumor burden
  • SFLC < 0.125 or > 8, BMPC \(\ge\) 10%, Serum M Band \(\ge\) 3 g/dL

Blood, 2008; https://doi.org/10.1182/blood-2007-08-108357

High Risk for progression (contd …)

• IgA subtype
• Immunoparesis with reduction of 2 uninvolved Ig subtypes
• Aberrant plasma cell immunophenotype
• Increased circulating plasma cells (>5% of PCs per 100 cytoIg+ PBMC or >5x10⁶ PC/L)
• t(4;14), del 17p, gain 1q21, hyperdiploidy (effect more prominent in patients with low tumour load)

Complications of SMM

Increased risk of fractures and thromboembolic disease

Trial 1 (RCT)

• Hjort and colleagues, 1993, Eur J Hemat https://doi.org/10.1111/j.1600-0609.1993.tb00148.x
• MP vs observation
• 25 vs 25
• 2 patients in observation arms developed vertebral fractures
• 2 patients in treatment arm developed acute leukemia
• No difference in response rate, response duration, survival

Deferring chemotherapy is feasible in well informed and well controlled patients

Trial 2

• Mateos and colleagues, 2013, NEJM, https://doi.org/10.1056/NEJMoa1300439
• Phase 3, open label, randomised controlled trial
• 119 patients of High risk SMM (M Band > 10%, SFLC > 10, BM FCM > 95% aberrant PC among all PC)
• Len-Dexa (9 cycles, followed by len maint) vs observation
• Primary end point: time to progression to symptomatic disease

• Median follow up: 40 months
• Median time to progression: NR vs 21 months (HR: 0.18, p < 0.001)
• 3 year OS: 94% vs 80% (HR: 0.31, p = 0.03)

• Median follow up: 75 months
• Median time to progression: NR vs 23 months
• Progression to myeloma: 39% vs 86%
• Death: 18% vs 36%

Support use of early treatment in high risk SMM

Various study related issues were raised

Trial 3

• Ola Landgren and colleagues, 2015, JAMA Oncology, https://doi.org/10.1001/jamaoncol.2015.2010
• 8 cycles of KRd followed by Len maint 24 cycles
• High risk SMM (prior to 2014 IMWG definition)
• 12 patients
• All achieved CR
• MRD (FCM based) negativity 11/12 (92%)
• All patients remained progression free at 12 months of follow up

General management strategies

• Except of Allogenic SCT, myeloma is an incurable disease as on today
• PCD is a heterogenous disease, with markedly differing rate of progression
• Aim is to identify patients with aggressive disease with rapid rate of progression and treat them to halt the progression
• Risk assessment is predominantly based on tumor load
• Higher tumor load patients have higher chances of having more aggressive disease (but they do have some chances of having indolent disease)
• Direct way to assess aggressiveness of the disease is to re-assess tumor load at multiple closely spaced time points

Personal strategy

1. SMM \(\rightarrow\) close monitoring for disease progression

2. If progression to asymptomatic myeloma and/or rapid progression \(\rightarrow\) TREAT AS MYELOMA

3. Else \(\rightarrow\) OBSERVE and follow point 1

Emerging concepts in myeloma treatment

• 40 - 50 ongoing trials registered at CTRI on various regimens on SMM

• Myeloma treatment

  • Balance between myeloma related complications \(\leftrightarrow\) treatment related complications

• Trend towards reduction in treatment related complications (safer drugs, better care and mgt of complications)

• We aim
  • Identifying patients with aggressive disease with higher rate of progression as early as possible (may be at the time of presentation)
  • Anti myeloma treatment only to those patients (Personalised Treatment) \(\rightarrow\) retardation of disease progression \(\rightarrow\) delay in myeloma related complications
• We are more inclined towards
  • Using anti-myeloma treatment at early stage to patients with aggressive disease with aim to halt progression of the disease and curing it