Smoldering Myeloma: Controversies and Solutions

Manni Mohyuddin, MD

Assistant Professor

No relevant conflicts of interest to declare

@ManniMD1 @HuntsmanMM

Clinical Case

A 65 year old male with no medical history presents to PCP for his annual checkup. He feels great.

Routine labs are ordered.

• WBC 5.8, Hb = 14.2, Plt = 272, MCV 92
• Cr 0.8, Ca 9.8, Total protein 9.4, Albumin 4.0.
• PCP orders SPEP/IFE/sFLC due to elevated total protein.
• SPEP = M-spike 2.6 g/dL, IFE IgGk, K 50, L = 2, K/L = 25.
• PET/CT = normal
• Bone marrow biopsy = 11% kappa restricted plasma cells. Cytogenetics = hyperdiploid
• What should your doctor discuss as part of informed decision making?

@ManniMD1 @HuntsmanMM

Important Questions

• What is the diagnosis?
• What is this patient’s risk of progressing to symptomatic disease?
• Should we be recommending treatment?

@ManniMD1 @HuntsmanMM

IMWG Diagnostic Criteria

Multiple Myeloma

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• Clonal marrow PCs > 10% or > 1 biopsy-proven plasmacytoma
• SLiM-CRAB

Smoldering Myeloma

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• M-protein > 3 g/dL (serum) or > 500 mg/d (urine)
• Clonal marrow PCs 10 – 59%
• No SLiM-CRAB

MGUS

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• M-protein < 3 g/dL
• Clonal marrow PCs < 10%
• No SLiM-CRAB

Rajkumar et al, Lancet Oncol, 2014

Myeloma and its precursors are ”patchy” diseases

@ManniMD1 @HuntsmanMM

Credit to Dr. Goodman/UCSD for image

SLiM Criteria have not aged well

We thought the risk of progression in 2 years was 80%.. Turns out its closer to 30%

Ludwig, EclinMed, 2023

I see harm from the SLiM criteria often- A real case

• 68 yr old gentleman on routine physical in 2021 found to have elevated protein (M Spike=3.2, bone marrow plasma cell % of 50
• Diffusion weighted MRI shows no bone abnormalities, and no other CRAB features
• A subsequent bone marrow biopsy a year later (labs stable) now shows plasma cell percentage of 60%, imaging still normal
• Patient gets started on twice a week bortezomib, with lenalidomide and dexamethasone
• 6 months later, and now with crippling Grade 3 peripheral neuropathy, he sees me for a transplant consult. I recommend treatment D/C.
• 1 year later, labs have stayed stable, neuropathy persists

The seminal paper that defined natural history of SMM, but is outdated today

@ManniMD1 @HuntsmanMM

RA Kyle 2007, NEJM

Know the name of this person?

“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states”

Advances in imaging and diagnostic reclassifications have changed the natural history of SMM

Imaging modalities evolve and come of age

Today, plasma cells more than 10% in marrow, normal X-Ray often gets upstaged to myeloma based on MRI or PET

2008: Data beings to emerge that X-Ray can miss 50% of lytic lesions

Previously, plasma cells more than 10% in marrow and normal X-Ray is called Smoldering Myeloma

So not only are risk stratification models outdated, they also are discordant

Hill, JAMA Onc. 2021.

PETHEMA-GEM : A Phase III for smoldering myeloma

Both progression free survival benefit and overall survival benefit shown

Mateos, NEJM 2014

High-risk smoldering myeloma

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[P3 (N = 125)

RANDOMIZATION

Lenalidomide/dexamethasone

Observation

Primary Endpoint: Progression Free Survival

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• No advanced imaging performed; the control arm rapidly progressed- likely many had myeloma
• Control arm not given lenalidomide upon progression, received older cytotoxic therapy
• Trial not powered for overall survival, with such a small number, results could be spurious
• Diagnostic changes in 2014, further affects applicability of results today
• Definition of high-risk smoldering not used today in the US

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What are the problems here?

E3A06 : Another Phase III for smoldering myeloma

Progression free survival benefit shown for all-comers

Lonial, JCO, 2020

Smoldering myeloma

(not limited to high-risk)

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[P3 (N = 182)

RANDOMIZATION

Lenalidomide

Observation

Primary Endpoint: Progression Free Survival

The authors conclude that only high-risk should be treated, based on this data

• Lenalidomide: 22 patients (28%)
• Observation: 31 patients (33%)

Too few patients to reasonably conclude anything

Lonial, JCO, 2020

By giving lenalidomide, are we preventing fractures or just asymptomatic lab abnormalities?

Unclear if true morbidity prevented- granularity not provided

47% of patients had MRI abnormality at baseline

Lonial, JCO, 2020

The GEM-CESAR Approach

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Despite this extensive therapy, only 23% of patients sustaining MRD negativity after 4 years of follow-up

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Mateos, ASH, November 2022

High-risk smoldering myeloma

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[P2 (N=90)]

Induction with

carfilzomib

/lenalidomide/

dexamethasone

Stem cell

Transplant

Consolidation with 2 more cycles, followed by 2 years of maintenance

Per authors “safety profile was acceptable”

• 4 deaths were reported potentially due to treatment
• Cardiac arrest
• “Massive ischemic stroke during induction”
• MDS
• Lung cancer
• Other notable toxicity
• Cardiac failure due to respiratory infection
• ≥ grade 3 infections = 21%
• A-fib, HTN, cytopenias

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Whether this trial hastened death or extended life is unknown.

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Mateos, ASH, November 2022

The ASCENT trial

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The ASCENT trial also failed to meet endpoint

Stringent Complete Response Rate of only 38%

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Kumar, ASH, 2022

High-risk smoldering myeloma

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[P2 (N=87)]

6 cycles of daratumumab/

carfilzomib/

Lenalidomide

/dexamethasone

induction

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6 cycles of daratumumab/

carfilzomib/

Lenalidomide

/dexamethasone

consolidation

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12 cycles of lenalidomide

and daratumumab maintenance

Primary Endpoint:

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Stringent Complete Response of at least 65%

Most clinicians recognize SMM should not be treated

Mohyuddin, eclinMed, 2023

92% of clinicians recommended against treatment of high-risk SMM, preferring surveillance instead

Yet we aren’t allowed observation as a control arm

Single arm trials run rampant

• PANGEA risk of progression to myeloma
• 2 year = 11%
• 10 year <50%
• 12 patient treated with tec
• Primary objective = CR = 42%
• ≥ grade 3 neutropenia = 33%
• ≥ grade 3 non-heme = 25%
• Hepatitis
• Pancreatitis
• Infections in 75%!
• Grade 2 uveitis
• CRS in 75%
• 100% required IVIG

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Nadeem, ASH 2023.

FDA label update for Cilta-cel (CARVYKTI)

• CARTITUDE-1 study
• Median follow up 28 months
• MDS/AML occurred in 10/97 (10%) of patients
• Median time to onset 485 days
• 9/10 patients died
• Median 7.5 prior therapies

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• Most common primary endpoints:
• Response Rate (40.6%)
• PFS (31.2%)
• Only 1 study with OS as endpoint!!!
• 23/32 (71.9%) assessed regimens with established safety/efficacy in symptomatic myeloma

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What lessons are we learning from these single arm trials?

Mohyuddin, Leukemia & Lymphoma, 2021

Our trial (SPOTLIGHT)

Our trial (SPOTLIGHT)

We define morbid progression as:

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• Lytic lesion (not focal marrow lesion, which is a precursor)
• Death due to plasma cell dyscrasia
• Renal function that does not promptly reverse
• AL Amyloidosis
• Plasma Cell Leukemia
• Fracture

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We hypothesize that progressions to MM (if they do occur) will represent asymptomatic changes in lab values rather than catastrophic events

Perhaps the tide is turning?

When the editor of Blood writes a perspective about how these trials are harmful, you know change is happening!

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• No convincing evidence exists that patients live longer or better with starting treatment early
• It may be that smoldering myeloma is actually less responsive than MM, as evidenced by low persistent MRD negativity rates
• Trials do not allow control arms with observation, despite over 90% of clinicians not treating high-risk SMM off trial
• We hope to show that patients can stay safe off therapy with advanced imaging
• We hope to validate future endpoints of morbid progressions, as an alternative to waiting a long period of time for overall survival

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Conclusions