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Expert Guidance on Therapeutic Strategies for Multiple Myeloma
  • CME
  • CE

Charise Gleason, MSN, NP-BC, AOCNP
Sagar Lonial, MD
Kathryn Maples, PharmD, BCOP
Released: May 1, 2020

Diagnosis and Management of Patients With Smoldering MM

Patient Case: High-Risk Smoldering MM

Charise Gleason, MSN, NP-BC, AOCNP:
Let’s consider our first patient case example from the interactive polling questions. This patient is a 62-year-old woman with a past medical history significant for osteopenia, diverticulitis, hypothyroidism, and fibromyalgia. She presented asymptomatic to her primary care provider for an annual physical and had noted abnormal labs, which prompted further workup. Her bone marrow biopsy revealed 40% plasma cells and blood work revealed 5.44 g/dL IgG lambda M-protein and a FLC ratio of 6.84. She has no end-organ damage (CRAB score of 0) with no lytic disease found on bone imaging.

Currently, there is much debate on how we should be managing patients like this one.

IMWG Criteria for Diagnosis of MM

Sagar Lonial, MD:
This first patient case—high-risk smoldering MM—is probably the most controversial one discussed in this activity. This discussion is based on recent clinical data that suggest that a subset of patients with high-risk smoldering MM may benefit from early intervention.

But first, let’s discuss the key differences in the diagnosis of smoldering MM vs active MM. In 2014, the International Myeloma Working Group (IMWG) published updated criteria for diagnosis of active MM.[1] Previously, the definition of active MM required > 10% of plasma cells in the bone marrow and at least 1 CRAB feature as specified on this slide.

In the updated criteria for diagnosis, the IMWG identified 3 new criteria that selected patients who had an 80% chance of developing a CRAB feature in the subsequent 2 years from diagnosis, and patients with these criteria are now considered as having active MM. The criteria include the presence of ≥ 60% plasma cells in the bone marrow, a FLC ratio of > 100 (involved-to-uninvolved), or the detection of > 1 focal lesion on MRI that is 5 mm or larger.

These IMWG criteria now define smoldering MM as: M-protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine), clonal plasma cells in bone marrow ≥ 10% to 60%, and no MM-defining events.

IMWG Risk Stratification for Smoldering MM: 2/20/20 Model

Sagar Lonial, MD:
In addition to the updated diagnostic criteria for active disease, ways are being explored to identify the remaining patients with smoldering MM who are at high risk for progressing to active disease. Criteria such as the older Mayo[2] and the Spanish classifications[3] have been used for more than 10 years but are suboptimal at identifying high-risk patients with smoldering MM.

As a result, in 2019, the Mayo Clinic revised their high-risk classification for smoldering MM as a “2/20/20” model.[4] In this system, patients with smoldering MM and ≥ 2 of the 3 criteria—> 20% plasma cells, M-protein > 2 g/dL, or a FLC ratio > 20—are considered to be at highest risk of progression to active MM. This was based on a study of more than 1000 patients with smoldering MM in which those with 0 risk factors were at low risk and had a 2-year risk of progression of 5%. Those with 1 risk factor had a 17% risk of progression at 2 years. But those with 2 or 3 risk factors (36% of patients) had a 46% risk of progression by 2 years (HR: 5.63 vs low risk). Patients with 2-3 risk factors plus known high-risk cytogenetics, for example, t(4;14), have a risk of progression as high as 60%.


This system can be further refined, as each risk factor has a different HR. At ASCO 2019, San Miguel and colleagues[4] also presented a total risk score from 0 to > 12 that was calculated based on incremental increase in the levels of FLC ratio, M-protein, and involved bone marrow plasma cells as well as information on cytogenetics. Those with a total risk score of 0-4 had only a 3.7% chance of progressing at 2 years, with the risk increasing to 72.6% for those with a total risk score of 12 or higher.

E3A06: Single-Agent Lenalidomide vs Observation in Intermediate-Risk or High-Risk Smoldering MM

Sagar Lonial, MD:
Based on the risk of progression to active diseases for patients with high-risk smoldering MM, trials have been designed to ask if clinicians should recommend early treatment for these patients. The E3A06 trial was designed to investigate whether patients with high‑risk smoldering MM would have a decreased risk of progression when they received early intervention with single-agent lenalidomide vs continuing observation.[5] For both the nonrandomized phase II and randomized phase III parts of E3A06, patients had to have intermediate-risk or high-risk smoldering MM as defined using the Mayo risk classification. Eligible patients had no lytic bone disease on skeletal survey, no MRI evidence of bone disease, measurable M-protein in serum and/or urine, an abnormal FLC ratio of < 0.20 or > 1.65, and ≥ 10% bone marrow involvement.


In the phase II part, 44 patients received lenalidomide until they experienced progressive disease or unacceptable toxicity; the primary endpoint was safety and success of stem cell mobilization. In the phase III part, 182 patients were randomized to lenalidomide vs observation and continued on study until they experienced progressive disease or unacceptable toxicity. The phase III primary endpoint was PFS and the secondary endpoints included OS, ORR, quality of life, and safety. Patients receiving lenalidomide therapy also received aspirin as prophylaxis for venous thromboembolism.

The study met the phase III primary endpoint of PFS: lenalidomide significantly improved PFS vs observation in the intention-to-treat population after a median follow-up of 35 months (HR: 0.28; 95% CI: 0.12-0.63; P = .0005). The PFS rates at 1, 2, and 3 years were consistently higher with lenalidomide vs observation, with the difference between the arms growing over time. Of importance, results showed a 91% risk reduction in the risk of progression at 3 years for patients who were randomized to lenalidomide compared with observation.

An analysis of PFS was performed that incorporated the risk criteria from the 2008 vs 2018 Mayo models. When patients were risk stratified using the newer criteria, those with high-risk disease benefited the most from early intervention with lenalidomide vs observation.

Phase III QuiRedex Study of Rd vs Observation in High-Risk Smoldering MM: Survival Results

Sagar Lonial, MD:
In a similar Spanish trial, the phase III QuiRedex study, the combination of Rd was compared with observation in patients with high-risk smoldering MM (N = 119).[6] In this study, high-risk disease was defined as either ≥ 10% bone marrow plasma cell or presence of M-spike (IgG ≥ 3 g/dL or IgA ≥ 2 g/dL, or Bence Jones proteinuria > 1 g/24 hrs), or both, AND ≥ 95% phenotypically aberrant plasma cell in bone marrow plasma cell compartment with immunoparesis (reductions in 1 or 2 uninvolved immunoglobulins of > 25% compared with normal values). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg/day on Days 1-21, plus dexamethasone 20 mg/day on Days 1-4 and 12-15), followed by maintenance therapy (lenalidomide 10 mg/day on Days 1-21) for up to 2 years.


Results showed that the combination of Rd provided a significant increase in time to progression for treated patients vs the observation group: Median time to progression was not reached vs 23 months, respectively (HR: 0.24; P < .0001). Although median OS was not reached, at data cutoff 18% of patients in the treatment arm had died vs 36% in the observation group, resulting in a HR of 0.43 (95% CI: 0.21-0.92) and P value of .024.

Phase II GEM-CESAR: KRd as Curative Regimen for High-Risk Smoldering MM

Sagar Lonial, MD:
For the last trial I will mention, the phase II GEM-CESAR trial enrolled patients with high‑risk smoldering MM with a goal not to delay progression but rather to potentially cure these patients.[7] Patients were treated with a regimen similar to what we use for patients with active MM who are transplant candidates: induction with six 28-day cycles of KRd followed by high-dose melphalan therapy (HDT) and ASCT, followed by consolidation with 2 additional cycles of KRd and then 2 years of maintenance therapy with Rd. The primary endpoint for this study was sustained measurable residual disease (MRD) negativity after HDT with ASCT and at 3 and 5 years after HDT ASCT. The median age of participants was 59 years, with an upper age limit of 70 years since enrolled patients were candidates for transplant.

It is interesting that this study included not only patients with high-risk disease but also patients considered to be “ultrahigh risk” (33% of patients), defined as those who have an approximately 80% probability of progression in fewer than 2 years. By current standards, these ultrahigh-risk patients are now recognized as having active MM (> 60% clonal plasma cells in the bone marrow, a FLC ratio > 100, and/or > 1 MRI focal lesion) requiring treatment but were not defined as such at the time of the design of the study.

GEM-CESAR: Outcomes

Sagar Lonial, MD:
After 6 induction cycles, 41% of patients achieved a CR and 30% of patients achieved MRD negativity, with no differences in response rates observed between high-risk (n = 60) and ultrahigh-risk (n = 30) patients. Analysis of the adverse event profile during this induction showed what is to be expected for KRd: grade 3/4 neutropenia and thrombocytopenia in 3% and 5% of patients, respectively, and grade 3/4 infections in 10% of the patients. Overall, however, the regimen was tolerated quite well.

After HDT and ASCT, the CR rate increased from 41% to 64% and the MRD negativity rate increased from 30% to 56% with, again, no differences observed between high-risk and ultrahigh-risk patients. It is important to mention that peripheral blood stem cell mobilization after cycle 4 of induction was very successful; in fact, with only granulocyte-colony stimulating factor, a successful harvest was achieved in 93% of patients, and only 7% of patients required plerixafor as well.


After consolidation and 1 year of maintenance, which has now been completed in 77 of the 90 patients, response rates are even higher. Indeed, the CR rate increased to 75% with consolidation and 81% after maintenance. Also, the MRD negativity rate increased to 65% with consolidation and is sustained in 62% or patients with maintenance. At a median follow-up of 35 months, PFS is 92% and OS is 96%. Three patients have died and only one was considered a treatment-related death.

Of note, the 3-year PFS was 92% in the GEM-CESAR trial and 91% in ECOG A3A06, which suggests that more aggressive regimens may be less important than achieving immunologic control. A randomized trial could help answer the question of whether more-intensive therapy is beneficial in smoldering MM.

Patient Case Considerations: Smoldering MM

Sagar Lonial, MD:
In general, these data suggest that there may be subsets of patients with smoldering MM who can benefit from early therapy, and it is certainly reasonable to discuss some form of therapy with patients. In my practice, we may consider lenalidomide or Rd for some patients with high-risk smoldering MM. However, it is also reasonable to consider waiting to begin therapy for patients with smoldering MM and monitoring them until there is a sense of the tempo of their disease. For patients who prefer to wait to begin therapy, biomarkers should be rechecked every 6-8 weeks rather than annually. The goal of early therapy or close monitoring of smoldering MM is not just preventing the development of CRAB symptoms but also other MM-related complications.

Kathryn Maples, PharmD, BCOP:
From a pharmacist and nursing perspective, we also need to consider each patient’s comorbidities and other medications prior to counseling him or her on whether to start systemic treatment. Considerations for beginning therapy include any preexisting conditions or comorbidities with increased risk for thrombosis, peripheral neuropathy, or cardiac disease as well as whether a female patient is of childbearing age.

In ECOG E3A06, for example, the median duration of lenalidomide treatment was approximately 2 years and the longer patients are on lenalidomide therapy, the higher their risk of gastrointestinal toxicity. The diarrhea associated with lenalidomide is due to bile acid malabsorption, so patients may end up needing a colestipol-type medication to help control the lenalidomide-induced diarrhea. There is also a risk for thrombosis, and daily prophylaxis with baby aspirin should be considered.

Sagar Lonial, MD:
Let’s go back and consider our patient case example: This is a 62-year-old woman with 40% plasma cells in her bone marrow biopsy, and blood testing revealed IgG lambda M-protein at 5.44 g/dL and a FLC ratio of 6.84, but her CRAB score is 0 and no lytic disease was seen on bone imaging. Based on the 2/20/20 criteria, she has 2 risk features (M-spike > 2 g/dL and bone marrow plasma cell > 20 but not FLC > 20), suggesting a high risk of progression to active disease. Based on this information, I would recommend treatment with lenalidomide with or without dexamethasone or a clinical trial for smoldering MM.

Kathryn Maples, PharmD, BCOP:
If this patient agrees to lenalidomide-based therapy, she is no longer of childbearing age, so there is no risk for embryo-fetal toxicity. There is always a risk for thrombosis with lenalidomide, so she should receive aspirin as prophylaxis. This patient also has a past medical history of hypothyroidism, which lenalidomide can affect, so clinicians should monitor thyroid-stimulating hormone levels.

Charise Gleason, MSN, NP-BC, AOCNP:
In addition to the considerations Dr. Maples mentioned, this patient also has a history of osteopenia and a baseline vitamin D levels is important to obtain with continued follow-up for symptoms of bone disease. This patient had bone imaging but we recommend extensive imaging at diagnosis, with MRI of the entire spine or a PET scan, to ensure that there is not more active disease than initially detected.

Finally, it is also important to consider the psychosocial aspects of patient care. For patients who are just being diagnosed with cancer, there is a lot of teaching about their disease and close follow-up to understand the tempo of the disease and ensure that the patient understands and is coping well.

Provided by the Annenberg Center for Health Sciences at Eisenhower
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Annenberg Center for Health Sciences at Eisenhower
39000 Bob Hope Dr
Dinah Shore Bldg.
Rancho Mirage, CA 92270

Melissa Velasquez, Accreditation Specialist
(760) 773-4506
(760) 773-4550 (Fax)
ce@annenberg.net
http://www.annenberg.net/

Supported by educational grants from
AbbVie
Amgen
Celgene Corporation
Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC
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