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Therapeutic Strategies in Myeloma

CE / CME

Therapeutic Strategies in Multiple Myeloma: Overview of Current and Emerging Treatment Options

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: April 26, 2023

Expiration: April 25, 2024

Shaji K. Kumar
Shaji K. Kumar, MD
CME/CE Information

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

When discussing management of MM and related disorders, it is important to think about high-risk smoldering multiple myeloma (SMM). SMM is thought to be an intermediate stage between MGUS and active MM. This condition has garnered much interest over the past decade, primarily because it offers an opportunity to intervene before patients develop end organ damage. It could also offer an opportunity to eradicate the underlying clone and potentially cure the disease. Studies designed to understand the natural history of SMM have been going on for many decades.

In 2014, the MM diagnostic criteria were revised so patients with high-risk SMM and a ≥80% risk of progression within 2 years were considered active MM and were able to be treated before a catastrophic event occurred in terms of end organ damage.7

Once the ultrahigh-risk patients were removed from that overall diagnostic group of SMM it was important to reassess the risk of progression. So, a large study initially conducted by the Mayo Clinic developed the 20/2/20 model that used M spike, serum FLC ratio, and bone marrow plasma cell percentage to define those at high risk of progression. It was thought that patients with ≥50% risk of progression in the initial 2 years after diagnosis could be considered for early intervention.8

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IMWG: Risk Score to Predict Progression Risk at 2 Yr

This 20/2/20 model was further expanded by the IMWG, using a large cohort of approximately 2000 patients with SMM. This model used calculated risk scores to categorize patients into various risk groups and evaluated what their risk of progression to active MM would be, thus allowing them to be considered for clinical trials or early intervention.8,9

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High-Risk SMM: Factors Identifying 50% Risk of Progression at 2 Yr

Now that we are able to identify patients with a high risk of progression from smoldering to active MM, the next question is how best to manage these patients. Several prognostic factors have been described that predict progression to active MM, including an evolving phenotype, presence of high-risk cytogenetics, and various genomic and imaging abnormalities. As the field moves forward, more of these factors will be incorporated into the risk scoring models.10-16

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QuiRedex Trial: Rd vs Observation in High-Risk Smoldering MM

Two large phase III trials in high-risk SMM inform current practice. The open-label QuiRedex trial randomized newly diagnosed patients with high-risk SMM to either lenalidomide/dexamethasone (Rd) or observation. The primary endpoint was time to progression to symptomatic disease, and secondary endpoints included overall survival (OS), response, and safety.17,18

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QuiRedex Study (12-Yr Update): Survival

The QuiRedex trial demonstrated that early treatment with Rd given until disease progression was associated not only with a delayed time to progression to active MM, but also improved OS. This trial was also able to demonstrate no adverse impact of early initiation of therapy.

There are, however, some important caveats with this trial. One is that advanced imaging was not used, so it is possible that a percentage of these patients (up to one quarter) already had MM that was not appropriately diagnosed. The second is that it used the combination of lenalidomide and dexamethasone, raising the question of whether dexamethasone was necessary in this specific setting.18

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

A second phase II/III trial, E3A06, randomized patients with high-risk SMM to lenalidomide alone vs observation. This trial showed similar results to those from QuiRedex in that there was a delayed time to progression to active MM amongst those patients receiving early intervention with lenalidomide.19

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E3A06: PFS in ITT Patient Population (Phase III)

Additional analysis of the E3A06 trial showed that most of the benefit was limited to patients with a 20/2/20 high risk according to the Mayo criteria, again highlighting that not only can we use these types of risk stratification tools, but patients with a high risk of progression per these tools can benefit from some form of early intervention.19,20

Another important unanswered question is whether we should treat patients with high-risk SMM with minimal therapy such as lenalidomide alone or should we treat them like active MM? An ongoing ECOG phase III trial is assessing Dara-Rd vs Rd in patients with high-risk SMM (NCT03937635).

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GEM-CESAR: Carfilzomib/Len/Dex as Curative Regimen for High-Risk Smoldering Myeloma

In addition, phase II trials are exploring the option of administering intense therapy for a defined time period with the goal of eradicating the underlying clone. One such trial is GEM CESAR, which evaluated a combination of KRd given along with stem cell transplant for a total of 3 years of therapy.21

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GEM-CESAR: PFS and OS

Results from the GEM-CESAR trial showed that, at an estimated 6-year follow-up, 94% of patients had not progressed to active MM. Historically for this group of patients, over half would have progressed by that time. The majority of the patients were alive at this follow up. However, as this is a single arm trial, we cannot draw any conclusions about the optimal treatment approach, but we can gain insight as to whether an intense therapy approach in this population could potentially be curative.22

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Phase II ASCENT: Carfilzomib + Lenalidomide + Dexamethasone + Daratumumab for High-Risk SMM

The open-label phase II ASCENT trial enrolled patients with high-risk SMM to receive KRd with daratumumab (KRd-D) without transplant. The goal was to determine whether using a nontransplant based approach for 2 years could actually eradicate the disease. The primary endpoint was rate of confirmed stringent complete response (sCR), and secondary endpoints included measurable residual disease (MRD), negativity, OS, PFS, and safety.23,24

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Phase II ASCENT: Responses (Primary Endpoint: sCR)

The ASCENT trial showed that 97% of patients responded to the combination of KRd-D. In fact, the majority of patients (92%) achieved a very good partial response or better and 84% became MRD negative in the bone marrow. We do not yet have long term follow-up data on whether any of these patients have been cured. To date, however, 4 patients have progressed with a median of approximately 2 years of follow-up; continued follow-up in this cohort is necessary to understand the impact of these intensive therapies.24

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Phase II ASCENT: Safety

It is important to note that these intensive therapies come with toxicities. However, toxicities in this patient population were the same as those experienced by patients with newly diagnosed MM. Safety results showed grade ≥3 hematologic toxicity in 18% and nonhematologic toxicity in 51% of patients. Overall, the quadruplet regimen KRd-D is well tolerated in patients with high-risk SMM. Nevertheless, it is important to continue to monitor these patients for long term toxicity.24

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Key Points for Clinical Practice: SMM

  • Patients with SMM should be considered for clinical trials.
  • At the minimum, patients with high-risk SMM should be treated with lenalidomide or Rd, but preference for these patients should be clinical trials.
  • Investigational approaches using more aggressive treatment regimens that are standard in newly diagnosed active MM are also being evaluated in SMM with the goal of cure.
  • A multidrug combination could be considered for patients with high-risk SMM who may quickly progress to active MM, but questions remain about whether there is additional benefit.
  • Patients with SMM who are not started on therapy should be monitored very closely, every 3 months initially with increasing intervals if the markers of disease remain stable.

A 51-year-old asymptomatic woman was found to have an IgAk paraprotein during a routine exam. On further examination, her M-protein component was 1.2 g/dL but her free light chain ratio (FLC), renal function, hemoglobin, and calcium levels were normal.
A diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was established and follow-up every 6 months was recommended.


She remained stable for 3 years, at which time she consulted with a myeloma expert and her M-protein component was found to be 2.3 g/dL, with FLC ratio of 35 and Bence-Jones proteinuria of 500 mg/24h. Bone marrow biopsy revealed 32% plasma cells (97% clonal), with t(4;14) cytogenetics. A CT scan was negative, but MRI showed 1 focal lesion in her right femur.
A diagnosis of smoldering MM (SMM) was established.

Would this patient with SMM be a candidate for initiation of treatment at this time?

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