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Deep Responses in Smoldering Multiple Myeloma Linked to Improved Outcomes
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Key Takeaways
- High-risk SMM patients achieving minimal residual disease negativity showed significantly improved progression-free survival, emphasizing the importance of deeper treatment responses.
- The I-PRISM trial demonstrated a 93% overall response rate, with 31% achieving complete response and 45% very good partial response.
Risk stratification remains a challenge when selecting patients for treatment of smoldering multiple myeloma.
Deeper responses to treatment can predict therapy outcomes in patients with high-risk smoldering multiple myeloma (SMM) based on data from the single-arm I-PRISM phase 2 trial (NCT02916771).1
Magnified bone marrow tissue showing multiple myeloma cells | Image Credit: © Curie - stock.adobe.com
SMM is a precancerous disease that is a precursor to multiple myeloma (MM), the second most common hematologic malignancy. In SMM, low levels of myeloma cells are detected but are not high enough to result in significant symptoms or to be classified as overt MM. Traditionally, treatment is limited to observation; however, advancements in immunotherapies have opened avenues for treatment of SMM to reduce end-organ damage and mitigate disease progression.2
Treating SMM is controversial due to its status as a precancerous condition. Stratification of patients and determining who will benefit most from treatment over observation remains a challenge. Health care providers use the SLiM-CRAB criteria, the diagnostic framework for MM.3
“SMM is more of a pre-cancer diagnosis,” Ming-Hei Tai, PharmD, BCOP, oncology pharmacist at the Karmanos Cancer Institute in Flint, Michigan, explained in a Pharmacy Times® interview. “It means that there is a risk that you have this thing going on with your plasma cells, which could develop into myeloma, but right now it hasn't developed into myeloma. And usually, we define myeloma as SLiM-CRAB. So, it means you have 60% of your plasma cell infraction in bone marrow. It means you have light chains over 100, or you have a bone lesion on your MRI. That's a SLiM criterion. Or you have the CRAB criteria, which are hypercalcemia, renal dysfunction, and anemia. And so, if you don't meet the SLiM-CRAB criteria, you are classified, usually as smoldering myeloma.”3
Advancements in risk stratification have suggested that early therapeutic intervention may improve prognoses and prevent MM-related morbidity, and various clinical trials have shown benefits in treatment of SMM with immunotherapies. In one phase 2 trial (NCT02415413), 90 patients with high-risk SMM were treated with carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc.), lenalidomide (Revlimid; Bristol Myers Squibb), and dexamethasone (KRd). At the follow-up, about 62% of patients achieved improvements in undetectable measurable residual disease, of which 31% sustained for 4 years.4-6
The data from the phase 2 I-PRISM study offers a deeper understanding of the impact of treatment for patients with SMM, particularly those who are high-risk. The researchers evaluated treatment with ixazomib (Ninlaro; Takeda Pharmaceutical Company), lenalidomide, and dexamethasone in 55 patients with high-risk SMM (median age 64 [range 40–84], 55% male). The primary end point was median progression-free survival (PFS), with secondary end points including biochemical PFS, overall response rate (ORR), complete response (CR), and very good partial response (VGPR). Risk stratification was determined through cross-study comparisons of the Mayo 2008, Mayo 2018, IMWG risk score tool, and high-risk cytogenetics models.6
The primary end point of PFS was not reached, and the secondary end point biochemical PFS was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in 8 patients. The ORR was favorable at 93%, of which 31% of patients achieved a CR and 45% achieved a VGPR. CR was strongly associated with the absence of SLiM-CRAB and biochemical progression.6
Patients who were minimal residual disease (MRD)-negative (at a sensitivity of 10⁻⁵) had a 100% biochemical PFS at 5 years, compared with 40% for MRD-positive patients (P = 0.051). This shows that deeper responses significantly delay progression. Exploratory single-cell RNA sequencing found that tumor MHC class I expression was tied to better responses to proteasome inhibitors, while a lower percentage of GZMB+ T cells in expanded CD8+ T cells was linked to poorer outcomes.6
Achieving deeper responses, such as MRD negativity, was linked to significantly improved PFS, highlighting the importance of refining risk stratification to identify patients who may benefit most from treatment. As research continues to uncover biomarkers that predict therapy response, the evolving landscape of SMM management could shift toward a more proactive approach, ultimately aiming to delay or even prevent the onset of symptomatic MM.
