ASCO 2023: A Maintenance Regimen for High-Risk Myeloma

Cytogenetically defined high-risk multiple myeloma patients do not experience the same luxury as their standard-risk counterparts when it comes to long, durable responses to standard-of-care myeloma treatments. 

How does one define cytogenetic high-risk disease in myeloma? It depends on the results of your FISH test.

Those with the following genetic characteristics are considered to be high-risk. 

• t(14;16) 
• t(14;20)
• del17p13 
• t(4;14)
• 1q gain or amplification 

If you're unsure about your own FISH results or cytogenetic characteristics of your disease, please consult your treating physician/myeloma team who should be able to provide you with more information. 

While myeloma research continues to improve standard-risk outcomes, the high-risk myeloma community remains an unmet need patient population. 

So what good news is there? Combination maintenance therapies (using more than one drug as maintenance therapy) have shown promising results. 

In the phase 2 study presented at the ASCO 2023 Conference, Dr. Ajay Nooka from Emory in Atlanta, GA, shared results for high-risk myeloma patients on the maintenance regimen of carfilzomib, pomalidomide and dexamethasone (KPd). 

Learn more about their promising study below: 

What question was this clinical trial trying to answer? What phase was this trial in? 

How well do carfilzomib, pomalidomide, and dexamethasone work as maintenance therapy in patients with high-risk myeloma? 

This trial was a Phase II (2) trial, meaning that the drug combination had already been proven safe for human use in a Phase I (1) trial, and now the proper dosing and complete response rate would be tested in the second phase. This trial still needs a Phase III (3) component that proves it to be more beneficial than the current standard of care maintenance therapy for high-risk myeloma patients. 

How many people participated? What were the qualifications?

Twenty-nine (29) patients were enrolled.

 
Inclusion criteria: 

• Newly diagnosed high-risk myeloma patients that have achieved ≥ partial response (PR) post-ASCT.
• High-risk myeloma was defined by the presence of one or more genetic mutations: t(4;14), t (14;16), del17p by FISH or cytogenetics, or the presence of >20% of circulating plasma cells (primary plasma cell leukemia).
• Double hit myeloma was defined by presence of two or more high-risk cytogenetic abnormalities including gain of 1q.

Demographics:

• Median age was 60 years (range 46-75)
• 58.6% male
• 58.6% black

Myeloma Characteristics:

• 65.5% R-ISS stage III at diagnosis
• 54.5% of whites had double-hit disease (two or more high-risk characteristics)
• 64.7% of blacks had double-hit disease (two or more high-risk characteristics)
• Median time from diagnosis to study: 9.3 months
• Median time from transplant to study: 2.89 months

How long did the study last, and when was it completed?

This is an ongoing study. It has been running for four years and four months. It began on January 25, 2019, and is estimated to be completed in August 2024.

What were the preliminary results?

Complete response (CR) rates were evaluated two years after the study started as the primary outcome. 
Complete response rates will be determined for KPd maintenance. 

• At study entry, ≥ CR (complete response) rate was 24%, which deepened to 79.3% during the study.
• At study entry, ≥ VGPR (very good partial response) rate was 68.9%, which deepened to 100% during the study.
• The median time to best response was 2.07 months (1.22 - 14.26). 

Fifteen patients had available minimal residual disease (MRD) data. This test is for those with no detectable disease after achieving a complete response but wish to have a more sensitive test measure any remaining disease. 

Because the MRD testing/results were written in as an amendment to the original clinical trial design, not all patients enrolled in the study were tested for minimal residual disease results. 

Of the fifteen (15) patients who were MRD tested: 

• MRD negativity (10-5) was attained in 80% of patients
• MRD negativity (10-6) was attained in 53.3% of patients

Secondary Outcomes:

• The 36-month progression-free survival (PFS) was 63.2%, with no difference by race 
• The 36-month overall survival (OS) was 72.4%; unfortunately, black patients had inferior results compared to whites (61.1% vs 85.7%)
• Double-hit disease was an independent predictor for progression and death
• At data cut-off, 37.9% of patients were still receiving treatment; the most common reason for permanent discontinuation was progressive disease (27.6%)
• During the study, six patients died; the most common cause of death was progressive disease (83.3%)
• Most common (>20%) adverse events were fever, fatigue, diarrhea, nausea, cough, muscle cramps, acneiform rash
• Adverse effects of interest were cardiac (10.3%), cataracts (17.2%), neutropenia (6.9%), and anemia (10.3%)

Why is this trial important to patients within today’s myeloma?

The use of maintenance therapy has become a standard of care in most myeloma patients, regardless of their transplant eligibility. Single-drug therapy with IMiDs (for example, lenalidomide, a.k.a. REVLIMID) has been shown to improve progression-free survival (PFS) and overall survival (OS) following transplant.

High-risk patients represent a challenge to treat and often benefit from combination therapy (IMiD + proteasome inhibitor) as a maintenance regimen. Giving next- generation proteasome inhibitor, carfilzomib aka KYPROLIS, plus the IMiD pomalidomide or Pomalyst, and dexamethasone may deepen responses with subsequent more prolonged progression-free survival and overall survival. As a phase II trial, this study aims to evaluate the efficacy of this strategy; and so far, it has provided promising results in high-risk patients, while results among double-hit patients remain poor, warranting the development of different strategies aiming for remission. 

We thank the following people for making this trial and its results possible, along with the patients who participated and their supportive caregivers.

Primary investigators: Ajay K. Nooka (first author)
Co-authors: Nisha S Joseph, Madhav V. Dhodapkar, Craig C. Hofmeister, Vikas Anand Gupta, Joel S Andrews, Charise Gleason, Anuja A Sharma, Bryan J Burton, Quanta R Cato, Ching Siong Tey, Manali Rupji, Yuan Liu, Ian McFadden, Rani Najdi, Lawrence H Boise, Jonathan L. Kaufman, Sagar Lonial

Organizations: 
Winship Cancer Center of Emory University, Atlanta, GA
Emory University
Emory University School of Medicine
Biostatistics Shared Resource
Amgen, Thousand Oaks, CA, 
Amgen Inc., Newbury Park, CA