Right time: stopping multiple myeloma maintenance Free

Dr John sang about being in the right place but the wrong time, whereas the exciting study under discussion is in the right place and the right time. In this issue of Blood, Terpos et al¹ have demonstrated the utility of testing minimal (or measurable) residual disease (MRD) (low levels of malignant plasma cells in the bone marrow [BM]) with positron emission tomography/computed tomography (PET-CT) imaging to determine if maintenance lenalidomide therapy could be discontinued in selected patients with multiple myeloma (MM) after induction therapy, autologous hematopoietic cell transplant (auto-HCT), and single-agent lenalidomide.

Of 194 consecutive patients, 52 (27%) had sustained MRD negativity at every 6-month BM testing with negative PET-CT imaging for 3 years. These patients stopped lenalidomide and were followed. Twelve became MRD⁺ after stopping maintenance; all started back on lenalidomide. Four patients had biochemical disease progression or clinical progression. All patients were alive at a median follow-up of 3 years from the 3-year MRD⁻ time point with a 7-year progression-free survival (PFS) from diagnosis of 90%. For this subgroup, stopping lenalidomide was safe, and most who had recurrent MRD⁺ BM converted back to MRD⁻ BM.

MM remains incurable.² However, with novel agent development, median PFS and overall survival (OS) rates continue to increase beyond 5 and 10 years, respectively, and continue to improve. This improvement is due to incorporation of novel agents in induction regimens for patients who are transplant ineligible (TIE) and patients who are transplant eligible (TE) for prolonged therapy to control disease. The Perseus study demonstrated high response rates by adding daratumumab to standard lenalidomide, bortezomib, and dexamethasone.³ 

There is a need for future study of MRD testing for patients who are TIE. Most studies examining MRD testing have focused on patients who are TE and receiving induction therapy followed by stem cell collection, auto-HCT, and maintenance with or without consolidation therapy. Single-agent lenalidomide is standard maintenance therapy after auto-HCT, demonstrating improved PFS and OS leading to US Food and Drug Administration (FDA) approval.⁴ Although not FDA approved for maintenance, daratumumab with or without lenalidomide improves PFS and likely OS following auto-HCT.^3,5 Daratumumab, unlike lenalidomide, usually is given for a fixed duration. Southwest Oncology Group (SWOG) 1803 examines lenalidomide with or without daratumumab maintenance therapy and the safety and of stopping maintenance. Patients who are BM MRD⁻ after 2 years of maintenance will be randomized to stop or continue (Clinical Trials ID: NCT04071457).

Prolonged therapy can result in toxicities impacting patient quality of life. Toxicities of lenalidomide, a member of the immunomodulatory drug family, include myelosuppression, increased risk for infections, thromboembolic events, hypersensitivity reactions, and increased second primary malignancies. Important considerations of continued therapy are determining which patients with MM can safely stop maintenance and which patients will require augmented therapy to attain MRD negativity. Can more patients be identified who can stop therapy and, if they have relapse or disease progression, be successfully retreated without impacting survival? There is also a need to identify early surrogate markers for long-term outcome, allowing patients and their treating clinicians to determine if stopping lenalidomide is a safe option.

MRD testing is a defined modality for determining depth of response. Several studies have demonstrated the utility of BM MRD testing at different time points after auto-HCT. Patients attaining MRD negativity have an improved PFS and often OS.⁶ Depth of response correlates with long-term outcome on maintenance. The 2 major MRD BM techniques are next-generation flow cytometry (NGF) at detection levels of 10⁻⁵ to 10⁻⁶ and next-generation sequencing (NGS) often at level closer to 10⁻⁶. NGF can be used for most patients. NGS relies on informative monoclonal DNA or RNA sequences of the malignant plasma cells and may not be possible in approximately 5% to 10% of cases. Consistent and comparable measurements are needed to compare trial results and inform clinicians and patients of the appropriate form of testing. Other important factors are the conversion of BM MRD positivity to negativity over time. In the Terpos et al study, 15% of patients were initially MRD⁺ after auto-HCT and converted to MRD⁻ over time. Thus, it is important to determine the time to MRD negativity and as emphasized in this study, sustained MRD negativity, which was 3 years. Imaging is another important modality in determining complete response.⁷ A MRD⁻ BM test and PET-CT were required for this study. Other forms of MRD testing such as mass spectrometry are becoming standard for assessing depth of response.⁸ This is important as BM testing every 6 months can be painful for the patient and is labor-intensive relative to a peripheral blood sample.

A recent pooled analysis of individual patient BM MRD testing from randomized trials was recently published.⁹ This analysis and another pooled analysis were submitted to the FDA, leading to Oncologic Drugs Advisory Committee approval for MRD testing as an early end point for clinical trials in TE patients with MM.¹⁰ It is expected that for future trials, MRD-based evaluation as an early clinical trial end point will become standard.

In the Terpos et al study, many of the MM patient cohort did not fulfill eligibility to discontinue lenalidomide maintenance. It is critical for patients not achieving or maintaining MRD negativity to be offered new agents that can increase and sustain the depth of response. Continued improvements in induction regimens, by incorporating novel agents including molecular glue degraders such as cereblon E3 ligase modulators, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapies, will deepen responses for most if not all patients. This will allow more patients to be eligible for testing maintenance therapy cessation. As patients with MM live longer with new treatments, using biomarkers that correlate with long-term outcome such as BM MRD testing and peripheral blood mass spectrometry is critical. This is especially pertinent for studies with OS as the primary end point as these studies remain open for many years to meet this end point. Thus, early biomarker study end points as surrogates for OS will be necessary to allow for faster testing of novel agents to find the cure for all patients with MM. This will be the right place and the right time.

Conflict-of-interest disclosure: P.M. is a consultant for Bristol Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, and Karyopharm and receives honoraria from BlueBird Biotech, Bristol Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, and Karyopharm. H.M. declares no competing financial interests.