2026 Treatment Algorithms for Newly Diagnosed and Smoldering Multiple Myeloma
Key Points
- In smoldering multiple myeloma, active surveillance is the predominant management strategy, although recent trials have led to the approval of systemic therapy.
- Quad-class regimens are the frontline standard of care for transplant-eligible patients with newly diagnosed multiple myeloma.
- For transplant-ineligible patients, reduced-intensity quadruplet regimens or triplet regimens are used as induction therapy and modified for continued maintenance therapy.
- Minimal residual disease (MRD) testing can help guide de-escalation decisions across treatment settings, including the deferment of transplants in standard-risk patients.
Newly Diagnosed Multiple Myeloma Treatment Algorithm
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, invited myeloma specialist Gurbakhash Kaur, MD, of Mount Sinai, to discuss the treatment algorithms for newly diagnosed and smoldering multiple myeloma.
Surveillance Versus Treatment in Smoldering Multiple Myeloma
Smoldering multiple myeloma is traditionally managed with active surveillance. In 2025, the FDA approved single-agent daratumumab for patients with high-risk smoldering multiple myeloma based on the AQUILA trial. Despite the approval, Dr. Kaur has not incorporated systemic therapy for patients with high-risk smoldering multiple myeloma in her practice. She may offer treatment to highly motivated patients determined to receive therapy, but generally her preference is to enroll these patients in clinical trials. Overall, the decision to start systemic therapy for smoldering multiple myeloma should be individualized based on each patient’s characteristics and risk factors.
Frontline Therapy for Newly Diagnosed Multiple Myeloma
The current frontline standard of care for patients with newly diagnosed multiple myeloma is a quadruplet regimen consisting of an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug, and a corticosteroid. Excluding corticosteroids, there are multiple options for each class and regimens can be tailored for different patient populations. For example, Dr. Kaur usually reserves carfilzomib–based regimens for younger or more fit patients, and leans towards bortezomib–based regimens for frail or elderly patients.
Historically, transplant eligibility played a large role in frontline treatment decisions for patients with newly diagnosed multiple myeloma. However, the advancements in frontline treatment over the past several years have reduced the proportion of patients who go to transplant, regardless of eligibility. That said, transplant remains an effective treatment option, especially for younger or more fit patients, and transplant may be particularly warranted for patients with high-risk disease, said Dr. Kaur.
For transplant-ineligible patients, frontline quadruplet regimens or triplet regimens that drop the proteasome inhibitor are the standard of care. Quadruplets primarily use bortezomib and are often modified with reduced doses as a “lite” regimen. Even with modified quadruplets or triplets, Dr. Kaur will further reduce doses, extend the length of treatment cycles, and drop the corticosteroid entirely to improve tolerability. She often makes these adjustments after 1 to 2 cycles, although she may try to maintain higher dose levels for patients with a high disease burden.
Maintenance Therapy
The treatment algorithm for multiple myeloma calls for maintenance therapy in post-transplant or post-induction, transplant-ineligible patients. In post-transplant patients, maintenance regimens are based on recurrence risk. For standard-risk patients, single-agent lenalidomide is standard, although single-agent daratumumab may be an alternative with improved tolerability. For high-risk patients, doublet regimens such as daratumumab plus lenalidomide or carfilzomib plus lenalidomide are standard. Data have emerged for triplet maintenance regimens that include dexamethasone, but Dr. Kaur typically only considers triplets for transplant-deferred patients that may better tolerate them.
In transplant-ineligible patients, frontline induction regimens are often de-escalated for tolerability, and many patients may receive ongoing single-agent or doublet therapy, much like post-transplant patients. The choice of how many cycles of an induction regimen to give before de-escalating should be made on an individual patient basis, although MRD assessment can offer some guidance, said Dr. Kaur.
The Role of MRD in the Multiple Myeloma Treatment Algorithm
MRD assessment can inform treatment decisions across the treatment algorithm for multiple myeloma. In addition to guiding de-escalation of induction therapy for transplant-ineligible patients, MRD assessment may be able to guide cessation of maintenance therapy in post-transplant patients who achieve sustained MRD negativity. However, Dr. Kaur does not de-escalate in patients with high-risk multiple myeloma, as data show this population has an increased risk of recurrence. Notably, MRD assessment is also growing as a tool to guide transplant deferment in transplant-eligible patients with standard-risk multiple myeloma who achieve MRD negativity after induction therapy.