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MM FAQ
Experts Discuss Contemporary Treatment of Multiple Myeloma

Released: March 05, 2025

Expiration: March 04, 2026

Jens Hillengass
Jens Hillengass, MD, PhD
Carol Ann Huff
Carol Ann Huff, MD
Shaji K. Kumar
Shaji K. Kumar, MD
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Key Takeaways
  • Quadruplet therapy can now be considered for many patients with newly diagnosed multiple myeloma.
  • Numerous BCMA-targeted therapies may be considered for relapsed/refractory multiple myeloma.

Introduction
In this commentary, expert faculty respond to healthcare professional (HCP) questions from a live webinar and share their perspectives on optimal treatment of patients with newly diagnosed (ND) and relapsed/refractory (R/R) multiple myeloma (MM).

When do you consider quadruplet therapy for transplant-ineligible MM?

Jens Hillengass, MD, PhD:
Patients with NDMM who are ineligible for transplant respond very well to triplet therapy and even better to quadruplet therapy, with the addition of an anti-CD38 antibody, which most patients can tolerate well. Therefore, if patients can tolerate quadruplet therapy, it is an excellent option. It is very important to consider frailty status when determining which patients this therapeutic strategy is appropriate for. It can be quickly determined whether patients can tolerate this therapy, and with maintenance the medication can be stepped down or removed, depending on the side effects, allowing patients to quickly enter deep remission. I have started using quadruplet therapies more frequently in elderly patients based on data from recent clinical trials.

In the phase III IMROZ trial, quadruplet therapy with isatuximab plus bortezomib, lenalidomide, and dexamethasone (VRd) improved progression-free survival (PFS) in patients with transplant-ineligible NDMM vs VRd alone, without greatly increasing adverse events. The rate of minimal residual disease (MRD), a very important marker in MM, was significantly better in the isatuximab plus VRd arm than in the VRd alone arm. The ongoing phase III BENEFIT trial is examining the addition of bortezomib to isatuximab plus lenalidomide and dexamethasone in transplant-ineligible patients not considered frail. Early results suggested that the quadruplet resulted in a higher MRD-negative rate across all subgroups after 12 months regardless of disease stage. Addition of the fourth drug—in this case, bortezomib—significantly improved the complete response rate and MRD endpoints, even the MRD-negative rate, at 18 months, again demonstrating that 4 drugs are stronger than 3.

Similarly, the phase III CEPHEUS trial comparing daratumumab plus VRd vs VRd alone in patients who are either ineligible for a transplant or defer transplant as initial therapy demonstrated excellent outcomes for the triplet arm but even better outcomes for the quadruplet arm. In the quadruplet arm, MRD negativity was achieved fairly early on during treatment, and the MRD-negative rate was excellent. Early follow-up results are promising.  

What are your goals for patients with transplant-eligible NDMM?

Jens Hillengass, MD, PhD:
My goal is for patients with transplant-eligible NDMM to achieve rapid, deep remission before high-dose chemotherapy, and quadruplet therapies that include a CD38 antibody, proteasome inhibitor (PI), immunomodulatory drug (IMiD), and dexamethasone have helped patients achieve this goal. Survival rates have improved significantly in recent years as quadruplet therapies have become the standard of care for induction treatment. Achieving rapid, deep remission and getting the disease under control very quickly is important so that there is not a prolonged effect of the myeloma on the patient because it often takes a long time for these patients to receive a diagnosis. 

Induction should achieve at least a very good partial response (VGPR). With quadruplet therapies, it is realistic to achieve even more than a VGPR, but transplant and consolidation should bring patients into even deeper remission. Furthermore, maintenance therapy keeps patients in an MRD-negative state, which is sometimes referred to as sustained MRD negativity (eg, if lasting longer than 1 year). The longer the patient remains MRD negative, the better the outcomes.  

How do you select between BCMA-targeted agents for R/R MM?

Shaji K. Kumar, MD:
Currently approved options include CAR T-cells and bispecific antibodies. Each has its own advantages and disadvantages. CAR T-cells can be expensive, and large referral centers are needed to take care of patients receiving this treatment. Bispecific antibodies can quickly be moved into a community setting after being initiated in a tertiary center.

Belantamab mafodotin is a BCMA-targeted antibody–drug conjugate (ADC) conjugated to MMAF, a microtubule-disrupting agent. Phase I and II studies in the DREAMM series reported objective response rates ranging from approximately 30% to 60% and a PFS duration as long as approximately 1 year. Subsequently, the phase III DREAMM-3 trial compared single-agent belantamab mafodotin to pomalidomide plus low-dose dexamethasone (Pd) but failed to show superiority for belantamab mafodotin, leading to its withdrawal from the market.

The phase III DREAMM-8 trial compared belantamab mafodotin plus Pd (BPd) vs bortezomib plus Pd. This trial showed a significant improvement in PFS with BPd. Consistent with other trials, the main adverse event was ocular toxicity, which was reported in nearly 90% of patients. When looking at grade 3 or higher ocular toxicity, blurred vision was reported in 17% of participants. The phase III DREAMM-7 trial, in which belantamab mafodotin plus bortezomib/dexamethasone was compared with daratumumab plus bortezomib/dexamethasone, demonstrated a toxicity profile very similar to that reported in DREAMM-8, particularly ocular toxicity. Results also indicated that belantamab increased PFS vs daratumumab when combined with bortezomib and dexamethasone.  

If a patient progressed on quadruplet therapy, how would you determine which agent the patient is refractory to, and would you switch either or both the IMiD and PI?  

Jens Hillengass, MD, PhD:
It is difficult to determine, but even if 1 drug was working, the patient would remain in remission. However, because the combination is synergistic, it is a bit more complicated. I recommend trying different PIs and different IMiDs. For example, I may switch from lenalidomide to pomalidomide or from bortezomib to carfilzomib, or from 1 antibody target like CD38 with isatuximab and daratumumab to another like SLAMF7 with elotuzumab. And again, CAR T-cell therapy is a good option as a second-line therapy.

Shaji K. Kumar, MD:
I completely agree. If a patient becomes refractory (ie, progresses on a quadruplet), which is fortunately very uncommon, it means they are refractory to all the agents. If this happens early on, it is usually indicative of poor biology and a need for aggressive therapy, possibly in clinical trials.  

Carol Ann Huff, MD:
I also agree. There are also additional PIs and IMiDs that can be options unless of course they were prescribed in the frontline setting. 

In the era of quadruplet induction, is it necessary to recommend frontline transplant? 

Carol Ann Huff, MD:
I believe transplant still holds value, as it allows patients to achieve deeper remission. As deeper MRD-negative remissions are observed with contemporary therapeutic regimens, there may be an opportunity to forego transplant, particularly for patients at average risk or other favorable patients. I approach this decision with patients via shared decision-making and discuss what is most important to each patient. 

Shaji K. Kumar, MD:
I completely agree. Although we don't have randomized trials with a quadruplet setting, the same question was asked in triplet and doublet settings, and the answer is always the same. I think it is appropriate to undergo transplant early on, but it is also ok if someone chooses to delay the procedure, in which case stem cells can be collected and stored.

Your Thoughts
How do you manage your transplant-eligible and -ineligible patients with NDMM? How do you choose therapy for R/R MM? Answer the polling question and join the conversation by leaving a comment. 

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