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ASH 2023 Multiple Myeloma

CE / CME

Conference to Clinic: Expert Analysis of the Top Multiple Myeloma Abstracts From the 2023 ASH Annual Meeting

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Pharmacists: 1.00 contact hour (0.1 CEUs)

Released: March 07, 2024

Expiration: March 06, 2025

Sagar Lonial
Sagar Lonial, MD, FACP
CME/CE Information

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Final Analysis of CENTAURUS: Daratumumab Monotherapy in Intermediate- or High-Risk SMM

Sagar Lonial, MD, FACP:
I will wrap up this discussion with a trial that focuses on a rapidly emerging and complex set of clinical trial data in patients with high-risk smoldering multiple myeloma.

The CENTAURUS trial was a randomized, open-label phase II study of single agent daratumumab in patients with untreated smoldering multiple myeloma of intermediate or high risk.18 The diagnosis of smoldering myeloma used SLiM CRAB criteria and risk criteria for this trial included: bone marrow plasma cells ≥10% AND ≥1 of the following: serum M-protein ≥3 g/dL (IgA ≥2 g/dL), urine M-protein >500 mg/24 hr, abnormal free light chain (FLC) ratio (<0.126 or >8) with serum M-protein >1 to <3 g/dL, absolute involved sFLC ≥100 mg/L with abnormal FLC ratio (<0.126 or >8). Patients were treated with daratumumab in long, intermediate, or short regimens.

Each group began with the standard approach of weekly dosing for one 8-week cycle. The short arm received only 1 cycle of therapy. The intermediate arm received 1 cycle of weekly dosing, then transitioned to dosing every 8 weeks for 20 cycles, with an optional extension phase of up to 7 years. The long intense treatment group received 1 cycle of weekly dosing, then transitioned to every 2 week dosing for Cycles 2 to 3, then every 4 week dosing for Cycles 4 to 7, followed by every 8 week dosing for Cycles 8 to 20, with an optional extension phase of up to 7 years.

This study was published previously, but the final analysis was presented at ASH this year.

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Final Analysis of CENTAURUS: Response

Sagar Lonial, MD, FACP:
The ORR was higher for the long intense (58.5%) vs the intermediate (53.7%) and short arms (37.5%).18 This was to be expected as a longer duration of treatment is associated with better ORR.

At a median duration of follow-up of 85.2 months (range: 0-94.3 months), the DoR was not reached with the long intense treatment arm vs 83.4 months with intermediate and 72.7 months with short treatment arms.

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Final Analysis of CENTAURUS: Survival and Time to Next Treatment

Sagar Lonial, MD, FACP:
Examining PFS, OS, and time to next treatment is difficult and requires additional follow-up; however, the long intense therapy approach appears to provide the most benefit in terms of PFS and time to next treatment.18

The median PFS per protocol has not been reached for any arm, but the median PFS including the extension phase has not been reached for the long intense arm vs 84.4 months for the intermediate treatment and 74.1 months for the short treatment. The median time to next treatment has not been reached for the long intense and intermediate treatment arms but was 76.3 months for the short treatment arm.

The number of subsequent treatments suggests that the short duration therapy likely was not as effective, and that the long or the intermediate durations were more effective.

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Final Analysis of CENTAURUS: Safety Summary

Sagar Lonial, MD, FACP:
Though the incidence of treatment-emergent AEs was similar among all 3 groups, the rate of infectious complications seemed to be higher in the long intense treatment arm than in the short or intermediate arms.18 A large number of treatment-emergent AEs were thought to be related to daratumumab, but few led to treatment discontinuation.

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Final Analysis of CENTAURUS: Grade 3/4 TEAEs, Serious TEAEs, Deaths

Sagar Lonial, MD, FACP:
Despite the number of treatment-emergent AEs attributed to daratumumab, the longer follow-up suggests there were not major safety concerns with this treatment.18 With the use of daratumumab in smoldering multiple myeloma, the most common serious treatment-emergent AE was pneumonia, which only occurred in 4 patients in the long treatment group, vs 1 in either the intermediate or short treatment groups.

Secondary malignancies were relatively similar between the long and intermediate treatment groups. None of the deaths that occurred during this study were thought to be related to daratumumab.

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Key Takeaways

Sagar Lonial, MD, FACP:
In summary, I think it is clear from the PERSEUS study that patients with newly diagnosed multiple myeloma benefit from the addition of daratumumab to VRd, regardless of risk status.1,2 Further, real world experience demonstrated similar benefits from the use of Dara-VRd compared to VRd, with benefits in PFS and potentially to OS.

Although the OS data are still immature for the PERSEUS trial, I am hesitant to wait for these forthcoming results given that the median survival of patients with myeloma is well over 10 years now and OS for patients with R/R multiple myeloma also depends heavily on their subsequent lines of therapy. I think OS should not be used as a primary marker of efficacy for new treatment options for patients with newly diagnosed multiple myeloma, but prolonging PFS should be the main goal in those settings, because median patient survival is already very high. If a new therapy substantially prolongs PFS, I believe that should be sufficient to change practice.

In that context, the findings from the PERSEUS study and confirmation in real-world data and data from the IsKia EMN24 trial all clearly demonstrate that anti-CD38 antibodies are standard of care in newly diagnosed transplant-eligible multiple myeloma.1,2,7,8

For bispecific antibodies, patients who received talquetamab clearly maintained a response after dose reduction and dose modification.10 Many HCPs use preemptive dose modification for almost all the T-cell–engaging bispecific antibodies. The talquetamab data provide reassurance as efficacy was maintained with this practice.

The updated data from LINKER-MM1 suggested that linvoseltamab may have a different AE profile from other bispecific antibodies. Its safety profile certainly looks as good, if not better, than other bispecific antibodies targeting BCMA.11

The next study reported additional confirmatory data suggesting that venetoclax in combination with daratumumab and dexamethasone is not only safe, it is highly effective, and achieves a high rate of PFS and MRD negativity.14 This then translates into long term benefit over DVd in patients with t(11;14)-positive multiple myeloma.

Finally, the CENTAURUS study gave us food for thought on single-agent daratumumab.18 There are a number of studies looking at either bispecifics, IMiDs or combination therapies in smoldering myeloma. CENTAURUS gave us evidence that low-intensity therapy is clearly safe and offers benefit for patients with intermediate- or high-risk smoldering myeloma.

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