Kumar Reviews Key Trials on Multiple Myeloma Presented at ASH 2022

In an interview with Targeted Oncology, Shaji K. Kumar, MD, discussed the presentations from ASH 2022 that stood out as most important to the multiple myeloma landscape.

Shaji K. Kumar, MD

Shaji K. Kumar, MD

At the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition, international teams of hematology researchers presented important updates on studies investigating treatment for multiple myeloma.

Many questions have lingered in the field of multiple myeloma treatment, including the optimal approach to therapy for high-risk patients, the benefit of autologous stem cell transplant (ASCT), the best induction and maintenance regimens for newly-diagnosed disease, and the value of new therapy types such as chimeric antigen receptor (CAR) T-cell therapy. Looking back on ASH 2022, clinical trials demonstrated progress in addressing some of these crucial questions.

For example, early intervention approaches have shown potential in high-risk smoldering disease, leading to high rates of minimal residual disease (MRD)-negative complete remission in the GEM-CESAR (NCT02415413) and ASCENT (NCT03289299) trials. Increasing treatment intensity with 4- and 5-drug combinations with doublet maintenance have shown high efficacy in patients with high-risk disease. There is evidence that some older patients would have better outcomes without upfront ASCT or with reduced steroid use, warranting further investigation.

Data were presented on the advances in immune-based therapies including monoclonal antibodies, CAR T-cell therapies, and bispecific antibodies. Researchers have learned a great deal about the efficacy and tolerability of these agents as later lines of therapy and are exploring their potential to improve outcomes as part of combinations in earlier lines.

In an interview with Targeted OncologyTM, Shaji K. Kumar, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, discussed the presentations from ASH 2022 that stood out as most important to the multiple myeloma landscape.

Targeted OncologyTM: What studies presented at ASH 2022 showed progress in the area of newly-diagnosed high-risk smoldering myeloma?

SHAJI K. KUMAR, MD: There are a couple of studies that have looked at the role of early intervention in patients with high-risk smoldering multiple myeloma. Both are single-arm trials. The Spanish GEM-CESAR trial looked at using a combination of carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone with ASCT for transplant-eligible patients. [This trial] demonstrated that patients can get high rates of MRD negativity and deep responses. At 3 to 4 years follow-up, very few patients have progressed and a significant number of the patients remain in sustained MRD negativity.1

A similar trial done in the United States, the ASCENT trial, also looked at carfilzomib, lenalidomide, and dexamethasone but added daratumumab [Darzalex], did not include ASCT, and enrolled a wider age spectrum of patients with high-risk smoldering myeloma, as defined by the International Myeloma Working Group [IMWG] criteria. These patients often received a defined 2 years of treatment. The early results suggest that by using this combination, we can get deep responses with nearly two-thirds of the patients getting to be MRD negative.2

With longer follow up, what we're trying to see with these 2 trials is whether the MRD negativity can be sustained over time, and whether that could be a step towards curing some of these patients. Clearly, there is a lot more that needs to be learned with the use of more intense therapies in this patient population and it should be done only in the context of clinical trials. But there are other phase 3 trials already ongoing that are looking at using myeloma-type treatments, building upon prior phase 3 trials demonstrating value for treating these patients with high-risk smoldering myeloma with lenalidomide or lenalidomide plus dexamethasone.

What other updates were there on newly-diagnosed multiple myeloma?

Myeloma is a very heterogeneous disease and there is increasing awareness that we cannot treat all these patients the same way and we need to be exploring different options for patients with high-risk disease. High-risk myeloma, mostly defined along the lines of using high-risk cytogenetic abnormalities, were enrolled in several different trials. There were data from the United Kingdom group [on the OPTIMUM/MUKnine trial (NCT03188172)] demonstrating that the combination of cyclophosphamide, bortezomib [Velcade], lenalidomide, daratumumab, and dexamethasone—essentially a 5-trunk combination for initial therapy—ASCT, and then intense consolidation for the prolonged 2-trunk maintenance, can give outcomes that are better than what has historically been noted in their own previous phase 3 trials.3 These are very early data but still suggest that this kind of intense approach might be what is required for improving the outcomes in patients with high-risk multiple myeloma.

There were data from the German cancer trial that looked at the combination of isatuximab [Sarclisa], carfilzomib, lenalidomide, and dexamethasone in a single-arm trial that included both transplant-eligible and transplant-ineligible patients, with the former group getting an ASCT along with the 4-drug combination. These patients also remained on long-term therapy with 2-drug combinations. Hopefully, these trial data will demonstrate the value of targeting MRD negativity in patients with high-risk disease. A significant proportion of these patients became MRD negative with these intense treatment approaches.4

There were also retrospective data from a Memorial Sloan Kettering Cancer Center study that looked at combination of carfilzomib, lenalidomide, and dexamethasone in comparison with bortezomib, lenalidomide, dexamethasone. [Investigators] also tried to look at the outcomes based on whether the patients received transplant. In their cohort of high-risk patients, as defined by the IMWG criteria, we saw that patients who received carfilzomib-based induction therapy and transplant had one of the better outcomes amongst that group of patients.5

Finally, there were data from China in a relatively small trial [NCT04935580] which looked at using a dual-targeted CAR T-cell therapy that targeted both CD19 and BCMA [B-cell maturation antigen]. It was a small cohort of patients but nevertheless all these patients responded, and the majority of those patients are MRD negative.6 So hopefully with longer-term follow-up, we can see if a modern immunotherapy, whether it be a multi-drug combination or a CAR T-cell therapy approach, might be an appropriate way to tackle high-risk multiple myeloma right from the beginning.

What data were presented on optimizing early-line therapy options for patients with multiple myeloma?

There are data looking at the outcomes in the older patient population. There was a randomized phase 3 trial from France [IFM2017-03] that looked at using daratumumab and lenalidomide in a steroid-sparing fashion, using steroids for only 2 cycles and also using 20 mg instead of 40 mg of dexamethasone and comparing that with lenalidomide and dexamethasone in a frail, advanced population with newly diagnosed myeloma. Their trial clearly showed that the use of the steroid-sparing approach was quite efficacious, and the responses appear to be better than just using lenalidomide plus dexamethasone.7 We don't have long-term data or data with respect to progression-free survival [PFS] or overall survival [OS] outcomes for these patients.

There's also a German study [DSMM XIII; NCT01090089] that looked at the utility of ASCT in the older patient population. They randomized patients to getting lenalidomide/dexamethasone or lenalidomide/dexamethasone induction followed by an ASCT using a lower dose of melphalan for conditioning. [The investigators] demonstrated that ASCT did not seem to add much more benefit in older patients, especially those over 60 years of age.8 I think it brings up the question whether we need transplant upfront for everyone or especially for those people over 65. But randomized clinical trials have not systematically demonstrated a benefit.

This is particularly relevant as we have several new therapies coming in, and we are seeing data from phase 3 trials with nice long-term outcomes from non–transplant-based approaches and combinations. We had updated data from the MAIA study [NCT02252172] that looked at newly-diagnosed patients with myeloma who were not eligible to undergo ASCT. These patients were randomly assigned to getting lenalidomide and dexamethasone versus daratumumab, lenalidomide, and dexamethasone. With up to 5 years follow-up, the median PFS is a little bit over 5 years, which is one of the longest that we have seen in this patient population, and it's also associated with a significant improvement in OS.9 This is this was achieved without any significant increase in the adverse events, with the exception of some increasing hematological toxicity as well as increased risk of infections associated with the use of a 3-drug combination.

What updates have there been in newer classes of immune-targeted therapies?

Bispecific antibodies seem to be a very promising class of drugs. We saw data for elranatamab, which is a BCMA-targeted bispecific antibody, in a heavily pretreated patient population with a median of 5 prior lines of therapy [MagnetisMM-1; NCT03269136]. Nearly 80% of these patients were triple-class refractory, and the response rates were 50% to 60%, depending on the subgroups of patients they're looking at.10 In the subgroup of patients who have previously been exposed to the same targeted agent, it appears to retain efficacy, albeit at a slightly lower level. The toxicity was as predicted, with 60% to 70% of patients with cytokine release syndrome. Fortunately, most of them had grade 1 or 2. There was some hematological toxicity, particularly neutropenia and thrombocytopenia. There was no significant neurological toxicity, but across all bispecifics, we do see a signal for increased risk of infection that needs to be better delineated, especially as we start doing randomized clinical trials.

Given that there's a plethora of anti-BCMA targeted agents, there's a lot of interest in exploring alternate targets. We had the updated data from [the MonumenTAL-1 trial (NCT04634552) of] talquetamab [JNJ-64407564], which is an GPRC5D-targeted bispecific, looking at a large cohort of patients with triple-class refractory disease predominantly, and also patients who have seen multiple lines of therapy. The drug seems to be quite active, with almost a 50% to 60% response rate and also a pretty reasonable durability of response given this patient population.11

In terms of other therapeutics, we saw data from a trial [NCT03215030] of modakafusp alfa (TAK-573), which is an anti-CD38 targeted monoclonal antibody bound to an attenuated interferon, in a very heavily pretreated patient population. There were response rates of about 40% to 50%, especially when you look at subgroups of patients who have previously not been exposed to some of the newer agents, and toxicity appeared to be predominantly hematologic.12

Data were presented on some of the newer therapies, including CELMoD® [agents], which are oral drugs targeting IKZF1 [Ikaros] and IKZF3 [Aiolos], for their anti-myeloma activity. There are promising data from the trial [CC-92480-MM-001 (NCT03374085)], which looked at mezigdomide with dexamethasone. Hopefully, as phase 3 trials look at combinations and move ahead, we will learn more about those.

What unmet needs still exist in the multiple myeloma space as a whole?

There are a lot of questions that still need to be asked: What is the optimal management of high-risk patients? How do we approach patients with significant frailty? How long do we need to continue treatment? Where exactly do we place these immunotherapies, especially the CAR T-cell therapies and bispecifics, with a view of bringing them closer to the earlier stages of the disease? Patients with myeloma continue to relapse, so we need to understand the mechanisms of resistance better, and a lot more needs to be learned about the biology of the disease as a whole.


1. Mateos MV, Martínez-López J, Rodríguez-Otero P, et al. Curative strategy (GEM-CESAR) for high-risk smoldering myeloma (SMM): Post-hoc analysis of sustained undetectable measurable residual disease (MRD). Blood. 2022;140(Supplement 1):292-294. doi:10.1182/blood-2022-159606

2. Kumar SK, Alsina M, Laplant B, et al. Fixed duration therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone for high risk smoldering multiple myeloma-results of the Ascent Trial. Blood. 2022;140(Supplement 1):1830-1832. doi:10.1182/blood-2022-168930

3. Kaiser MF, Hall A, Smith I, et al. Extended intensified post-ASCT Consolidation with daratumumab, bortezomib, lenalidomide and dexamethasone (Dara-VRd) for ultra-high risk (UHiR) newly diagnosed myeloma (NDMM) and primary plasma cell leukemia (pPCL): The UK Optimum/Muknine Trial. Blood. 2022;140(Supplement 1):1833-1835. doi:10.1182/blood-2022-159540

4. Weisel K, Besemer B, Haenel M, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients with high-risk newly diagnosed multiple myeloma: Planned interim analysis of the GMMG-concept trial. Blood. 2022;140(Supplement 1):1836-1838. doi:10.1182/blood-2022-156309

5. Tan C, Nemirovsky D, Derkach A, et al. Carfilzomib, lenalidomide and dexamethasone (KRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) as induction therapy in newly diagnosed high-risk multiple myeloma. Blood. 2022;140(Supplement 1):1817-1819. doi:10.1182/blood-2022-169161

6. Du J, Fu W, Qiang W, et al. Phase I open-label single-arm study of BCMA/CD19 dual-targeting FasTCAR-T cells (GC012F) as first-line therapy for transplant-eligible newly diagnosed high-risk multiple myeloma. Blood. 2022;140(Supplement 1):889-890. doi:10.1182/blood-2022-162295

7. Manier S, Corre J, Hulin C, et al. A dexamethasone sparing-regimen with daratumumab and lenalidomide in frail patients with newly-diagnosed multiple myeloma: Efficacy and safety analysis of the phase 3 IFM2017-03 trial. Blood. 2022;140(Supplement 1):1369-1370. doi:10.1182/blood-2022-159933

8. Straka C, Schaefer-Eckart K, Hertenstein B, et al, Long-term outcome of a prospective randomized trial comparing continuous lenalidomide/dexamethasone with lenalidomide/dexamethasone induction, MEL140 with autologous blood stem cell transplantation and single agent lenalidomide maintenance in patients of age 60-75 years with newly diagnosed multiple myeloma. Blood. 2022;140(Supplement 1):287-288. doi:10.1182/blood-2022-159357

9. Kumar SK, Moreau P, Bahlis NJ, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): Updated analysis of the phase 3 maia study. Blood. 2022;140(Supplement 1):10150-10153. doi:10.1182/blood-2022-163335

10. Raje N, Bahlis NJ, Costello C, et al. Elranatamab, a BCMA targeted T-Cell engaging bispecific antibody, induces durable clinical and molecular responses for patients with relapsed or refractory multiple myeloma. Blood. 2022;140(Supplement 1):388-390. doi:10.1182/blood-2022-166494

11. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C Group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1. Blood. 2022;140(Supplement 1):384-387. doi:10.1182/blood-2022-159707

12. Vogl DT, Atrash S, Holstein SA, et al. Final results from the first-in-human phase 1/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2022;140(Supplement 1):1357-1359. doi:10.1182/blood-2022-162253

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