Novel Agents Highlight Changes in Myeloma Field

Elizabeth “Betsy” O’Donnell, MD

Therapeutic options for the treatment of patients with multiple myeloma (MM) are growing across the spectrum of care, with recent clinical findings shedding new light on the optimal use of combination regimens and paving the way for another generation of novel therapies, according to a panel of experts.

During a recent OncLive Peer Exchange, leading investigators in the MM field discussed the latest clinical trial findings, many of which were presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in June. The wide-ranging discussion featured insights into selecting combination regimens, with and without transplant, for patients with newly diagnosed MM, and the breadth of exciting novel agents in the pipeline in the relapsed/refractory space.

The panelists were most enthusiastic about the prospects for integrating immunotherapeutic options, such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies, into the MM paradigm.

“I think about the time that I’ve been [treating patients with] myeloma, going from transplant, doublets, triplets, and now quadruplets,” Elizabeth “Betsy” O’Donnell, MD, said. “Now we have this whole expansive field of immunotherapy. I am excited for where we are now in terms of the options we have, but I’m even more excited for the future of how we take these tools and really start to cure [patients] and take that next step in the next 5 to 10 years.”

“I’m excited about incorporating some of these novel immunotherapies in a way that we can really start to think about deeply controlling myeloma and talking about fixed-duration therapy,” Susan Bal, MD, said. “That’s an area that is important to patients. They value that and therefore [it should be] important to all of us.”

At the same time, the development of these therapies shows how “complex and unbelievably multifaceted myeloma is,” Joshua Richter, MD, who served as program moderator, said. He encouraged oncologists treating patients in community settings to contact specialists at academic centers to discuss potential options, even if the patient is not referred for care.

The changes that will be necessary are similar to those that have taken place since daratumumab (Darzalex) became the first monoclonal antibody that the FDA approved for MM in 2015,¹ O’Donnell said. Community practices initially referred patients to centers for the first several doses of daratumumab therapy before gaining expertise with the agent.

“There has to be an evolution of practice,” O’Donnell said. “… All these new therapies, [although they are] so exciting, [they] are [also] really the province of academic centers. And that’s a challenge as we develop therapy within myeloma—because we’re making great therapies, but they’re not necessarily accessible to everybody. I do think we have to have an eye on how we [can] get these things back into the community so we have equity and access.”

Newly Diagnosed MM

Although autologous stem cell transplant (ASCT) remains a linchpin of treatment for eligible patients newly diagnosed with symptomatic MM,² there is considerable controversy over when and how to use transplant, O’Donnell said. She noted that the addition of monoclonal antibodies to frontline therapy has resulted in a “tremendous depth of response” in progression-free survival (PFS), although not necessarily in overall survival (OS), prompting some patients to defer transplant.

Natalie S. Callander, MD, sees a continuing role for ASCT, citing PFS findings from the phase 3 DETERMINATION study (NCT01208662) in patients with newly diagnosed MM. The study tested triplet therapy with lenalidomide (Revlimid), an immunomodulatory drug (IMiD); bortezomib (Velcade), a proteasome inhibitor (PI); and dexamethasone, a corticosteroid (RVd) compared with RVd plus ASCT with high-dose melphalan.

The median PFS was 46.2 months among patients who received RVd vs 67.5 months for participants treated with RVd plus ASCT (HR, 1.53; 95% CI, 1.23-1.91; P < .001). For patients with standard-risk MM, the median PFS was 53.2 months with RVd alone vs 82.3 months with RVD plus ASCT (HR, 1.38; 95% CI, 1.07-1.79).³

“There is nothing else out there that has given a PFS that long, particularly in standard-risk patients,” Callander said. “I feel very confident about recommending that to patients. We also would agree that with our high-risk patients, that’s an option we very much want them to consider.”

For patients who are candidates for ASCT, there are multiple induction regimens that clinicians can consider as primary therapy. These include regimens based on the CD38-directed monoclonal antibodies daratumumab and isatuximab-irfc (Sarclisa).⁴

Recently reported data help illuminate regimens for transplant-eligible patients with newly diagnosed MM. The phase 2 GRIFFIN trial (NCT02874742) evaluated the induction combination of daratumumab added to RVd (D-RVd). Investigators presented findings from the final analysis at the 19th International Myeloma Society Annual Meeting in August 2022.⁵

After a median follow-up of 49.6 months, patients who received D-RVd (n = 104) experienced a reduction of 55% in the risk of disease progression or death (HR, 0.45; 95% CI, 0.21-0.95; P = .0324) compared with participants who received RVd (n = 103). The estimated 48-month PFS rates were 87.2% vs 70.0%, respectively.⁵

The GRIFFIN results inform several important factors, Alfred Garfall, MD, said. “There was no safety signal that should make us concerned about adding daratumumab or using a quadbased induction. These patients do get into autologous stem cell collection and transplant. Even though there does seem to be a little bit of a decreased stem cell yield—maybe a little more difficulty collecting—it doesn’t preclude transplant in anybody.

“You might have to hold the daratumumab a little longer to get the stem cells collected, but it’s not going to preclude that transplant option,” Garfall said. “Even though we’re not using this universally for our patients, we’re very comfortable using it when we think we need it in patients we’re worried about. I could easily see this becoming the standard.”

The single-arm phase 2 MASTER trial (NCT03224507) evaluated a quadruplet similar to that used in GRIFFIN, combining daratumumab with carfilzomib (Kyprolis), a different PI, plus lenalidomide and dexamethasone (Dara-KRd) in patients with newly diagnosed MM. Participants received Dara-KRd induction therapy, followed by autologous hematopoietic cell transplantation, and Dara-KRd consolidation, with treatment ending for patients who reached negative minimal residual disease (MRD) in 2 consecutive assessments.⁶

At a median follow-up of 25.1 months, the MRD negativity rate (< 10^–5) in 118 evaluable patients was 80% following transplant, including a 66% rate of patients with an MRD of less than 10^–6. Additionally, the 2-year PFS rate was 87% and the 2-year OS rate was 94%.⁶

“These are very encouraging data for transplant [-eligible patients],” Bal, who is among the study coauthors, said. “Of course, it needs to be carefully weighed against the patient’s preferences and all of the other things we know of [ASCT], but it was great to still see the benefit of alkylators [melphalan] in this setting.”

Nevertheless, the 2-year PFS differed when patients were stratified for the presence of high-risk cytogenetic abnormalities. PFS was 91% and 97%, respectively, for patients with 0 or 1 abnormality but significantly inferior at 58% among participants with 2 or more high-risk factors (P < .001). The trial defined high-risk features as the gain or amplification of 1q21 and t(14;20) or abnormalities in t(4:14), t(14;16), and del(17p).⁶

Callander, who helped design the MASTER study, said that participants with a 1q alteration plus another aberration seemed to have the worst outcomes. “They went into remission, they were MRD negative, but then you start to see them relapse quickly,” she said. “By 1 year, we’re starting to see a sizable amount, and then at almost a 2-year follow-up, [approximately] 60% of them are still in remission or have not undergone progression.”

Findings from MASTER and other studies show that “high-risk patients are still falling out” of remission, Callander added. “This is the area where we’re going to probably be incorporating different agents with different mechanisms,” she said.

Another quadruplet regimen incorporating isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) is being tested in the phase 2 GMMG-CONCEPT trial (NCT03104842) in patients newly diagnosed with high-risk MM. Isa-KRd was administered as induction and consolidation therapy with high-dose melphalan for patients eligible for transplant. High risk is defined as the presence of del(17p), t(4;14), t(14;16), or more than 3 copies of 1q21 in combination with stage II or stage III disease.⁷

Investigators reported findings for 99 participants treated with Isa-KRd who were eligible for transplant and 26 who received the quadruplet but were not transplant candidates during the American Society of Hematology Annual Meeting and Exposition in December 2022.

Patients in both the transplant and nontransplant arms experienced a significant benefit in terms of MRD negativity (P = .0004 and P = .012, respectively). The overall response rate (ORR) among transplant-eligible patients was 94.9%, with a 72.7% rate of complete remission (CR) or better and an 18.2% very good partial response rate. Meanwhile, 57.7% of patients who did not undergo transplant displayed a CR or better and 30.8% had a very good partial response.⁷

“We’ve been early adopters of anti-CD38 monoclonal antibody–based therapy and up-front therapy both for transplant-eligible and -ineligible patients,” Bal said. “Routinely, we are incorporating a monoclonal antibody in our transplant-eligible patients and using it in a quadruplet setting, mostly because the benefit that high-risk patients achieve is certainly worthwhile.”

Bal said that although transplant plays an important role in high-risk patients, those with standard-risk disease also benefit greatly. It is therefore reasonable to offer the option to all eligible patients, she said.

Another option for transplant-ineligible patients with newly diagnosed disease is the combination of daratumumab plus lenalidomide and dexamethasone (D-Rd). This triplet was compared with Rd alone in the phase 3 MAIA trial (NCT02252172).⁸

At a median follow-up of 64.5 months, patients who received D-Rd (n = 368) had a median PFS of 61.9 months vs 34.9 months for participants who received RD (n = 369), which translated into an HR of 0.55 (95% CI, 0.450.67; P < .0001), according to updated findings presented at the ASH meeting. D-Rd therapy also improved OS, with an HR of 0.66 (95% CI, 0.53-0.83; P = .0003).⁸

Additionally, the estimated 60-month OS rates with D-Rd and RD were 66.6% vs 53.6%, respectively, and the ORRs were 92.9% vs 81.6%, respectively (P < .0001). The MRD negativity rates were 32.1% vs 11.1%, respectively (P < .0001).⁸

The MAIA findings provide evidence of a safe, effective regimen that is easy to administer for patients who are truly not eligible for transplant, Garfall said. He and other panelists noted that therapy could be tailored to the needs of the individual patient with the addition of a PI.

Novel Agents in Relapsed/Refractory MM

Bispecific Antibodies

Bispecific antibodies are emerging as an important innovation in MM and other malignancies, Garfall noted. These novel agents join CAR therapies as options that are being introduced in the relapsed/refractory setting.

In October 2022, teclistamab-cqyv (Tecvayli) became the first bispecific antibody to gain FDA approval in MM.⁹ Teclistamab is a T-cellengaging antibody that binds to the CD3 receptor on the surface of T cells and B-cell maturation antigen (BCMA) expressed on the surface of MM cells, as well as some healthy B lineage cells.¹⁰ It is approved for the treatment of adults with relapsed/refractory MM following at least 4 previous lines of treatment including a PI, an IMiD, and an anti-CD38 antibody.⁹

The approval of teclistamab was supported by findings from the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098). Single-agent therapy demonstrated an ORR of 61.8% (95% CI, 52.1%-70.9%), with an estimated duration of response (DOR) rate of 66.5% (95% CI, 38.8%-83.9%) at 9 months.^9,10

Updated findings from the study with extended follow-up were presented during ASCO 2023. At a median follow-up of 22 months, patients who received the recommended phase 2 dose of teclistamab (n = 165) achieved a median DOR of 24 months (95% CI, 16.2-NE), a median PFS of 12.5 months (95% CI, 8.8-17.2), and a median OS of 21.9 months (95% CI, 16.0-NE). Notably, 43% of patients achieved at least a CR, and the median DOR among those who experienced a CR was not yet reached (95% CI, 24.0-NE).¹¹

During the Peer Exchange program, the panelists discussed a case study of a 74-year-old woman with IgAλ MM who was treated with teclistamab after undergoing 4 prior lines of therapy, including 2 PIs, 2 IMiDs, and a monoclonal antibody. She achieved a stringent CR (sCR), but had difficulty battling upper respiratory infection symptoms and COVID-19.

Garfall, who is among the key investigators in MajesTEC-1, said that teclistamab’s efficacy was “remarkable” for a patient refractory to prior therapies, but that the patient faced complications.

“Without teclistamab, we would be thinking about salvage stem cell transplant for this patient in her mid-70s or recycling prior agents, with a real risk of complications and progressive disease,” he said. “She’s been in a complete response now for years. But nonetheless, she did not handle otherwise routine infections well. [She] ended up getting a subsequent superinfection. So the myeloma is under tremendous control, but she’s had some complications.”

Besides teclistamab, several other bispecific antibodies have reached the later stages of clinical development. These include elranatamab (PF-06863135), talquetamab (JNJ-64407564), and linvoseltamab (REGN5458; Table^9,12-14).

Table. Select Bispecific Antibodies in Late-Stage Development in MM^9,12-14

The FDA has granted a priority review for a biologics license application (BLA) for elranatamab, which targets BCMA and CD3, for patients with relapsed/refractory MM; a decision is expected in 2023.¹² A BLA for an indication in a similar setting is pending for talquetamab, a bispecific T-cell engager that targets GPRC5D and CD3.¹³ Meanwhile, a regulatory filing is planned in 2023 for linvoseltamab, which also is directed at BCMA and CD3.¹⁴

Updated findings from pivotal trials involving these agents were presented during the 2023 ASCO meeting. In each study, the bispecifics were administered as monotherapy to patients who had undergone at least 3 prior lines of therapy.

TABLE. Select Bispecific Antibodies in Late-Stage Development in Multiple Myeloma^12-14

In the phase 2 MagnetisMM-3 trial (NCT04649359), patients who received elranatamab (n = 123) exhibited an ORR of 61.0% (95% CI, 51.8%-69.6%), including 35.0% with a CR or sCR after a median follow-up of 14.7 months. The median DOR had not yet been reached and the estimated 15-month DOR rate was 71.5% (95% CI, 58.8%-80.9%).¹⁵

In the phase 2 MonumenTAL-1 study (NCT03399799; NCT04634552),patients who received talquetamab achieved ORRs of 74.1% and 71.7% when treated on a dosing schedule of weekly (n = 143) and once every 2 weeks (n = 145) therapy, respectively. The median DORs were 9.5 months (95% CI, 6.7-13.3) and not reached (95% CI, 13.0-NE), respectively.¹⁶

In the phase 2 LINKER-MM1 trial (NCT03761108), patients who received the agent at the recommended 200-mg dose (n = 117) achieved an ORR of 71%, including a CR rate of 14% and an sCR rate of 16%, at a median follow-up of 5.6 months. The median PFS for patients who received this dose had not yet been reached.¹⁷

Many questions about the use of bispecifics in clinical practice remain unanswered, the Peer Exchange panelists indicated. “We’re going to have to see whether there are some real differences that emerge [between these agents]—probably not so much in terms of response rate, but more administration time and possibly cytokine release syndrome differences,” Callander said. “The biggest issue is going to be the sequencing. Let’s say this patient walks in the door and you have the option to do a bispecific or a CAR T-cell [therapy]. What are you going to do first?”

CAR T-Cell Therapy

Beyond bispecific antibodies, CAR T-cell therapies continue to gain a foothold in the relapsed/refractory MM treatment paradigm. There are 2 FDA-approved CAR T-cell treatments for patients with MM: idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cita-cel; Carvykti).

Ide-cel became the first FDA-approved cellbased gene therapy for MM when the agency gave it the green light for patients who had undergone 4 or more lines of therapy in March 2021.¹⁸ In February 2022, the FDA approved cilta-cel for patients with relapsed/refractory MM following treatment with at least 4 prior lines.¹⁹

Ide-cel was approved based on findings from the phase 2 KarMMa trial (NCT03361748). At the time of ide-cel’s approval, patients in the efficacy population who received the agent (n = 100) experienced an ORR of 72% (95% CI, 62%-81%), with an sCR rate of 28% (95% CI, 19%-38%).¹⁸

Results from the phase 1/2 CARTITUDE-1 trial (NCT03548207) supported the approval of cilta-cel. This trial demonstrated that patients who received cilta-cel (n = 97) experienced an ORR of 97.9% (95% CI, 92.7%-99.7%) including an sCR of 78.4%.¹⁹

Final results from CARTITUDE-1, presented during ASCO 2023, showed that the median PFS was 34.9 months (95% CI, 25.2-NE). The 30- and 36-month PFS rates were 54.2% and 47.5%, respectively.²⁰ Study authors noted that “longer median PFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated patients with relapsed/ refractory [MM].”²⁰ The phase 4 CARTINUE study (NCT05201781) will monitor patients treated with cilta-cel for new safety and survival signals for up to 15 years.²⁰

Differences in clinical trial populations make it difficult to compare response of CAR T-cell therapies with emerging bispecifics, Garfall said. “I would caution against overinterpreting those top-line response rates and think of all these together as remarkable options for patients.”

The next front in CAR T-cell therapy involves moving these agents into earlier lines of MM treatment. During ASCO 2023, investigators presented results from the phase 3 CARTITUDE-4 trial (NCT04181827) in patients with lenalidomide-refractory MM following 1 to 3 prior lines of therapy. The study compared treatment with cilta-cel vs standard of care with pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone.²¹

At a median follow-up of 15.9 months, the median PFS was not reached (95% CI, 22.8-NE) in patients who received the CAR T-cell therapy (n = 208) compared with 11.8 months (95% CI, 9.7-13.8) in patients (n = 211) treated with standard-of-care therapies (HR, 0.26; 95% CI, 0.18-0.38; P < .0001). The 12-month PFS rates were 76% vs 49%, respectively.²¹

Findings from CARTITUDE-4 form the basis for a supplemental BLA for the use of cilta-cel in patients with relapsed and lenalidomide- refractory MM who have received at least 1 prior therapy, including a PI and an IMiD.²²

Another phase 3 study, the KarMMa-3 trial (NCT03651128), is also aiming to test CAR T-cell therapy in earlier treatment lines by comparing the safety and efficacy of ide-cel with that of 5 standard-of-care regimens. The study enrolled patients with relapsed/refractory MM whose disease was refractory to the last regimen and had received 2 to 4 total previous regimens. In all, 386 participants were randomly assigned 2:1 to receive either ide-cel or a standard regimen.²³

At a median follow-up of 18.6 months, the median PFS in the ide-cel arm (n = 254) was 13.3 months (95% CI, 11.8-16.4) vs 4.4 months (95% CI, 3.4-5.9) in the standard regimen arm (HR, 0.49; 95% CI, 0.38-0.65; P < .001). Moreover, the ORRs were 71% (95% CI, 66%-77%) vs 42% (95% CI, 33%-50%), respectively (OR, 3.47; 95% CI, 2.245.39; P < .001), with respective rates of CR or sCR of 39% vs 5%. The safety profile of the CAR T-cell agent was found to be consistent with what had been previously reported.²³

Interim findings from KarMMa-3 support a supplemental BLA that the FDA is reviewing for ide-cel in patients with MM who have relapsed after therapy with an IMiD, a PI, and an anti-CD38 monoclonal antibody. The agency is scheduled to decide on the application by December 16, 2023.²⁴

“There [was some] disappointment that the PFS wasn’t better [in KarMMa-3],” Callander, who participated in the study, said. However, she noted that participants were highly refractory. “Most of them were triple refractory. They had a high incidence of high-risk cytogenetics, so it’s not an accident that the control group did as [poorly] as they did. That sort of indicates where [this population] is. [These results] may give us a very big signal about whether we want to move CAR T[-cell therapies] up as soon as possible.”

Garfall agreed that earlier use of CAR T-cell therapy should be considered for both logistical as well as therapeutic reasons in light of the difficulties inherent in arranging the treatments for heavily relapsed patients. “Even if [CAR T-cell agents] have similar efficacy in the intermediate-relapse setting, there’s still a great case to move them up from a feasibility perspective, because those patients do have a little more time to wait in the 1 to 3 prior lines of therapy ranges compared with [those in] the 4-plus prior lines of therapy range.”

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21. Dhakal B, Yong K, Harrison SJ, et al. First phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 17):LBA106. doi:10.1200/JCO.2023.41.17_suppl.LBA106
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24. Regulatory applications accepted across three regions globally for Abecma for earlier use in adults with triple-class exposed relapsed and/or refractory multiple myeloma. News release. Bristol Myers Squibb. April 17, 2023. Accessed June 25, 2023. https://news.bms.com/news/corporate-financial/2023/Regulatory-Applications-Accepted-Across-Three-Regions-Globally-for-Abecma-for-Earlier-Use-in-Adults-with-Triple-Class-Exposed-Relapsed-andor-Refractory-Multiple-Myeloma/default.aspx