More Novel Therapies Are on the Horizon in Multiple Myeloma

Ajai Chari, MD

When you're an oncologist and clinical trialist who finds yourself at the epicenter of a global health crisis, what do you do? Ajai Chari, MD, professor of medicine and the director of clinical research in the multiple myeloma (MM) program at the Icahn School of Medicine at Mount Sinai in New York, NY, saw an opportunity to contribute from the earliest days of the COVID-19 pandemic.

Even as New York City recorded nearly 25% of US deaths from COVID-19 in spring 2020 and the rest of the world watched in horror as the city set up makeshift morgues in refrigerated trucks,^1,2 Chari spearheaded an international clinical study on behalf of the International Myeloma Society (IMS) to gather the initial data and perform the f irst large-scale analysis of patients with MM who contracted COVID-19.³

Chari’s longtime mentor and colleague Sundar Jagannath, MBBS, director of the Center of Excellence for Multiple Myeloma at Mount Sinai, believes his mentee’s work on this study sums up Chari very well. “It was an honor [that Chari was] chosen to lead the IMS’s study and it shows that he is highly respected and well thought of in the international myeloma community,” Jagannath said. “He is devoted to his patients and his trainees and is extraordinarily detail-oriented in everything he does.”

This fall, Chari will turn that attention to detail to cochairing the 40th Annual CFS^®: Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow®. Physicians’ Education Resource^®, LLC (PER^®) is hosting the 3-day event November 9 to 11 as a hybrid meeting featuring live, interactive presentations in New York, NY, along with a virtual option.

Multiple Myeloma's Changing Landscape

When Chari sat down recently with OncologyLive^® to discuss current trends in therapeutics in MM, he started with a story to illustrate just how quickly the treatment landscape is changing. In 2018, he discussed hospice with a patient with advanced MM refractory to all available therapies and chronic kidney dysfunction that made it difficult to enroll him in nearly all clinical trials. Fortunately, he was able to participate in one study. “Four years later he is in a stringent complete remission and in a bit of an existential crisis because he didn’t think he’d be alive today,” Chari said. “This case highlights the unprecedented pace of myeloma research in the last few years.”

Chari’s patient joined the phase 2 STORM trial (NCT02336815), which evaluated the combination of oral selinexor (Xpovio) plus low-dose dexamethasone in patients with refractory heavily pretreated MM. The patient saw significant clinical improvements, including in his renal function, enabling him to join other clinical trials. When the FDA approved selinexor for patients with MM in 2019,⁴ the patient was able to receive the therapy again in combination with other MM agents. After his disease went into remission again, this patient has now received 2 different T-cell–redirection therapies when those remissions ended.

Chari contrasts the current regulatory environment with that of even a few years ago. “Historically, in multiple myeloma, to receive accelerated approval for a new drug for patients with an unmet need (ie, those who had exhausted all available therapies), you needed a 20% to 30% response rate for 3 to 4 months. Now we have game-changing T-cell–redirecting therapies, such as CAR [chimeric antigen receptor] T-cell therapies and bispecific antibodies,” he explained. “These agents have shown outstanding results, blowing those previous numbers out of the water. T-cell–redirection therapies are now giving anywhere from 60% to 100% response rates that are lasting upward of 9 months to we don’t even know how long, because they’re so durable.”

Moving the Goalposts on Unmet Need

Even as new MM therapies receive approval, areas of unmet need remain. “The definition of unmet need in myeloma is constantly changing as the drugs get better and better, but we have much more work left to do,” Chari said.

Current areas of unmet need include as follows:

• Multidrug-refractory MM
• Extramedullary MM
• MM in frail, elderly patients
• Central nervous system relapse of MM
• Patients with MM with persistent renal dysfunction

Although many of these needs will ultimately be tackled by new therapeutics, sometimes these challenges can be addressed by refining standards of care. This is one of Chari’s particular strengths, said Hearn Jay Cho, MD, PhD, chief medical officer of the Multiple Myeloma Research Foundation and associate professor of medicine at the Icahn School of Medicine at Mount Sinai. He cited a recent phase 2 study (NCT02176213) from Chari and colleagues that examined a regimen combining pomalidomide (Pomalyst), cyclophosphamide, and dexamethasone in patients with relapsed/refractory MM (RRMM).⁵

Chari and colleagues hypothesized that daily dosing of oral cyclophosphamide would yield good results while meshing well with oral formulations of the other 2 drugs. In 33 evaluable patients, the overall response rate (ORR) was 73%, the median progression-free survival (PFS) was 13.3 months (95% CI, 7.9-not reached [NR]) and the median overall survival (OS) was 57.2 months (95% CI, 42.2-NR). The investigators concluded that adding daily cyclophosphamide to the regimen is a cost-effective oral strategy with encouraging PFS. “All-oral treatment options that are well tolerated are especially important for older patients or those who can’t travel to receive care frequently,” Cho said. “This is a great example of Chari applying a creative solution to an unmet need in the myeloma field.”

Since 2010, when Chari and Jagannath joined Mount Sinai, Chari has served as principal investigator on 36 clinical trials and as a co-investigator on 68 additional trials. What’s more, he has developed 6 investigator-initiated clinical trials with a cumulative $4.3-million budget and worked on virtually every recent FDA approval for MM therapies. Chari offered a snapshot of key therapeutic advances in MM, all of which will be discussed at the CFS^® meeting.

T-cell Redirection: CAR T-cell Therapies

One of the most stellar achievements of the past decade in myeloma has been the development of CAR T-cell therapies, in which patients’ own T cells are collected and genetically modified prior to reinfusion. First came idecabtagene vicleucel (ide-cel; Abecma), a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy that received FDA approval in March 2021.⁶

This approval covers adult patients with RRMM who have received 4 or more prior lines of therapy, including an anti-CD38 monoclonal antibody (mAb), a proteasome inhibitor (PI), and an immunomodulatory (IMiD) agent. Approval was based on the phase 2 KarMMa trial (NCT03361748) in which 33% of treated patients had a complete response (CR).⁷ Investigators confirmed minimal residual disease (MRD)negative status in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a CR or better. After a median follow-up of 13.3 months, the ORR among all treated patients was 73% (95% CI, 66%-81%).

In February 2022, the FDA approved ciltacabtagene autoleucel (cilta-cel; Carvykti), also a BCMA-directed CAR T-cell therapy, for patients with RRMM after 4 or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb.⁸ The decision was based on findings from the phase 1/2 CARTITUDE-1 trial (NCT03548207), an open-label, multicenter study that tested the treatment in 97 patients with RRMM. The ORR was 97.9% (95% CI, 92.7%-99.7%). Among 95 responders, the median duration of response (DOR) was not reached.^8,9

“Both ide-cel and cilta-cel have been game-changers for our patients in that they are nearly one-and-done therapies. Patients who used to get continuous therapy indefinitely get this one intervention and then enjoy treatment-free intervals that didn’t seem possible not long ago,” Chari said. “Their success has caught us by surprise because usually patients with myeloma have pretty beat-up immune systems with 5 or 6 years of chemotherapy and transplant behind them, so it’s remarkable that these T cells even work, let alone work this well.”

Chari is mindful of the CAR T-cell therapies’ significant shortcomings, including limited availability from manufacturers, supply chain challenges, and high price tags. “There are newer forms of CAR T cells under development that are looking at shorter manufacturing times [due to] an off-the-shelf design,” he said.

Bispecific Antibodies Gain Attention

Bispecific antibodies are another novel therapy on the horizon in MM. Although no such agents have received FDA approval for MM so far, many therapeutics appear promising. In the MM space, there are at least 12 bispecific antibodies undergoing clinical testing, and additional agents are in preclinical development, Chari and colleagues at Mount Sinai wrote in a recent clinical review in Blood Cancer Discovery.¹⁰ They said this class of drugs likely will become an important addition to the field, particularly for triple-class refractory, heavily treated disease.

Two of these bispecifics, talquetamab (JNJ64407564) and teclistamab (JNJ-64007957), have been in the spotlight at recent conferences. Chari has been instrumental in studies of both therapies.

Talquetamab is an investigational T-cell–redirecting bispecific antibody targeting both GPRC5D, a novel MM target, and CD3, a T-cell receptor. MonumenTAL-1 (NCT03399799), a phase 1 first-in-human dose-escalation study, showed that talquetamab monotherapy administered subcutaneously (sub-Q) evoked high overall responses that deepened over time at 2 different dosing schedules in patients with triple-class and penta-drug refractory disease, according to findings presented at the 2022 American Society of Clinical Oncology Annual Meeting (2022 ASCO).¹¹

With a median follow-up of 13.2 months, the ORR was 70.0% among 30 patients treated with talquetamab at 405 µg/kg weekly, including a very good partial response (VGPR) in 56.7% of participants. The ORR was 63.6%, including a VGPR of 56.8%, among 44 patients who received talquetamab at 800 µg/kg every other week after a median follow-up of 7.7 months. The median DOR was 10.2 months (95% CI, 3.0-not estimable [NE]) among participants who responded to weekly dosing and 13.0 months (95% CI, 5.3-NE) for the biweekly dosing. The most common nonhematologic adverse events (AEs) were cytokine release syndrome (CRS), skin-related AEs, and dysgeusia, mostly of grade 1 or 2 severity. Grade 3/4 AEs included 1 patient with CRS at the weekly dosing level and 1 with skin-related reactions with biweekly dosing.

Talquetamab monotherapy is being evaluated at both dosing levels in the phase 2 multicohort TALMMY1001-PT3 study (NCT04634552), which seeks to enroll an estimated 320 participants with RRMM after 3 or more prior lines of therapy. Additionally, the agent is undergoing testing in combination with other therapies in phase 1 studies.¹¹

Chari also is an investigator on the multicohort phase 1b TRIMM-2 study (NCT04108195) testing daratumumab with hyaluronidase-fihj (Darzalex Faspro), a sub-Q formulation of daratumumab, plus talquetamab or teclistamab with or without pomalidomide (Pomalyst).^12,13

Sub-Q daratumumab is itself a relatively novel form of the anti-CD38 mAb; the FDA initially approved the formulation in May 2020 as monotherapy and in combination for several indications held by the intravenous (IV) form of daratumumab (Darzalex).¹⁴ Teclistamab is a bispecific antibody that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells.¹⁵

During the 2022 European Hematology Association Annual Meeting, investigators presented updated findings for 51 evaluable patients who received talquetamab plus sub-Q daratumumab across dosing levels during TRIMM-2. At a median follow-up of 5.1 months across dosing cohorts, the ORR was 80.4%, including a CR or better in 29.4% and a VGPR or better in 62.7%. Additionally, the ORR was 77.3% among patients (34 of 44) with prior exposure to an anti-CD38 mAb and 72% among participants (18 of 25) with prior BCMA-targeted treatment. The safety profile of the combination was comparable with what has been reported with each agent separately.¹⁶

At 2022 ASCO, investigators reported findings for the TRIMM-2 cohort that received teclistamab plus sub-Q daratumumab. In 51 evaluable patients, the ORRs were 75.0% (15 of 20 patients), 74.1% (20 of 27 patients), and 100% (4 of 4 patients) at teclistamab dosing levels of 1.5 mg/kg weekly, 3 mg/kg biweekly, and 3 mg/kg weekly, respectively. All patients received 1800 mg of sub-Q daratumumab with each cycle.¹⁷

Teclistamab also demonstrated efficacy as monotherapy in the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098), whose results were simultaneously presented at 2022 ASCO and published in the New England Journal of Medicine (NEJM). The ongoing study involves patients with RRMM who have received at least 3 lines of therapy, including an IMiD, a PI, and an anti-CD38 mAb. Patients were treated with a weekly sub-Q injection of teclistamab dosed at 1.5 mg/kg of body weight after receiving 2 step-up doses.^15,18

Among 165 patients who received teclistamab, the ORR was 63.0% (95% CI, 55.2%-70.4%), with 39.4% having a CR or better and 58.8% having a VGPR or better at a median follow-up of 14.1 months. Overall, 26.7% (95% CI, 20.1%34.1%) tested negative for MRD. Among the 65 patients with a CR or better response, the MRD negativity rate was 46.0%. The median DOR was 18.4 months (95% CI, 14.9-NE). The median PFS was 11.3 months (95% CI, 8.8- 17.1). Median OS data were immature.

Getting New Therapies Approved

When it comes to novel therapies for MM, the research team at Mount Sinai has been particularly prolific. “We’ve been involved in almost every single drug that’s been FDA approved in the last 10 to 15 years,” Chari said.

The list includes belantamab mafodotin-blmf (Blenrep), an antibody-drug conjugate directed against BCMA that obtained FDA accelerated approval in August 2020 for patients with RRMM who have received at least 4 prior lines of therapy.¹⁹ The drug was the first approved agent to target BCMA, a cell-surface receptor broadly expressed on MM cells but not on naive and memory B cells. Chari was among the investigators on the pivotal phase 2 DREAMM-2 study (NCT03525678).²⁰

Additionally, Chari was the first author on an article in the NEJM describing the findings of the STORM trial, which paved the way for the FDA’s approval of selinexor in combination with dexamethasone for adults with RRMM who have received at least 4 prior therapies and whose disease is refractory to at least 2 PIs, at least 2 IMiDs, and an anti-CD38 mAb. Selinexor inhibits exportin 1, which enables nuclear export of cargo proteins such as tumor suppressor proteins and is overexpressed in MM.^4,21

Meanwhile, the further development of sub-Q daratumumab also has been on Chari’s radar. Daratumumab is a workhorse of the MM treatment landscape. Initially approved in 2015 as monotherapy for double- or triple-refractory MM after at least 3 prior lines of therapy, the IV formulation of daratumumab now carries multiple indications for relapsed and newly diagnosed disease in combination with other agents such as bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), and pomalidomide.²²

The sub-Q formulation of daratumumab requires shorter administration time—3 to 5 minutes compared with 7 hours for the first infusion of IV daratumumab, and with 3 to 4 hours for subsequent cycles—according to findings from the COLUMBA trial (NCT03277105). Clinical outcomes with the sub-Q version were noninferior to those with the IV format and there were fewer infusion-related reactions.²³

Chari and colleagues demonstrated the efficacy of sub-Q daratumumab in several standard-of-care MM combination regimens in the phase 2 PLEIADES trial (NCT03412565).²⁴ The study findings formed the basis for the FDA’s approval of 3 indications for combination regimens incorporating the sub-Q format: with bortezomib, melphalan, and prednisone in patients with newly diagnosed MM who are ineligible for transplant; with lenalidomide/ dexamethasone for RRMM; and with carfilzomib/dexamethasone in RRMM.²⁵

“The PLEIADES study looked at various daratumumab combinations in the subcutaneous formulation,” Chari said. “Key takeaways were that subcutaneous daratumumab has efficacy and pharmacokinetics comparable with what you would expect based on monotherapy and IV combinations of the respective agents.”

One Size Doesn't Fit All: Debating the Role of Transplant

The plethora of novel therapies that have been introduced to the MM treatment paradigm in recent years has ignited debate about the future role of autologous stem cell transplant (ASCT).

Findings from the phase 3 MAIA study (NCT02252172) in patients with newly diagnosed MM who were not eligible for ASCT demonstrated that the addition of IV daratumumab to lenalidomide plus dexamethasone resulted in superior outcomes compared with a lenalidomide/dexamethasone combination.²⁶

After a median follow-up of 56 months, the median PFS among patients who received daratumumab (n = 368) was not reached (95% CI, 54.8-NR) compared with 34.4 months (95% CI, 29.6-39.2) in participants (n = 369) treated with lenalidomide/dexamethasone alone (HR, 0.53; 95% CI, 0.43-0.66; P < .0001). Median OS was not reached in either group. The median age of participants was 73 years (range, 70-78) in the daratumumab-containing arm and 74 years (range, 70-78) in the control arm.²⁶

Chari said the MAIA findings, published in Lancet Oncology in October 2021, represent a noteworthy advancement for older patients with MM. “The problem with older patients in particular is that they don’t always get to the umpteenth line of therapy,” Chari said. “Sometimes you get 1 or 2 shots [at effective treatment].”

A median PFS not reached with nearly 5 years of follow-up for those who received daratumumab in MAIA is “amazing, considering this is without ASCT in an older MM population,” Chari said.

More recently, the MM community has been dissecting findings from the phase 3 DETERMINATION trial (NCT01208662), whose results were simultaneously presented at 2022 ASCO and published in the NEJM.^27,28 This trial explored the question of whether ASCT improves outcomes for patients with newly diagnosed MM who are eligible for transplant and receive triple induction therapy with lenalidomide, bortezomib, and dexamethasone (RVd).

Investigators randomized patients (n = 357) to treatment with RVd for 2 to 3 cycles followed by RVd for 4 to 8 cycles or RVd plus melphalan and ASCT (n = 365) followed by RVd for 4 to 5 cycles. All patients were eligible for lenalidomide maintenance therapy until progression. The median age of patients was 57 years (range, 25-66) in the RVd-alone arm and 55 years (range, 30-65) in the RVd plus ASCT arm.

After a median follow-up of 76.0 months, the median PFS was significantly shorter in patients who received RVd alone at 46.2 months (95% CI, 38.1-53.7) than among participants treated with RVd plus ASCT at 67.5 months (95% CI, 58.6-NR). The risk of disease progression or death was 53% higher among those who did not receive ASCT (HR, 1.53; 95% CI, 1.23-1.91; P < .0001). However, 5-year OS, a key secondary end point, was similar between the 2 arms (HR, 1.10; adjusted 95% CI, 0.73-1.65; P = .99).

Chari expects the debate about the clinical utility of ASCT to continue for the foreseeable future. “On the one hand, transplant is integral in the improvement of outcomes in patients with myeloma, especially globally, because it’s a relatively cost-effective standard,” he said.

The benefit, however, favors younger patients, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. “If you look at Medicare SEER data, the patients whose survival has improved most are not the frail, older elderly, but the younger patients [who can tolerate transplant],” Chari said.

“Does transplant still have a role with all these amazing therapies?” Chari continued. “Many people want OS as a primary end point, but it’s nearly impossible to do that in large, randomized studies, given the innumerable and also ever-increasing number of salvage therapy options as well as the prohibitively long follow-up time that would be required for a disease where the median OS for some patients with MM is more than 10 years. So, there’s this constant back-and-forth about the role of transplant, especially in newly diagnosed patients.”

For his part, Chari remains dedicated to exploring ways to improve outcomes for patients with MM through better use of existing regimens and the development of novel therapies. “What’s more gratifying than seeing people who are alive and in complete remission for years beyond where they thought they would be? You have patients who are bedridden or bed-bound and within a few months are back to their pre-myeloma quality of life because the therapeutics are so effective, and symptoms of myeloma can be so rapidly reversed. It’s really gratifying.”

References

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14. FDA approves daratumumab and hyaluronidase-fihj with pomalidomide and dexamethasone for multiple myeloma. FDA. May 1, 2020. Accessed June 13, 2022. https://bit.ly/3Qg4lO5 
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17. Rodríguez-Otero P, D’Souza A, Reece DE, et al. A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma (RRMM): updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody). J Clin Oncol. 2022;40(suppl 16):8032. doi:10.1200/JCO.2022.40.16_suppl.8032
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19. FDA granted accelerated approval to belantamabmafodotin-blmf for multiple myeloma. FDA. August 6, 2020. Accessed June 7, 2022. https://bit.ly/39jWTk9 
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21. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455
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24. Chari A, Rodriguez-Otero P, McCarthy H, et al. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label phase II study. Br J Haematol. 2021;192(5):869-878.doi:10.1111/bjh.16980
25. DarzalexFaspro. Prescribing information. Janssen Biotech;2022. Accessed June 14, 2022. https://bit.ly/3xM1aoX
26. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/ S1470-2045(21)00466-6
27. Richardson PG, Jacobus SJ, Weller E, et al. Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): the phase 3 DETERMINATION trial. J Clin Oncol. 2022;40(suppl 17): LBA4.doi:10.1200/JCO.2022.40.17_suppl.LBA4
28. Richardson PG, Jacobus SJ, Weller E, et al; DETERMINATION Investigators.Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. Published online June 5, 2022.doi:10.1056/NEJMoa2204925