Multiple Myeloma Paradigm Moves Forward With Promising Portfolio

There was no shortage of exciting developments at the 2020 ASCO Virtual Scientific Program in multiple myeloma, according to Peter Voorhees, MD, member of the Plasma Cell Disorders Division and director of Outreach and Medical Operations for the Department of Hematology Oncology and Blood Disorders at Levine Cancer Institute, Atrium Health. He explained all of the pivotal data in myeloma therapeutics in a virtual presentation during the 2020 ASCO Direct Highlights^TM webcast, a program developed by Physicians’ Education Resource^®(PER^®), LLC.

Newly Diagnosed Disease

Proteasome inhibitors have been an important component of treatment in multiple myeloma for over a decade, said Voorhees. In the phase 3 ENDEAVOR trial,^1,2 investigators showed that carfilzomib (Kyprolis), in particular, conferred a large advantage in progression-free survival (PFS) and overall survival (OS) in combination with dexamethasone (Kd; n = 464) versus bortezomib (Velcade; Vd; n = 465) and dexamethasone in patients who had received 1 to 3 prior lines of therapy.

The results, which showed a median PFS of 18.7 months and 9.4 months and a median OS of 47.6 months and 40.0 months in the Kd and Vd arms, respectively, engendered a lot of interest in evaluating carfilzomib in the frontline setting, said Voorhees.

As such, the phase 3 ENDURANCE trial3 was designed to evaluate the addition of carfilzomib versus bortezomib to lenalidomide (Revlimid) and dexamethasone in patients with newly diagnosed disease. In the trial, patients received 36 weeks of induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) or bortezomib, lenalidomide, and dexamethasone (VRd). Following induction, patients received lenalidomide maintenance for 2 years or until unacceptable toxicity.

No statistically significant difference was reported with regard to overall response rate (ORR; P = .132) or complete response (CR) rate (P = .261). Although investigators reported an improvement in the depth of response among patients who achieved a very good partial response (VGPR) or better in the KRd arm (P = .002), this did not translate to an improvement in median PFS. At a median follow-up of 15 months, the median PFS was 34.6 months in the KRd arm versus 34.4 months in the VRd arm (HR, 1.04; 95% CI, 0.83-1.31; P = .742).

The OS curves were essentially superimposable, said Voorhees, with 3-year probabilities of 86% in the KRd arm versus 86% in the VRd arm.

As expected, KRd resulted in a higher incidence of grade 3 or higher cardiac, pulmonary, and renal adverse effects (AEs) versus VRd (16.1%. vs 4.8%, respectively), whereas VRd led to a higher rate of peripheral neuropathy compared with KRd (8% vs 0.8%, respectively).

“RVd remains an important standard of care in standard-risk, newly diagnosed multiple myeloma,” said Voorhees. “There is more neuropathy with RVd and more vascular toxicity with KRd. It’s important that therapy be guided by comorbidities and patient preference after you discuss these important differences [with your patients].”

Early Relapse

A number of phase 3 studies have been done to define the optimal therapy in the early relapse setting wherein patients have received 1 to 3 prior lines of therapy, said Voorhees. Several of these studies evaluated lenalidomide and dexamethasone-based triplet therapy, whether with ixazomib (Ninlaro), elotuzumab (Empliciti), carfilzomib, or daratumumab (Darzalex).

However, in the United States, the standard practice is to give lenalidomide in the frontline setting until disease progression or the emergence of unacceptable toxicity as it is associated with an improvement in median PFS, said Voorhees, who added that indefinite lenalidomide maintenance following autologous stem cell transplant (ASCT) has also shown an OS benefit.

As such, non–lenalidomide-based treatment regimens are needed. To that end, investigators launched the phase 3 BOSTON trial4, which evaluated weekly selinexor (Xpovio), bortezomib, and dexamethasone versus twice-weekly Vd in patients who had received 1 to 3 prior lines of therapy. Patients in the control arm received Vd twice weekly for the first 8 cycles followed by weekly dosing thereafter.

Selinexor is one of the latest agents to receive regulatory approval in multiple myeloma. In July 2019, the FDA approved the XPO1 inhibitor for use in combination with dexamethasone for patients with penta-refractory disease.

The results indicated that the selinexor arm outperformed the Vd arm in terms of ORR (76.4% vs 62.3%), CR rate (16.9% vs 10.6%), and VGPR or better rate (44.6% vs 32.4%), respectively. The median duration of response was also improved, at 20.3 months versus 12.9 months, respectively. The regimen translated to a 30% reduction in the risk of disease progression or death versus Vd (HR, 0.70; P = .0075).

However, the approximate 4-month gain in median PFS was met with additional hematologic toxicity, explained Voorhees. In particular, 39.5% of patients in the selinexor arm experienced grade 3 or higher thrombocytopenia versus 17.2% in the Vd arm. The rate of grade 3 or higher anemia and neutropenia were also higher in the selinexor arm, said Voorhees.

Although investigators reported less neuropathy in the selinexor arm, constitutional toxicity, such as asthenia and fatigue, as well as gastrointestinal toxicity, such as nausea, vomiting, and diarrhea—leading to decreased appetite and weight loss—occurred in higher frequency and severity in the selinexor arm.

On May 20, 2020, Karyopharm Therapeutics Inc., the developer of selinexor, submitted a supplemental new drug application to the FDA for the use of selinexor as a treatment for patients with multiple myeloma following at least 1 line of prior therapy, based on findings from the BOSTON trial.⁵

“Selinexor, bortezomib, and dexamethasone represents a new standard of care for patients with early relapsed multiple myeloma,” said Voorhees. “It’s an immunomodulatory drug (IMiD)-free regimen, so this is something that could be considered in a patient with IMiD-resistant or -intolerant disease.”

Late Relapse

Once patients develop disease that is refractory to CD38-directed monoclonal antibodies, a proteasome inhibitor, and an IMiD, they have an approximate median OS of 9 months. BCMA-directed treatments, which have been explored by way of CAR T-cell therapy, antibody-drug conjugates, and bispecific T-cell engagers, represent a lifeline for these patients, explained Voorhees.

BCMA is expressed exclusively on late memory B cells that are committed to plasma cells and plasma cell differentiation.

Idecabtagene vicleucel (ide-cel; bb2121) is among one of the many BCMA-targeted strategies under investigation. The CAR T-cell therapy was evaluated in the phase 2 KarMMa study6 in patients with relapsed/refractory disease. As of January 2020, 158 patients had been screened, 140 had undergone leukapheresis, and 128 were treated across target dose levels of 150 to 450 x 106 CAR T cells.

Patients had received a median of 6 prior lines of therapy. The majority of patients had undergone prior ASCT, and 84% were triple refractory.

The results demonstrated a best ORR and CRs, reaching 82% and 39%, respectively, at the highest dose level. The median PFS was 12.1 months at the 450 x 106 dose, mirroring what was seen in the phase 1 KarMMa trial, said Voorhees. Among patients who achieved CR/stringent CR, the median PFS was 20.2 months. OS, though immature at the time of the analysis, was 19.4 months.

On March 31, 2020, a biologics license application (BLA) was submitted to the FDA for ide-cel for patients with multiple myeloma who have received at least 3 prior therapies, including an IMiD, a proteasome inhibitor and an anti-CD38 antibody, supported by data from the KarMMA trial.⁷ In May 2020, the FDA issued a Refusal to File letter to the developers of the BCMA-directed CAR T-cell therapy, concluding that additional information was needed for the Chemistry, Manufacturing and Control module of the BLA.⁸

In terms of AEs across target dose levels, the majority of patients developed hematologic toxicity, which was attributed to the lymphodepleting chemotherapy and the cell therapy, said Voorhees.

“This is very promising data in a group of patients that’s incredibly hard to treat,” said Voorhees. “To see responses, PFS, and OS, of those magnitudes is really quite striking. To date, we haven’t seen a tail on the PFS curve, but the median PFS is far longer than any agent that has been tested in this patient population.”

However, the logistics of administration and potential for CRS and neurotoxicity have inspired alternative ways of delivering BCMA-directed therapy, explained Voorhees.

One such product that was developed in that regard is the BCMA x CD3 bispecific antibody, teclistamab. In a phase 1 study,⁹ the drug was given in 1 to 3 doses in a stepwise fashion in week minus 1, followed by weekly therapy in a 3-week cycle. 

Voorhees noted that patients had received a median of 6 prior lines of therapy, and the majority were either triple-class refractory (80%) or refractory to their last line of therapy (86%), a nearly identical patient population as that of the KarMMa trial.

Among evaluable patients in the 0.3 to 19.2 μg/kg (n = 12), 38.4 to 180 μg/kg (n = 44), and the 270 μg/kg (n = 12) cohorts, the ORRs were 0%, 30%, and 67%, respectively. Voorhees noted that half of the patients in the third cohort achieved a VGFR or better.

Hematologic toxicity, though present, was not as prominent compared with BCMA-directed CAR T-cell therapy, said Voorhees. The rate of grade 3 or higher CRS was 0%, and neurologic events were reported in 6 patients, 2 of which were grade 3 or higher.

“The early data are very promising, and this is incredibly important because this is an off-the- shelf option as opposed to CAR T-cell therapy,” said Voorhees. “It is important to note that while the severity of CRS and neurotoxicity appears to be higher with the CAR T-cell therapy products, [these AEs] remain a concern with bispecific antibody therapy.”

Waldenström Macroglobulinemia

Of note in Waldenström macroglobulinemia were the results of the phase 3 ASPEN trial,10 explained Voorhees. In the trial, patients with newly diagnosed or relapsed/refractory disease were randomized to receive zanubrutinib (Brukinsa), a potent and selective BTK inhibitor, or the first-generation BTK inhibitor ibrutinib (Imbruvica).

“The ORRs, PFS, and OS were very similar,” said Voorhees. “However, the toxicity profile of zanubrutinib was clearly better with less atrial fibrillation, less hypertension, and less edema and bleeding complications,” concluded Voorhees.

References

1. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. doi:10.1016/S1470-2045(15)00464-7
2. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327-1337. doi:10.1016/S1470-2045(17)30578-8
3. Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl 18):LBA3. doi:10.1200/JCO/2020.38.18_suppl.LBA3
4. Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: initial results of the phase III BOSTON study. J Clin Oncol. 2020;38(suppl 15):8501. doi:10.1200/JCO.2020.38.15_suppl.8501
5. Karyopharm Submits Supplemental New Drug Application to FDA for XPOVIO® (selinexor) as a Treatment for Patients with Multiple Myeloma After At Least One Prior Line of Therapy. Published May 20, 2020. https://yhoo.it/2XfYvBj. Accessed June 24, 2020.
6. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
7. Bristol Myers Squibb and bluebird bio announce submission of biologics license application (BLA) for anti-BCMA CAR T cell therapy idecabtagene vicleucel (Ide-cel, bb2121) to FDA. Published March 31, 2020. https://bit.ly/2UtAxm6. Accessed June 24, 2020.
8. Bristol Myers Squibb and bluebird bio Provide Regulatory Update on Idecabtagene Vicleucel (ide-cel, bb2121) for the Treatment of Patients with Multiple Myeloma. Published May 13, 2020. https://bit.ly/3bA5n1T. Accessed June 24, 2020.
9. Usmani SZ, Mateos MV, Nahi H, et al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2020;38(suppl 15):100. doi:10.1200/JCO.2020.38.15_suppl.100
10. Tam C, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenstrom macroglobulinemia (WM). J Clin Oncol. 2020;38(suppl 15):8007.