New Treatment Options for Patients with Relapsed Multiple Myeloma

Phoebe Starr

October 2018, Vol 9, No 3 - Drug Updates, Multiple Myeloma


Thanks to advances over the past decade, patients with multiple myeloma have experienced improved progression-free survival (PFS). However, because multiple myeloma is characterized by genetic heterogeneity, and evolving clones continue to outwit therapy, the disease will relapse in most patients after responding to newer treatments.

Shaji K. Kumar, MD, Division of Hematology, Mayo Clinic Cancer Center, Rochester, MN, discussed 5 promising classes of drugs for the treatment of relapsed multiple myeloma at the 2018 National Comprehensive Cancer Network Hematologic Malignancies Congress.

“Multiple myeloma is a complex disease characterized by multiple clones that continue to evolve. In fact, most patients die of clones that are barely visible at diagnosis. This highlights why we need new drugs for multiple myeloma,” explained Dr Kumar.

Targeting B-Cell Maturation Antigen

“B-cell maturation antigen [BCMA] is uniformly present in multiple myeloma and is becoming an increasingly relevant target,” Dr Kumar suggested.

The investigational drug GSK­2857916 is an anti-BCMA antibody. In preliminary studies, the drug showed excellent clinical activity in multiple myeloma, with deep and durable responses. In the phase 1 clinical trial DREAMM-1, which was reported at the 2017 American Society of Hematology meeting, the response rate in patients with relapsed or refractory multiple myeloma was 60%, with a median PFS of 7.9 months. More than 50% of the patients had received ≥5 lines of treatment.1

“Some of the responses were quite durable, lasting several months,” he pointed out.

CAR T-Cell Therapies

“We have exciting data with bb2121 anti-BCMA CAR T-cell therapy in multiple myeloma,” Dr Kumar said.

The investigational agent bb2121 was successfully manufactured in 18 patients in a phase 2 clinical trial. In an expansion phase of a phase 1 clinical trial of 44 patients with relapsed or refractory multiple myeloma, the median PFS was 11.8 months and the objective response rate was 95.5%. Of 10 evaluable patients, 9 met the criteria for minimal residual disease. A total of 5 patients have had responses lasting longer than 1 year, and the responses continue to improve as late as month 15.2

The phase 2 KarMMa clinical trial will recruit 94 patients who will receive bb2121.

Another novel CAR T-cell therapy in development that targets BCMA is LCAR-B38M, which has achieved durable and deep responses in patients with multiple myeloma. Other CAR T-cell therapies that target BCMA and use different vectors and co-stimulatory molecules are also in development.

Toxicity continues to be a major concern with CAR T-cell therapy, including cytokine-release syndrome and neurologic toxicity. Dr Kumar said that insertional oncogenesis is a possibility; he suggested that patients who receive CAR T-cell therapy should be followed for at least 15 years.

Bispecific T-Cell Engagers

“Another exciting platform is bispecific T-cell engagers [BiTE]. This is an off-the-shelf product, unlike CAR T-cell, which takes weeks to manufacture,” Dr Kumar said.

“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is ready-made off the shelf, which is not patient-specific, is quite attractive,” he emphasized.

The 2 BiTE agents that are in clinical trials are AMG 420 and PF-06863135.

Venetoclax

Venetoclax (Venclexta) is currently in clinical trials of multiple myeloma. Dr Kumar was the lead investigator of a study of venetoclax being investigated in 66 patients with relapsed or refractory multiple myeloma. The objective response rate was 21%, and 15% of patients achieved a very good partial response or better. In patients with translocation (11;14), the objective response rate was 40%, and 27% achieved a very good partial response or better.3

The combination of venetoclax plus bortezomib (Velcade) and dexamethasone has also achieved encouraging responses, including in patients with disease that was not refractory to previous therapy with bortezomib or to treatment with lenalidomide (objective response rates of 94% and 86%, respectively).4

A phase 3 clinical trial will compare venetoclax plus bortezomib and dexamethasone with bortezomib plus dexamethasone and placebo in patients with relapsed or refractory multiple myeloma, according to Dr Kumar.

Selinexor

Dr Kumar discussed selinexor, a first-in-class oral, selective inhibitor of exportin 1 that induces apoptosis in cancer cells. In the phase 2 clinical trial, STORM, selinexor plus low-dose dexamethasone achieved encouraging responses in 79 heavily pretreated patients with relapsed or refractory multiple myeloma—this included 48 patients with disease that is refractory to 4 previous drugs and 31 patients with disease that is refractory to 5 previous drugs.5

“Results suggest this will be a good option for patients with limited therapeutic choices. Many responses are durable,” Dr Kumar said.

Several clinical trials with selinexor, in combination with other agents for multiple myeloma, are ongoing.


References

  1. Trudel S, Lendvai N, Popat R, et al. Deep and durable responses in patients (pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. Blood. 2017;130:741.
  2. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-­BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. Presented at the American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL.
  3. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401-2409.
  4. Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Blood. 2016;128:975.
  5. Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:859-866.