Emerging Options and Sequencing Therapy in Relapsed Multiple Myeloma


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Shaji K. Kumar, MD

Shaji K. Kumar, MD

Advances in the treatment of multiple myeloma have led to longer progression-free survival, but the majority of patients will still relapse despite newer treatments. A number of new drugs and combinations are under study in the hope of improving outcomes.

“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 Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center, Rochester, Minnesota.

At the 2018 National Comprehensive Cancer Network® (NCCN®) Annual Congress: Hematologic Malignancies™, Dr. Kumar discussed five promising classes of drugs that have supportive data.1 Others are in earlier stages of development.

Venetoclax

Venetoclax (Venclexta) is a selective, orally available BCL2 inhibitor approved for the second-line treatment of chronic lymphoid leukemia with a 17p deletion, and the drug is under study in other hematologic malignancies. Experimental data show that single-agent venetoclax can induce cell death in multiple myeloma cell lines and in combination, venetoclax enhances the activity of bortezomib.

In a small clinical trial of 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 a translocation (11;14), the objective response rate was 40%, and 27% achieved a very good partial response or better. Venetoclax led to durable responses, especially among those with the translocation.2 Side effects associated with venetoclax include mild gastrointestinal toxicity, hematologic toxicity, and fatigue.

Update on Therapies for Relapsed Myeloma

  • Drug classes with supportive trial data in relapsed myeloma include BCL2 inhibitors (eg, venetoclax), exportin 1 inhibitors (eg., selinexor), anti-BCMA antibodies, CAR T-cell therapy, and bispecific T-cell engagers.
  • When treating relapsed disease, triplet therapies are often preferred over doublet therapies.
  • Performance status, age, and comorbidities, as well as prior and residual toxicities, should be considered when selecting agents and doses.

The combination of venetoclax and bortezomib was also studied in a phase Ib trial of 66 patients with relapsed or refractory myeloma. In that trial, the objective response rate was 67% in all patients, and in 37 patients whose disease was not refractory to prior bortezomib, the objective response rate was 94%. In those nonrefractory to prior lenalidomide (Revlimid), the objective response rate was 86%.3

In patients with a high expression of BCL2, the objective response rate was 94%. Those with a low BCL2 expression had an objective response rate of 59%. Progression-free survival was longer for those with a high expression of BCL2.

This trial has led to a larger phase III trial. It will compare venetoclax plus bortezomib and dexamethasone vs placebo/bortezomib/dexamethasone in patients with relapsed or refractory disease.

Selinexor 

Selinexor (KPT-330) represents a new class of drugs for the treatment of multiple myeloma; it is a first-in-class inhibitor of exportin 1 and induces apoptosis in cancer cells. In the phase II STORM trial, selinexor plus low-dose dexamethasone was shown to be active in 79 heavily pretreated patients with relapsed or refractory disease (48 refractory to 4 previous drugs and 31, to 5 previous drugs). The objective response rates were 21% in those with disease refractory to 4 previous drugs and 20% in those with disease refractory to 5 previous drugs. The objective response rate in those with high-risk cytogenetics was 35%.

Results suggest [selinexor] may be a good option for patients with limited therapeutic choices. Many responses are durable.
— Shaji K. Kumar, MD

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The most common adverse events were hematologic. Dose interruptions were needed in 52%; dose reductions, in 37%; and 18% discontinued therapy. Adverse events were manageable with supportive care measures.4

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

Multiple studies of selinexor are ongoing. It is being studied in combination with bortezomib and with daratumumab (Darzalex), respectively, and early results are promising, he noted.

Targeting BCMA

“B-cell maturation antigen [BCMA] is uniformly present in multiple myeloma and is becoming an increasingly relevant target,” Dr. Kumar told listeners. The drug GSK2857916 is an anti-BCMA antibody. In preliminary studies, the drug has shown clinical activity, with durable responses. At higher doses, the response rate in patients with refractory disease reaches 67%.5

CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy is now approved for B-cell leukemia and lymphoma. Early results suggest that this approach may turn out to be useful in multiple myeloma. “We have exciting data with CAR T-cell therapy in multiple myeloma,” Dr. Kumar said.

A single infusion of BCMA-targeted CAR T cells in patients pretreated with cyclophosphamide and fludarabine achieved a significant expansion of CAR T cells. This led to the development of bb2121, an anti-BCMA CAR T cell.

In an expansion phase of a phase I study, 44 patients with relapsed or refractory multiple myeloma were enrolled. The median progression-free survival was 11.8 months, and the objective response rate was 95.5%. Of 10 evaluable patients, 9 met the criteria for minimal residual disease. Five patients have had responses lasting longer than 1 year, and responses continue to improve as late as month 15.6

MORE ON MULTIPLE MYELOMA

For more on emerging treatment options for patients with relapsed myeloma, see an interview with Shaji K. Kumar, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.

The phase II KarMMa trial plans to recruit 94 patients and treat them with bb2121. Another CAR T-cell therapy called LCAR-B38M is also undergoing study in multiple myeloma, and there are others in the pipeline. 

Toxicity is a major concern with CAR T-cell therapy, including cytokine-release syndrome and neurologic adverse events. Insertional oncogenesis is a theoretical concern due to which patients may require follow-up for at least 15 years.

Bispecific T-Cell Engagers

“Another exciting platform is bispecific T-cell engagers [BiTEs]. This is an off-the-shelf product, unlike CAR T cells, which take weeks to manufacture,” Dr. Kumar said. Two BiTE agents are in clinical trials: AMG 420 (formerly Bi 836909) and PF-06863135.

Treatment Principles

Dr. Kumar outlined the following general principles for treating relapsed disease:

  • The duration of initial response defines biology.
  • Triplet therapies (two active classes and dexamethasone) are preferred over doublet therapies.
  • At least one drug from a nonrefractory class should be used.
  • Performance status, age, and comorbidity should be considered when selecting agents and doses.
  • Prior and residual toxicities should be taken into account.
  • Patients should be treated to maximal response and maintained on one drug until disease progression or intolerability.

For patients whose disease is not refractory to bortezomib, Dr. Kumar suggested carfilzomib (Kyprolis)/dexamethasone, daratumumab/bortezomib/dexamethasone or panobinostat (Farydak)/bortezomib/dexamethasone, or elotuzumab/bortezomib/dexamethasone. “Four randomized trials show that you can add a drug to bortezomib or replace bortezomib,” he said.

For patients whose disease is not refractory to lenalidomide, clinical trials suggest that carfilzomib/lenalidomide, ixazomid (Ninlaro)/lenalidomide, elotuzumab (Empliciti)/lenalidomide, or daratumumab/lenalidomide, all with dexamethasone, are good options. “For patients who are not refractory to lenalidomide, we want to add a proteasome inhibitor or monoclonal antibody to lenalidomide to improve outcomes,” he said.

First relapse is a little easier to treat because we have new drugs. But second and higher relapses are harder to treat because it is difficult to find drugs the patient has not been exposed to.
— Shaji K. Kumar, MD

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For patients whose disease is not refractory to either lenalidomide or bortezomib, options include bortezomib/lenalidomide/dexamethasone; a repeat of the induction regimen; any of the triplets previously discussed; or the triplet bortezomib, cyclophosphamide, and dexamethasone.

“The most challenging patient is refractory to both lenalidomide and bortezomib,” he continued. The combination of daratumumab/pomalidomide (Pomalyst)/dexamethasone is approved for this indication. About 43% of patients can achieve durable responses with this approach. 

“It is important to change the drug and the class of drug. Also, don’t forget to use salvage high-dose therapy. For the patient who has received a benefit from transplant, consider another transplant,” he told the audience.

“First relapse is a little easier to treat because we have new drugs. We have more choices, and it is important to use combinations. But second and higher relapses are harder to treat because it is difficult to find drugs the patient has not been exposed to,” he noted. “Clinical trials are a good option for these patients.” ■

DISCLOSURE: Dr. Kumar has received clinical research support from Abbott Laboratories, Amgen, Bristol-Myers Squibb, Janssen, Kite Pharma, MedImmune, Merck, Roche Laboratories, sanofi-aventis, and Takeda and has served as a consultant or advisor to Abbott Laboratories, Amgen, Celgene, Janssen, Karyopharm, Kite, Merck, Oncopeptides, Dr. Reddy’s Laboratories, and Takeda.

REFERENCES

1. Kumar SK: Emerging options and sequencing therapies for relapsed multiple myeloma. 2018 NCCN Annual Congress: Hematologic Malignancies. Presented September 22, 2018.

2. Kumar S, Kaufman JL, Gasparetto C, et al: Efficacy of venetoclax as targeted therapy for relapsed/refractory multiple myeloma. Blood 130:2401-2409, 2017.

3. Moreau P, Chanan-Khan AA, Roberts AW, et al: Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. 2016 ASH Annual Meeting. Abstract 975

4. Vogl DT, Dingli D, Cornell RF, et al: Selective inhibition of nuclear export with oral selinexor for the treatment of relapsed or refractory multiple myeloma. J Clin Oncol 36:859-866, 2018.

5. Trudel S, Lendvai N, Popat R, et al: Deep and durable responses in patients with relapsed/refractory multiple myeloma treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen: Preliminary results from part 2 of study BMA117159. 2017 ASH Annual Meeting. Abstract 741.

6. 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. 2018 ASCO Annual Meeting. Abstract 8007.


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