Multiple Myeloma (MM) is the 14th-most-common cancer, accounting for approximately 1.8% of all cancers and 17.0% of all hematologic malignancies in the United States.1,2 An estimated 32,110 new myeloma cases will be diagnosed in the United States in 2019, with an estimated 12,960 deaths, which represents 2.1% of all cancer-related deaths. MM is most frequently diagnosed in people aged 65 to 74 years, with a median age of 69 years at diagnosis and a median age of 75 years at death. 

The National Comprehensive Cancer Network MM panel prefers triplet therapy over doublet as the standard of care for all patients because of improved response rates, depth of response, and rates of progression-free survival (PFS) or overall survival.3 The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and a corticosteroid remains the cornerstone of frontline treatment for patients, regardless of eligibility for autologous stem cell transplant (ASCT). As an example, the bortezomib/lenalidomide/dexamethasone regimen is a preferred category 1 recommendation for transplant-eligible and -ineligible patients.

Many agents administered as frontline therapy for patients with MM are used in the relapsed/refractory setting. Choice of therapy is influenced by what was used in the frontline setting, patient comorbidities and organ function, response assessment from prior treatment, tolerability of prior therapy, and time to relapse. Despite numerous treatment combinations, the primary goals of therapy for all patients with MM are disease control, improved quality of life, and prolonged survival. MM remains incurable to date. This article reviews select novel treatments that have recently expanded the therapeutic landscape for patients with MM and highlights others in the pipeline. 

Daratumumab as Frontline Treatment for MM 
Daratumumab (Darzalex), an anti-CD38 monoclonal antibody, was initially approved on November 16, 2015, for the treatment of patients with relapsed/refractory MM.4 The FDA recently approved 2 daratumumab combination regimens as frontline treatment for patients with MM. 

The MAIA trial (NCT02252172), an open-label, randomized (1:1), active-controlled phase 3 study, compared daratumumab 16 mg/kg, in combination with lenalidomide (Revlimid), and low-dose dexamethasone (DRd) with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed MM who were ineligible for ASCT.5 A total of 737 patients were randomized, 368 to the DRd arm and 369 to the Rd arm. MAIA demonstrated an improvement in PFS in the DRd arm compared with the Rd arm. The median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (HR, 0.56; 95% CI, 0.43-0.73; P <.0001), representing a 44% reduction in the risk of disease progression or death in patients treated with DRd. In responders, the median time to response was 1.05 months (range, 0.2-12.1) in the DRd group and 1.05 months (range, 0.3-15.3) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI, 30.8—not estimable [NE]) in the Rd group. In patients with newly diagnosed MM who received DRd, the most frequent (≥20%) adverse ef fects (AEs) were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea, and cough. 

The CASSIOPEIA trial (NCT02541383), an open-label, randomized, active-controlled phase 3 study, compared induction and consolidation treatment with bortezomib, thalidomide, and dexamethasone (DVTd) with treatment with bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed MM who were eligible for ASCT.6 A total of 1085 patients were randomized, 543 to the DVTd arm and 542 to the VTd arm. CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm compared with the VTd arm. At a median follow-up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared with VTd alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). In patients with newly diagnosed MM who received DVTd, the most frequent (≥20%) AEs were infusion reactions, periph eral sensory neuropathy, constipation, asthenia, nausea, peripheral edema, neutropenia, thrombocytopenia, pyrexia, and paresthesia. AEs that occurred with ≥5% frequency in the DVTd arm were infusion reactions, nausea, neutropenia, thrombocytopenia, lymphopenia, and cough. No significant differences were observed in the number or type of serious AEs between the 2 treatment arms. 

Selinexor for Relapsed/Refractory MM 
Selinexor (Xpovio) offers a novel mechanism of action as a first-in-class selective inhibitor of nuclear export 1 (XPO1).7 XPO1 inhibition leads to accumulation of tumor suppressor proteins in the nucleus; reductions in several oncoproteins, such as c‐Myc and cyclin D1; cell cycle arrest; and apoptosis of cancer cells. Selinexor in combination with dexamethasone is indicated for adult patients with relapsed/refractory MM 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 monoclonal antibody.

Investigators evaluated the efficacy of selinexor plus dexamethasone in the STORM trial (NCT02336815), a multicenter, single‐arm, open‐label study.7,8 In STORM part 2, 122 patients were treated with selinexor 80 mg in combination with dexamethasone 20 mg on days 1 and 3 of every week. The overall response rate (ORR) was 25.3% (95% CI, 16.4-36.0), with 1 stringent complete response, no complete responses, 4 very good partial responses, and 16 partial responses. The median time to first response was 4 weeks (range, 1-10). 

The median duration of response was 3.8 months (95% CI, 2.3-NE). Common AEs reported in at least 20% of patients included thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection. 

It is important to note the first dose reduction is administered as 100 mg once weekly, followed by 80 mg and 60 mg once weekly for subsequent reductions.7 Patients should receive antiemetic therapy prior to doses of selinexor. 

Ongoing Clinical Trials 
Investigators continue to evaluate novel drug mechanisms and therapeutic combinations, aiming to optimize treatment outcomes and safety for patients throughout all stages of disease. B-cell maturation antigen (BCMA) targeting has demonstrated efficacy in treating MM.9 Anti-BCMA chimeric antigen receptor T-cell therapies, such as idecabtagene vicleucel, received FDA breakthrough therapy designation for treating relapsed/refractory MM based on data from the phase 1 CRB-401 trial. Antibody-drug conjugates such as belantamab mafodotin have demonstrated an ORR of 60% with a median duration of response >1 year, based on findings from the phase I DREAMM-1 trial.10 

The treatment landscape of MM is extremely bright, with novel agents and combinations in various clinical trial phases. Importantly, clinicians should remain up-to-date on novel therapies to provide optimal and safe therapeutic options for patients in all phases of treatment.


REFERENCES
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
  2. National Cancer Institute. Cancer stat facts: Myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed October 23, 2019.
  3. National Comprehensive Cancer Network. Multiple myeloma (Version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed October 23, 2019.
  4. FDA. Hematology/Oncology (Cancer) Approvals & Safety Notifications; 2019. www.fda.gov. Available from https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Accessed November 10, 2019.
  5. Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380(22):2104-2115.
  6. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38.
  7. Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm; 2019.
  8. 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. 
  9. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380(18):1726-1737.
  10. Trudel S, Lendvai N, Popat R, et al. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study.Blood Cancer J. 2019;9(4):37.