Table 1.
Agents approved in the United States.
| Agent/Class/Regulatory Approval(s) | Efficacy Data for Approval |
|---|---|
| Immunomodulatory Drugs (Thalidomide and its analogues) | |
| Thalidomide (Thalomid®) | |
| 2006 - For the treatment of patients with newly diagnosed multiple myeloma (NDMM) | Approval based on two RCTs:
|
| Lenalidomide (Revlimid®) | |
| 2006 - first indication. For the treatment adult patients with diagnosis of MM in combination with dexamethasone in patients who have received one, or more, prior therapies |
|
| 2015 - For the treatment of patients with NDMM in combination with dexamethasone for patients who are not eligible for autoHSCT. | FIRST trial in which 1,623 patients, who had received at least one prior therapy, were randomized to receive either Revlimid® with dexamethasone (Rd) given continuously for 18 months, or to melphalan, prednisone, and thalidomide (MPT). OS improved in the continuous Rd arm to 58.9 months versus 48.5 months with MPT. PFS was slightly superior at 25.5 months versus 21.1 months. OS at four years was 59% with continuous Rd versus 51% with MPT. [98] |
| 2017 - For use in maintenance for patients with MM following auto HSCST | Revlimid® was approved as first maintenance therapy for patients with MM following autologous hematopoietic stem cell transplant (auto-HSCST) based on 3 RCTs comparing Revlimid® to placebo, Revlimid® provided a 15 to 18-month survival advantage in PFS across trials. [99, 100, 101] |
| Pomalidomide (Pomalyst®) | |
| 2013 - For patients with RRMM in combination with dexamethasone who have progressed after receiving at least two prior therapies including Revlimid® and a proteasome inhibitor (PI). |
|
| Proteasome Inhibitors | |
| Bortezomib (Velcade®) | |
| 2003 - For RRMM patients who have received at least 2 prior therapies | Based on the results of the single arm SUMMIT trial that enrolled 202 patients (188 evaluable) after at least 2 prior therapies who were not considered candidates for high-dose therapy. The primary endpoint ORR was 28%. [32] |
| 2005 - For RRMM patients who have received 1 prior therapy | Approval based on a phase 2 RCT comparing Velcade® to dexamethasone in 669 patients who had received 1-3 prior therapies. The improvement in median time to progression (TTP) 6.2 vs. 3.5 months, OS (25 vs 15 deaths) and ORR (38% vs 18%) were all statistically significant. Velcade® was administered intravenously in this trial. [104] |
| 2008 - MM patients who are treatment naïve | Approval based on the VISTA trial which randomized 682 patients to receive Velcade®, melphalan, prednisone (VMp) versus Mp alone. The primary efficacy endpoint was time TTP which was 24 months for the Velcade® arm versus 16 months with Mp. ORR was 71% versus 35% and median duration of response was 19.9 vs 13.1 months. Velcade was administered IV in this study as well. [30] |
| 2012 - Subcutaneous (SC) approval | Subcutaneous approval was based on results of a phase 3 non-inferiority study comparing the two formulations. The trial enrolled 2922 patients receiving front-line therapy and demonstrated similar ORRs of 43% (IV) and 42% (SC)) with a reduction in peripheral neuropathy from 53% (IV) to 38% (SC). [33] |
| Carfilzomib (Kyprolis®) | |
| 2012 - Monotherapy for treatment of patients with RRMM who had received at least 2 prior therapies that included bortezomib and an IMiD and were deemed refractory to their last therapy | Kryprolis induced an ORR of 52% in patients who had not received bortezomib, and 20% in those who were bortezomib-refractory. [35] |
| 2015 - For patients with RRMM who had received one to 3 prior therapies in combination with Revlimid and Dexamethasone | Approval based on a multicenter phase 3 trial (ASPIRE) that enrolled 792 patients with RRMM who had received 1-3 prior therapies. Patients were randomized to the treatment arm of Kyprolis® + Revlimid® + dexamethasone (KRd) or the active control arm of Rd. KRd demonstrated superior response rates and deeper responses. [92] |
| 2020 - For the treatment of adult patients with RRMM who have received one to three lines of therapy in combination with daratumumab and dexamethasone. | Approval based on the CANDOR trial which enrolled 466 patients and compared the combination of Darzelex® + Kyprolis® + dexamethasone (DKd) to Kd and demonstrated improvement in PFS for those receiving DKd. ORRs were 84% and 75% in the DKd and Kd arms, respectively. [105] |
| Ixazomib (Ninlaro®) | |
| 2015 - For the treatment of patients with RRMM, in combination with Revlimid® and dexamethasone, who have received at least one prior therapy. Oral Agent. | The approval of Ninlaro® was based on the results of TOURMALINE-MM1, a RCT with 722 patients who received the combination of Ninlaro® + Revlimid + dexamethasone (NRd), compared to placebo, + Revlimid® and dexamethasone (Rd). The treatment arm containing Ninlaro® achieved a statistically significant improvement in PFS of 20.6 months versus 14.7 months. [40] |
| Monoclonal Antibodies | |
| Daratumumab (Darzelex®) | |
| 2015 – Monotherapy for patients with MM who have received at least three prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD. | The SIRIUS trial supported the approval of Darzelex® as monotherapy in patients who had received at least 3 prior therapies including a PI and an IMiD. The study achieved an overall response rate of 29.2%. [14] |
| 2016 – Combination with Revlimid® and dexamethasone (DRd) for RRMM who have received one prior therapy | The POLLUX study demonstrated an improvement in PFS in patients receiving DRd compared to those receiving Rd. The trial, conducted in 569 patients who had at least one prior treatment, reported a 63% reduction in the risk of disease progression or death in patients treated with DRd. [106] |
| 2016 - Combination with Velcade® and dexamethasone (DVd) for the treatment of patients with MM who have received at least one prior therapy | Approval based on the CASTOR trial, a phase 3 RTC that enrolled 498 patients and demonstrated improvement in PFS in those receiving DVd. [107] |
| 2017 - Combination with pomalidomide and dexamethasone for the treatment of patients with MM who have received at least two prior therapies including Revlimid and a PI. | A multicohort study, EQUULEUS, enrolled 103 patients to receive the combination of Darzelex® + pomalidomide + dexamethasone (DPd). ORR was 59.2%. [43] |
| 2017 - Combination with bortezomib, melphalan, and prednisone for the treatment of patients with NDMM who are ineligible for ASCT. | The ALCYONE RCT compared the combination of Darzelex® + Velcade® + melphalan and Ppednisone (D-VMP) in NDMM patients not eligible for transplant to VMP. PFS in the D-VMP arm was 71.6% versus 50.2% (MVP). The rate of infections was significantly higher in the D-MVP arm, with 23.1% grade ≥3 infections compared to 14.7% in patients who did not receive daratumumab. [108] |
| 2019 - Combination with Revlimid® and dexamethasone in NDMM patients who are ineligible for ASCT. | Approval based on the MAIA trial that compared the combination of Darzelex® + Revlimid® + dexamethasone (DRd) to Rd in 737 patients, and demonstrated significantly longer PFS, and higher and longer response rates in patients receiving DRd. [109] |
| 2019 - Combination with bortezomib, thalidomide, and dexamethasone for NDMM in patients who are eligible for ASCT. | Approval base on the CASSIOPEIA RCT that compared the combination of Darzelex® + Velcade® + thalidomide + dexamethasone (DVTd) with VTd for NDMM. The trial enrolled 1085 patients and demonstrated a superior ORR and PFS with DVTd. [110] |
| 2020 - Combination with carfilzomib and dexamethasone in MM patients who had received one to three prior lines of therapy. |
|
| Elotumumab (Emplicity®) | |
| 2015 - Combination with Revlimid® and dexamethasone (ERd) for patients with RRMM who have received one to three prior therapies | This combination was evaluated in the ELOQUENT-2 trial which demonstrated the triplet therapy to have a median OS of 48 months compared to 40 months in the Revlimid® + dexamethasone (Rd) arm. The ORR was 79% in the ERd arm compared to 66% in the Rd arm.[48] |
| Isatuximab (Sarclisa®) | |
| 2020 - Combination with pomalidomide and dexamethasone, for the treatment of adult patient with MM who have received at least 2 prior therapies including Revlimid and a PI. | Sarclisa® was approved based on efficacy and safety data in the ICARIA-MM trial. ICARIA was a phase 3 RCT that enrolled 307 patients randomized to receive isatuximab + pomalidomide + low-dose dexamethasone (Isa-Pd) or pomalidomide + low-dose dexamethasone (Pd). Efficacy was based on PFS which was improved in the Isa-Pd arm with a 40% reduction in risk of disease progression or death. Median PFS was 11.53 months and ORR was 60.4% with Isa-Pd versus 6.47 months and 35.3% in the Pd arm. [49] |
| Histone Deacetylase Inhibitors | |
| Panobinostat (Farydak®) | |
| 2015 - For the treatment of patients with RRMM who have received at least two prior regimens that included both bortezomib, and an immunomodulatory agent [Note: Farydak® was withdrawn in the United States in 2021 but remains available in other countries where approval had been granted] | Approval based on PANORAMA 1, a multicenter, phase-3 trial, that enrolled 768 patients who had received a median of two prior therapies and been treated with both bortezomib and an IMiD. Patients were randomized to receive Farydak® + bortezomib + dexamethasone (treatment arm) or bortezomib + dexamethasone (placebo arm). Median PFS was 11.99 months in the treatment arm, versus 8.08 months in the placebo arm. ORR was similar between groups (60.7% versus 54.6%). CR was significantly higher in the Farydak® containing arm (27.6% versus 15.7%) as was median DOR (13.14 versus 10.87 months) for patients who achieved a partial response or greater. [51] |
| Nuclear Export Inhibitor | |
| Selinexor (Xpovio®) | |
| 2019 - For the treatment of patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two IMiDs, and an anti-CD38 monoclonal antibody. | Approval was based on results of the STORM trial, which was a multicenter, single arm, phase 2 study that enrolled 122 patients with RRMM. The treatment regimen consisted of Xpovio® 80 mg orally with 20 mg of dexamethasone on days 1 and 3 of each week. For the 83 evaluable patients, ORR was 25.3%, with 1 stringent CR. Medan DOR was 4.4 months, median PFS was 3.7 months, and median OS was 8.6 months. [13] |
| B-Cell Maturation Antigen | |
| Belantamab mafodotin (Blenrep®) | |
| 2020 - For the treatment of patients with multiply relapsed MM after at least four prior therapies including an anti-CD 38 monoclonal antibody, a proteasome inhibitor and an IMiD. | Approval of Blenrep® was based on the DREAMM-1 and 2 trials that enrolled patients with RRMM. DREAMM-1 was the phase 1 study, that identified the phase 2 dose of 3.4 mg/kg in part 1. Part 2 demonstrated an ORR of 60% with a PFS of 7.9 months, with Blenrep® administered IV every three weeks for a maximum of 16 cycles. [59] To determine if a lower dose would be feasible, DREAMM-2 enrolled 196 patients randomized to receive either 2.5 mg/kg or 3.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. In the 2.5 mg/kg group (the approved dose), ORR was 31%, with 2% achieving a stringent CR versus 34% of patients in the 3.4 mg/kg arm. |
Abbreviations: CR, complete response; DOR, duration of response; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression free survival; RCT, randomized control trial; RRMM, relapsed refractory multiple myeloma; TTP, time to progression.