The incidence of multiple myeloma is estimated to be more than 63,000 patients in 2018 in the G7 countries1 and is incurable with current treatment options. For newly diagnosed multiple myeloma patients, treatment usually follows two paths. For young and fit patients, induction therapy followed by stem cell transplantation (SCT) is the preferred treatment, since it offers the best possibility for long term control. Because of the morbidity and mortality associated with SCT, elderly or unfit patients will usually receive systemic therapy alone without SCT. Approximately 40% to 50% of U.S. and Western European patients are eligible for transplants2, leaving the remaining 50% to 60% of patients dependent on systemic therapy (the rate of transplant-ineligibility is less in Japan, approximately one-quarter of patients2).
Traditionally, immunomodulatory agents (IMiDs) and proteasome inhibitors have been the pillars of treatment. Recently, there has been significant advances in the treatment of multiple myeloma with new agents that have novel mechanisms of actions as well as next generation IMiDs and proteasome inhibitors. These advances have led to durable responses; however, relapse is still an expected result, and 5-year survival rates are only around 45-50%1,3.
One new agent of interest is Darzalex® (daratumumab, Genmab / Janssen). Darzalex is a human monoclonal antibody directed against CD38, which is highly expressed on the surface of multiple myeloma cells. Darzalex targets and mediates destruction of CD38 expressing cells. This agent has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis4. Darzalex was first approved as a monotherapy in fourth-line, and has since gained approval in combination with RevDex [Revlimid® (lenalidomide, Celgene), dexamethasone], VelDex [Velcade® (bortezomib, Janssen), dexamethasone], and PomDex [Pomalyst® (Imnovid in Europe; pomalidomide, Celgene), dexamethasone] in relapsed / refractory patients, and has also recently received FDA approval for use in combination with VMP (Velcade, melphalan, and prednisone) in newly-diagnosed transplant-ineligible patients. Based on these approvals, Darzalex combinations receive good utilization in the relapsed / refractory setting, with about 25% utilization in second-line and about 35% in third-line2, and utilization in early lines growing based on influence of recent approvals. There are currently several ongoing trials in newly diagnosed multiple myeloma (both transplant-eligible and transplant ineligible) seeking to further expand the label for Darzalex.
The MAIA trial (NCT02252172), which combines Darzalex with RevDex (D-Rd), is one clinical trial of interest. Initiation of MAIA is supported by results from the POLLUX trial (NCT02076009) in the relapsed / refractory setting which showed that D-Rd significantly improved progression-free survival (PFS) compared to RevDex alone (44.5 months for D-Rd compared to a median PFS of 17.5 months in the RevDex arm; HR 0.44; p<0.0001)5.
The global MAIA trial is a phase III, randomized, open-label trial in newly diagnosed multiple myeloma patients who are not candidates for high dose chemotherapy or for a SCT. A total of 737 patients were randomized 1:1 to receive either D-Rd or Rd (both at standard dosing) and did so until disease progression or unacceptable toxicity. The trial primary endpoint is progression free survival (PFS). Secondary endpoints include overall response rate (ORR), complete response (CR) rate, minimal residual disease (MRD) negativity rate, duration of response (DOR), and overall survival (OS).
Interim results from the MAIA trial were presented at the American Society of Hematology (ASH) annual meeting on Tuesday, December 5, 20186. The addition of Darzalex reduced the risk of progression or death by an impressive 44% (median PFS for the D-Rd arm was not reached versus 31.9 months for the Rd arm (HR 0.56; p<0.0001). The experimental arm also produced significant (p<0.0001) increases in the CR rate (48% versus 25%) and the very good partial response (VGPR) rate or better (79% versus 53%). More patients in the D-Rd arm achieved MRD negativity compared to the Rd arm (25% versus 7%). At the time data was collected, only 19% of patients had died, but there is a slight trend to OS benefit favoring D-Rd (HR of 0.78).
The safety profile of the MAIA trial was very similar to other clinical trials of Darzalex. In general, the D-Rd arm had more treatment-emergent neutropenia compared to the Rd arm (any grades 57% versus 42%; Grade 3/4 50% versus 35%). Pneumonia was also increased in the experimental arm (23% any grade and 14% Grade 3/4) compared with the control arm (13% any grade and 8% Grade 3/4). As expected with Darzalex, the D-Rd arm had an increased rate of infusion-related reactions (41% any grade and 3% grade 3/4). Importantly, there was no difference between the arms in rates of secondary primary malignancies or death from TEAEs.
The future of Darzalex in multiple myeloma is promising. Darzalex combinations already have good utilization in the relapsed / refractory setting and physicians have embraced it whole-heartedly. Although the ALCYONE trial has already supported the approval of Darzalex in newly-diagnosed transplant-ineligible multiple myeloma, in combination with VMP regimen, the direct impact of that trial / approval has been muted (especially in the U.S.) because the VMP regimen is not commonly used. The positive results from the MAIA trial continue to support the use of Darzalex in newly-diagnosed multiple myeloma and specifically provide data for its use in combination with a regimen that more closely resembles the U.S. standard of care (SOC). As such D-Rd has the potential to establish itself as the new SOC for newly diagnosed transplant-ineligible patients.
Even with a positive outlook for the trial, there are still some questions that remain to be answered. One key question is how D-Rd compares with the RVD regimen (Revlimid, Velcade, dexamethasone), which has become the predominant induction regimen for these patients in the U.S. and Japan in recent years2. Head-to-head data for these two regimens is not available, so limited to the typical caveats of a cross-trial comparison, the data appears to favor D-Rd; the MAIA trial suggests higher ORR and longer PFS achieved with the D-Rd regimen than was reported for the RVD regimen in the SWOG-0777 trial7. D-Rd also appears more tolerable than the RVD regimen (which had increased incidence of neurologic and vascular toxicities compared to Rd alone7). Together, the efficacy and safety comparisons suggest that D-Rd could displace RVD as the preferred standard of care in this setting.
Another key question is the impact of Darzalex use in first-line on treatment of relapsed / refractory disease (where it is commonly used currently). Will physicians be willing to use Darzalex combinations across multiple lines of therapy, and simply change the combination partner? Although there is no data for this in myeloma, the concept of treatment across multiple lines of therapy exists in myeloma (with Revlimid and Velcade often used multiple times) and with various monoclonal antibodies in indications such as breast, colorectal, and lymphomas2. Would any physicians contemplate using RVD in the first-line setting and save Darzalex combinations for the relapsed / refractory setting? Given the PFS results from MAIA it seems very likely that it will be used in first-line, but there is still a chance it will be saved for later lines.
Darzalex is aiming for control of the whole front-line population (eligible and ineligible), with other trials ongoing. Part 1 of the Cassiopeia trial (NCT02541383) which combines Darzalex with Velcade, Thalidomide, and Dexamethasone (VTD) in newly-diagnosed transplant-eligible patients has met its primary endpoint of increasing the rate of stringent CR (sCR) compared to VTD alone (28.9% in the experimental arm versus 20.3% in the control arm, p≤ 0.001)8, although the impact of this study could be limited to Europe where VTD is more commonly used2. Additionally, the ongoing AQUILA trial (NCT03301220) is exploring a role for Darzalex in smoldering myeloma9. The success of the MAIA trial, along with all the other cosmic-themed Darzalex trials, strongly positions Darzalex to become the backbone regimen onto which other agents are added (and new combinations are compared) in multiple myeloma.
- Kantar Health, CancerMPact®, Patient Metrics, accessed December 1, 2018. Available at www.cancermpact.com
- Kantar Health, CancerMPact®, Treatment Architecture, accessed December 1, 2018. Available at www.cancermpact.com
- Krejcik J, Casneuf T, Nijhof IS, et al.; “Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma;” Blood 128(3): 384-394, 2016.
- Bahlis N, Dimopoulos M, White D, et al., “Three-Year Follow up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (RD) Alone in Relapsed or Refractory Multiple Myeloma (RRMM);” Abs 1996, ASH 2018.
- Facon T, Kumar SK, Plesner T, et al., “Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA)”; Abstract LBA-2, ASH 2018.
- Durie B, Hoering A, Abidi M, et al.; "Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial;" Lancet, 389(10068): 519-527, 2017.
- Genmab press release, October 21, 2018