Highlights from ASCO 2019

The MMRF has been on-site at the 2019 American Society of Clinical Oncology (ASCO) meeting in Chicago this week. On Sunday, results from a number of exciting clinical trials of new agents in multiple myeloma were presented; below is a synopsis of the most important findings:

Smoldering Mutiple Myeloma
A trial led by researchers from the Winship Cancer Institute of Emory University and Mayo Clinic, both members of the MMRC clinical network –the MMRC, conducted a large trial to determine whether it was beneficial to treat high risk smoldering myeloma (SMM) patients with Revlimid vs. waiting to treat them until progression, which is the current standard of care for SMM. In this phase 3 trial of 182 pts, the researchers found

  • An overall response rate of 48.9% for the Revlimid arm, with 0% in the observation arm
    The 1, 2, and 3 year PFS was 98%, 93%, and 91% for the Revlimid arm and 89%, 76%, and 66% for the observation arm, with no difference in patient quality of life assessments between arms
  • This is the largest randomized SMM trial to date. In conjunction with previous similar data in a Spanish trial, these findings may support a change in clinical practice from “watchful waiting” to active treatment of SMM. It is important to note, however, the researchers were not able to determine whether there was a positive impact on overall survival due to the limited follow-up of the study. As the data mature, determining whether there is a survival benefit associated with earlier treatment will be critical.

Italian investigators from the University of Torino tested the combination of Kyprolis/Revlimid/dexamethasone (KRd) induction followed by autologous stem cell transplant (ASCT) and KRd consolidation (KRd_ASCT_KRd), against 12 cycles of KRd without transplant, in a trial of 474 newly diagnosed patients. They found

  • These 2 regimens were equally effective in achieving deep responses and MRD negativity in all patients
  • In R-ISS stage 2/3 patients with more advanced disease, KRD_ASCT_KRd reduced the rate of early relapse
    ASCT reduced risk of early relapse in high risk patients
  • These data indicate that, despite the advent of many new and effective therapies available to myeloma patients, such as KRd, ASCT is still an essential treatment, especially for high-risk patients.

Relapsed/Refractory Multiple Myeloma
An international group of researchers, led by a team from the Dana Farber Cancer Institute, which is also a member of the MMRC, reported the results of the Phase 3 ICARIA trial, which tested isatuximab, an anti-CD38 monoclonal antibody in the same class as Darzalex (daratumumab), in combination with Pomalyst and dexamethasone (IsaPd), against Pomalyst and dexamethasone (Pd) in 307 relapsed/refractory myeloma patients. Enrolled patients had failed an average of 3 prior lines of therapy. They found

  • Median progression free survival (PFS), or length of time in remission before disease returned, was 11.5 months with IsaPd vs. 6.5 months with Pd
  • Overall response rate (ORR ) was 60.4% in the IsaPd group vs. 35.3%in the Pd group

The IsaPd combination significantly improved PFS and ORR vs. the Pd combination, and showed a manageable safety profile. IsaPd could become an important new treatment option for RRMM myeloma patients.

An international group of researchers led by a team in Salamanca, Spain and Levine Cancer Institute/Atrium Health, another member of the MMRC, compared Darzalex administered subcutaneously (SC route, injection under the skin) vs. Darzalex administered intravenously (IV route, injection into a vein) in 522 RRMM patients in a Phase 3 trial. The purpose of the study was to determine whether the SC administration was as effective as the IV administration. They found that

  • SC administration maintained at least 89% of the benefit of an IV treatment
  • The effectiveness and metabolism of Darzalex was the same for SC and IV administration, meaning the SC route is not inferior to the IV route
  • The duration of the SC injection was 5 minutes, vs. 7h, 4h, 3h for 1st, 2nd, 3rd IV infusions respectively
  • ORR was unchanged, 41% for the SC route vs. 37% for the IV route
  • PFS was unchanged, 5.6 months for the SC route vs 6.1 months for the IV route
  • Infusion-related reactions occurred in 12%of patients receiving Darzalex SC vs. 35% of patients receiving Darzalex IV.

With a shorter time of infusion, a lower incidence of infusion-related reactions and no change in effectiveness or response rate, the SC administration if approved by the US FDA, will make Darzalex treatments much more convenient for patients, and will decrease time and effort burdens in patients and cancer centers alike.

An international group of researchers led by the Winship Cancer Institute phase 1b/2a data on iberdomide (IBER), a potential new IMiD for myeloma treatment. IBER is a cereblon E3 ligase inhibitor (CELMoD) and has already been shown to overcome IMiD resistance and have synergy with Darzalex, Velcade, and dexamethasone (dex). There were 58 RRMM patients in the study, who had all been treated with at least 2 prior lines of therapy. 66% of these patients had progressed on Darzalex, and 100% had progressed on Revlimid and proteasome inhibitors (Velcade/Kyprolis). They found

  • IBER + dex showed favorable efficacy and safety in heavily pretreated RRMM patients who had failed multiple prior therapies
  • The main side effects were low blood counts, neuropathy, and fatigue

This study is ongoing with combinations of IBER with Darzalex or Velcade. If these initial results are validated in subsequent studies, this new IMiD could become an important new therapy option for myeloma patients.

The final clinical report of the session was from a German group led by the University Hospital of Wurzburg. This was a summary of the first in human study of AMG 420, a bispecific antibody which targets the BCMA molecule on myeloma cells and the CD3 molecule on T cells. By binding to both myeloma cells and T cells, this bispecific antibody brings the two cells close together; this enables the T cell to recognize and kill the myeloma cell.

The study included 42 pts, all of whom were heavily pretreated and had a history of receiving an average of 4 prior lines of therapy. Patients were dosed with a continuous infusion, via a pump, in 6 week cycles. They received an average of 2.6 cycles. The researchers found

  • At the maximal tolerated dose of 400 ug/day (received by 10 patients in the study), there was a 70% response rate
  • Serious side effects were seen in 50% of pts on the study, including infection and neuropathy
  • Responses lasted 5.6 – 10.4 months; however 4 patients are still on therapy, with some responses lasting over 1 year
  • In the 400 ug/day group, the average length of response was 9 months

These highly anticipated results show that bispecific antibodies may become an important therapy choice for heavily pretreated patients who have few treatment options remaining. More studies need to be done to ensure side effects are manageable and patients can receive the drug without having to undergo continuous infusion.