Improving frontline therapies for patients with multiple myeloma

As discussed by Sagar Lonial in the interview above, a key aim for transplant eligible NDMM is to increase the depth of response to frontline therapy in relation to MRD-negativity. To read more about MRD, click here, or watch Mohamad Mohty discuss the value of MRD in myeloma below.

Increasing the depth of response is an approach taken by the CASSIOPEIA and GRIFFIN trials, which are adding daratumumab to established triplet combinations. The phase III CASSIOPEIA is investigating the addition of daratumumab to the traditional triplet of bortezomib, thalidomide, and dexamethasone (dara-VTd). The results showed dara-VTd led to a 53% reduction in the risk of progression or death compared to VTd alone.⁸ Read the full results from part 1 of the trial here. These results led to the U.S. Food & Drug Administration (FDA) approving dara-VTd for patients with NDMM eligible for transplant.⁹ Meanwhile, the GRIFFIN study is investigating daratumumab in combination with bortezomib, lenalidomide, and dexamethasone (dara-VRd) compared to VRd. Recently, it was announced that the study met its primary endpoint with a higher percentage of patients achieving a stringent complete response compared to VRd.¹⁰ Read more here.

To learn more about how high-risk patients with NDMM should be managed after induction, view our interview with Ben Derman below.

Transplant-ineligible patients

By the nature of being ineligible for transplant, patients in this population tend to be older and frailer. They often receive therapies for other underlying conditions and therefore are more susceptible to toxicity associated with polypharmacy. Therefore, finding new treatment options for the frail and elderly is increasingly a focus of myeloma studies. This is also one population that would benefit particularly from novel therapies. Learn more about treating elderly and frail patients here.

For an overview of options for patients with NDMM who are transplant ineligible, watch our interview with steering committee member Paul Richardson below.

The ALCYONE trial is a phase III, randomized clinical trial investigating daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) vs bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible NDMM. The primary analysis revealed a significant PFS benefit with D-VMP vs VMP (HR 0.50; 95% CI, 0.38–0.65; p < 0.001).¹¹ Updated results with a median follow-up of 40.1 months were presented at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Florida, US. D-VMP significantly prolonged OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death vs VMP. There was also a continued significant PFS benefit with D-VMP, which was maintained during the subsequent line of therapy. Moreover, the responses with D-VMP continued to deepen over time, with improvement in rates of complete response (CR) and MRD-negativity.¹² Watch an interview with the study’s primary investigator, María Victoria Mateos, discussing the results below.

With regards to novel therapies for transplant-ineligible NDMM, next generation PIs are being investigated in clinical trials. For example, the multicenter phase II trial, HOVON 143, investigated the efficacy and feasibility of ixazomib (a new PI) plus daratumumab and low-dose dexamethasone in unfit and frail patients. You can watch our interview, discussing the results of the trial, with Sonja Zweegman below.

The phase III MAIA study is another key study in the transplant-ineligible NDMM population. MAIA is comparing daratumumab plus lenalidomide and dexamethasone (dara-Rd) to Rd alone. The second interim analysis showed dara-Rd led to a 44% reduction in the risk of progression or death compared to Rd alone.¹³ Read more about the second interim analysis results from MAIA here.

Other approaches

Chimeric antigen receptor (CAR) T-cell therapies, the topic of our previous educational theme, have been shown to improve outcomes of patients with relapsed and refractory MM. There are two ongoing phase III trials of CAR T-cell products in MM in the relapsed/refractory setting: bb2121 in the KarMMa-3 study and JNJ-4528 in CARTITUDE-4^14,15.  These products are also being investigated in different patient settings; KarMMA-4 will enroll patients with high-risk NDMM and CARTITUDE-2 will enroll four cohorts of patients, including patients with NDMM who have received auto-SCT as frontline therapy.^16,17 Read more here.  

One study, conducted in China, is investigating the efficacy and safety of anti-B-cell maturation antigen and anti-CD19 CAR T cells in combination with auto-SCT in the frontline setting for the treatment of high-risk patients. The preliminary results in ten patients showed a 100% rate of very good clinical response, including 70% CR and manageable toxicity.¹⁸

Watch Chengcheng Fu discuss dual targeted CAR T-cell therapy below.

Next generation PIs, IMiDs, and monoclonal antibodies

Another way of improving the frontline treatment of MM is with the development of new, more efficacious PIs, IMiDs, and monoclonal antibodies. Next-generation PIs, such as carfilzomib, are being incorporated into new combinations, with a potential role in bortezomib-refractory patients or in place of bortezomib. Additionally, new IMiDs, such as pomalidomide, may move to replace the current standard of care agents, such as lenalidomide and thalidomide.

The addition of daratumumab to established combination regimens has led to significant improvements in the treatment of NDMM, as discussed in this article. Other monoclonal antibodies, such as elotuzumab and isatuximab are also being investigated in MM and are approved in some combinations in the relapsed/refractory setting. Ongoing studies will provide evidence for these agents to move forward into the newly diagnosed setting.

• Elotuzumab is approved by the FDA for use in combination with pomalidomide and dexamethasone for patients with relapsed/refractory disease¹⁹
• Isatuximab was also very recently approved by the FDA for use in combination with pomalidomide and dexamethasone in the relapsed/refractory setting²⁰

Conclusion

The clinical development landscape, aiming to improve frontline therapies, is rapidly progressing, with more therapies demonstrating efficacy and gaining approval of relevant regulatory authorities. The clinical trials on CAR T-cell therapies and bispecific antibodies are slowly moving from relapsed and refractory settings into the NDMM. It is likely that transplantation will remain an important option for eligible patients and will be used in combination with novel agents that have a complementary mode of action and target multiple pathways involved in MM pathogenesis.

Many questions are remaining, including the impact of novel therapies on the response to the next-line agents and mechanisms of resistance. Research answering these questions will be intensified but will take time. During March, the MM Hub will be exploring this theme further and bringing you coverage of the latest data and expert opinions on the subject.