General MM,   Patients non-eligible for transplant,  Patients eligible for transplant

Improving frontline therapies for patients with multiple myeloma

The next educational theme on the Multiple Myeloma (MM) Hub is “Improvements in the frontline treatment of MM.” MM is a heterogeneous disease that, in the majority of cases, evolves from asymptomatic pre-malignant monoclonal gammopathy into a hematologic malignancy, where an individual patient’s prognosis is influenced by multiple factors.1

The prognosis for patients with MM has significantly improved in recent years as immunomodulatory drugs (IMiDs®), proteasome inhibitors (PIs), and, more recently, monoclonal antibodies have been incorporated into first-line treatment regimens. The median survival in MM is approximately 6 years but is lower in older patients, those with high tumor burden, and/or high-risk cytogenetics.1,2 The recommended treatment of newly diagnosed MM (NDMM) depends on patient risk group and eligibility for stem cell transplant (SCT).

Combinations of novel agents with different, often complementary, mechanisms of action are already available and new ones are being evaluated in clinical trials. Such combinations aim to increase anti-tumor activity and depth of response while lowering off-target toxicity.

This month, through a series of articles, the MM Hub will take a closer look at strategies to improve frontline therapies for MM. This article will provide an overview of the relevant articles and video interviews that have previously been covered. 

Transplantation

Frontline treatment of MM is dictated by transplant eligibility. Autologous SCT (auto-SCT) is more commonly used in MM, though allogeneic SCT (allo-SCT) may have a role in specific settings.3,4

Auto-SCT is the recommended first-line treatment for patients with MM who are ≤ 65 years and fit. To read more about the relationship between auto-SCT and chemotherapy, the impact of age on a successful outcome, optimal induction, conditioning and consolidation regimens, as well as the best strategy for stem cell mobilization, click here.

In the newly diagnosed setting, allo-SCT is not recommended as a standard of care. Young, fit patients with NDMM however may be considered for allo-SCT in the clinical trial setting.3 Read more about allo-SCT in MM here.

The MM Hub previously featured transplantation as a monthly educational theme; click here to learn more.

Frontline therapy for NDMM

Induction therapies for NDMM have changed over time with the advent of novel agents, such as PIs, IMiDs, and monoclonal antibodies. You can read a summary of commonly used induction regimens here and through the links below to learn more about some of the studies seeking to improve the efficacy and depth of response to frontline therapy.

LYRA (MMY2012, NCT02951819), a single-arm, open-label, multicenter, phase II study, investigated whether the addition of daratumumab, an anti-CD38 monoclonal antibody, to VCd (D-VCd) would improve outcomes in patients with NDMM and relapsed MM. The study also looked at the effect of administering the first dose of daratumumab as a split dose.5 The D-VCd regimen had manageable toxicity and, at the end of induction, induced overall response rates (ORR) in patients with NDMM of 81.4% (85) and a 12-month OS of 98.8%. More details about the study and the results are available here.

Upfront combination of carfilzomib (K), a PI, with immunomodulatory lenalidomide (R), and dexamethasone (d; KRd), with or without auto-SCT in patients with NDMM, was investigated in the FORTE trial. The results demonstrated that KRd-auto-SCT-KRd and KRd12 induced high response rates and minimal residual disease (MRD)-negativity. Auto-SCT proved to be beneficial in high-risk patients, reducing the risk of early relapse and leading to an approximate MRD-negativity rate of 50%.6 We spoke to Francesca Gay, University of Turin, Turin, IT, about the impact of the FORTE results on clinical practice. Watch the video below.

In a recently published phase I/II study NCT02002598, the triplet combination of carfilzomib, bendamustine, and dexamethasone (CBD) was found to have promising activity as frontline treatment in both transplant-eligible and ineligible patients. This is significant, as the combination does not involve using an IMiD, meaning IMiDs may be able to be saved for use in the relapse setting.7 Learn more here.

Transplant-eligible patients

There have recently been several significant advances in the frontline setting for transplant-eligible patients. We spoke to our co-chair, Sagar Lonial, about some of the highlights from the recent American Society of Hematology (ASH) meeting for this patient population (see below).

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-414,15.  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.

References
  1. Rajkumar V. Multiple myeloma: 2018 update on diagnosis, risk‐stratification, and management. Am J Hematol. 2018 Aug 16; 93(8):1091–1110. DOI: 10.1002/ajh.25117
  2. Durie B.G.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. 2017 Feb 4; 389(10068):519–527. DOI: 10.1016/S0140-6736(16)31594-X
  3. Mina R. & Lonial S. Is there still a role for stem cell transplantation in multiple myeloma? Cancer. 2019 Apr 15; 125(15):2534–2543. DOI: 10.1002/cncr.32060
  4. Al Hamed R. et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019 Apr 08; 9(4):44 DOI: 10.1038/s41408-019-0205-9
  5. Yimer H. et al. Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study. Brit. J Haem. 2019 March 03; 185(3):492–502. DOI: 10.1111/bjh.15806
  6. Gay F. et al. Carfilzomib, lenalidomide and dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma (FORTE trial) efficacy according to risk status. 2019 Jun. Abstract #S872: 24th European Hematology Association Annual Meeting, Amsterdam, NL
  7. Leng S. et al. Phase I/II study of carfilzomib, bendamustine, and dexamethasone (CBD) in patients with newly diagnosed multiple myeloma. Blood Cancer J. 2020 Feb 3; 10(2):13. DOI: 10.1038/s41408-020-0278-5
  8. Moreau P. et al. Phase 3 randomized study of daratumumab + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible newly diagnosed multiple myeloma: CASSIOPEIA Part 1 results. 2019 Jun 2. Abstract #8003: American Society of Clinical Oncology meeting 2019, Chicago, US
  9. Healio. FDA approves Darzalex-based combination for first-line multiple myeloma treatment. https://www.healio.com/hematology-oncology/myeloma/news/online/%7Bd8139b99-2bbd-4a55-8d27-10549d392456%7D/fda-approves-darzalex-based-combination-for-first-line-multiple-myeloma-treatment. Published 2019 Sep 26. [Accessed 2020 Mar 06]
  10. Genmab. Genmab announces positive topline results in the phase II GRIFFIN study of transplant eligible, newly diagnosed patients with multiple myeloma treated with daratumumab in combination with lenalidomide, bortezomib, and dexamethasone.https://ir.genmab.com/news-releases/news-release-details/genmab-announces-positive-topline-results-phase-ii-griffin-study. Published 2019 Jul 8. [Accessed 2020 Mar 06]
  11. Mateos M.V. et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8; 378(6):518–528. DOI: 10.1056/NEJMoa1714678
  12. Mateos M.V. et al. Daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in patients with transplant-ineligible newly diagnosed multiple myeloma: overall survival in Alcyone. 2019 Dec 9. Oral Abstract #859: ASH 61st Annual Meeting & Exposition, Florida, US
  13. Facon T. et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Eng J Med. 2019 May 30; 380(22):2104–2115. DOI: 10.1056/NEJMoa1817249
  14. Clinicaltrials.gov. Efficacy and safety study of bb2121 versus standard triplet regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3).https://clinicaltrials.gov/ct2/show/NCT03651128. Published 2018 Aug 29. [Accessed 2020 Mar 06]
  15. Clinicaltrials.gov. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE-4). https://clinicaltrials.gov/ct2/show/NCT04181827. Updated 2020 Mar 6. [Accessed 2020 Mar 06]
  16. Clinicaltrials.gov. A study to evaluate the safety of bb2121 in subjects with high risk, newly diagnosed multiple myeloma (NDMM) (KarMMa-4) (KarMMa-4).https://clinicaltrials.gov/ct2/show/NCT04196491. Updated 2020 Feb 18. [Accessed 2020 Mar 06]
  17. Clinicaltrials.gov. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in participants with multiple myeloma (CARTITUDE-2). https://clinicaltrials.gov/ct2/show/NCT04133636. Updated 2020 Feb 28. [Accessed 2020 Mar 06]
  18. Shi X. et al. Tandem auto-SCT and combined infusion of CD19 and BCMA-specific CART cells for high risk MM. 2019 Mar 27. Abstract OS12-1: 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
  19. Targeted Oncology. Elotuzumab Triplet Approved by FDA for Treatment of Myeloma.https://www.targetedonc.com/news/elotuzumab-triplet-approved-by-fda-for-treatment-of-myeloma. Published 2018 Nov 6. [Assessed 2020 Mar 06]
  20. U.S. Food & Drug Administration. FDA approves new therapy for patients with previously treated multiple myeloma.https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-patients-previously-treated-multiple-myeloma Published 2020 Mar 2. [Accessed 2020 Mar 6]
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