Combinations Mark Future of Immunotherapy in Multiple Myeloma

Kenneth C. Anderson, MD

Novel immunotherapeutic strategies will redefine multiple myeloma treatment, but these new approaches must be used in combination if patients are to achieve cures, according to Kenneth C. Anderson, MD, a leading expert in the malignancy who has been at the forefront of research for nearly 30 years.

“In the future, we’re going to do combination therapies. They will be used in a subset of patients better defined by profiling,” Anderson said. “If we’re going to have long-term disease-free survival—cure—we have to get minimal residual disease (MRD) negativity with our targeted therapies, and then we need to restore host immunity. We need to have no disease, and we need to have patients off therapy. Quality of life is just as important as having no disease.”

Anderson provided an overview of emerging developments involving monoclonal antibodies, immunomodulatory drugs (iMiDs), immunotoxins, bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies during a presentation at the Charlotte Plasma Cell Disorder Congress, held in North Carolina in August. He is the program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute and the Kraft Family Professor of Medicine at Harvard Medical School, both in Boston, and a 2014 Giant of Cancer Care^® award winner in multiple myeloma.

With 24 agents approved in myeloma, median survival has improved significantly, from 3 years to at least 8 to 10 years today, according to Anderson. With these advances, multiple myeloma has become more of a chronic illness for many patients, he added.

Vaccines Make a Comeback

In the future, immunologic-based interventions, such as vaccines, will be used early on in order to delete abnormal clones in precursor conditions that often lead to the development of myeloma, predicted Anderson. Currently, in smoldering myeloma, vaccine cocktails composed of immunogenic HLA-A2—specific XBP1, CD138, and CS1 peptides are being tested to induce multiple myeloma–specific and HLA-restricted cytotoxic T-lymphocyte responses.

“If you immune vaccinate with a cocktail of peptides you could get immune responses in all the patients we vaccinate, but I believe we need to use combinations. Therefore, we went on to add lenalidomide [Revlimid] to those vaccinations to augment these immune responses,” said Anderson. “This vaccine works just like any other vaccine that you might give for tetanus or the flu. You can actually mount in patients a central memory immune response against their own tumor.”

Prognostication Based on Immune Microenvironment Key

In addition to early immunization, Anderson predicts that the capability to prognosticate based on the immune microenvironment will be available in the not-too-distant future. Studying the microenvironment can reveal patterns responsible for clonal evolution within the myeloma cell and, subsequently, disease progression. Single-cell sequencing can detect active or inactive cells correlated with progression. Detecting patients with clonal evolution could allow for abnormal clones to be deleted at a very early stage, added Anderson.

“I believe we will have 2 categories. One may be called early multiple myeloma, where the tumor and the microenvironment show progression without clone evolution, and in my opinion, we’re going to treat [that] as early multiple myeloma,” explained Anderson. “In contrast, in those patients who have a tumor and bone marrow profile, patients who have clonal evolution with a longer time, we will call [that] monoclonal gammopathy of undetermined significance. In those patients, we will use IMiD-based interventions.”

Managing Newly Diagnosed Disease

Transplant-Eligible

In terms of the initial management of transplant-eligible patients with multiple myeloma, there are 3 preferred regimens: lenalidomide, bortezomib (Velcade), and dexamethasone (RVd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). However, quadruplet regimens will eventually become the standard, said Anderson.

“In the area of immunotherapies, triplets such as RVd will be supplemented by monoclonal antibodies—daratumumab [Darzalex] in particular—in transplant candidates,” Anderson added, based on data from the phase II GRIFFIN trial.¹ Updated results from the study showed that the addition of daratumumab to RVd induced a stringent complete response (sCR) rate of 42.4% versus 32.0% with RVd alone (odds ratio, 1.57; 95% CI, 0.87-2.82; P = .1359); this exceeded the statistical significance at a prespecified 2-side alpha level of 0.2. Additional data will be reported at an upcoming medical meeting.

Meanwhile, in September 2019, the FDA approved daratumumab in combination with bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) for patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

The decision was based on results from the phase III CASSIOPEIA (MMY3006) study, in which the sCR rate at postconsolidation therapy was 28.9% in patients who received the daratumumab regimen compared with 20.3% in those who received VTd alone following consolidation therapy (P = .0010). Treatment with the daratumumab regimen resulted in a reduction in the risk of progression or death by 53% compared with VTd alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001).²

Transplant-Ineligible

For newly diagnosed patients who are ineligible for transplant, the use of triplet regimens at attenuated dosing schedules is preferred. Doublets such as bortezomib and dexamethasone or lenalidomide and dexamethasone are often used in frail patients. Maintenance lenalidomide is used in standard-risk patients, while bortezomib with or without lenalidomide is often used in those who are high risk. Again, however, quadruplet regimens, such as “RVd lite” with or without daratumumab or a newer monoclonal antibody, isatuximab, will likely become standard.

Data from a phase I study presented at the 2018 American Society of Hematology Annual Meeting showed that isatuximab, when given upfront with RVd in transplant-ineligible patients with newly diagnosed myeloma, showed an overall response rate (ORR) of 100%; very good partial response or better was achieved in 92% of efficacy-evaluable patients.³ Moreover, 44% of MRD-evaluable patients achieved MRD negativity.

Managing Relapsed/Refractory Disease

In the relapsed setting, several monoclonal antibodies are available to use in combination. “We’re so lucky in myeloma. We have an armamentarium to choose from and we can consider, what has been the prior exposure? What are the factors in the patient that might inform the best treatment?” said Anderson. “I’ll just remind you that when we use antibodies in relapsed myeloma, there are often durable responses.”

For example, elotuzumab (Empliciti) in combination with lenalidomide and dexamethasone showed a median overall survival advantage over lenalidomide/dexamethasone alone in patients with relapsed/refractory (R/R) disease at 4 years (48.3 months vs 39.6 months; HR, 0.78; 95% CI, 0.63-0.96).⁴ The combination has also demonstrated a 46% reduction in the risk of progression or death when including patients resistant to lenalidomide and bortezomib.⁵

Another combination, daratumumab plus lenalidomide/dexamethasone, induced deeper responses than lenalidomide/dexamethasone alone in patients with relapsed disease, according to updated data from the phase III POLLUX trial.⁶ The daratumumab triplet was also associated with longer progression-free survival (PFS), said Anderson.

Lastly, data from the phase III ICARIA-MM trial showed that isatuximab in combination with pomalidomide (Pomalyst) and low-dose dexamethasone led to >40% reduction in the risk of disease progression or death compared with pomalidomide and dexamethasone (Pd) alone in this patient population.⁷ Furthermore, at a median follow-up of 11.6 months, median PFS was 11.53 months with the combination versus 6.47 months with Pd alone (HR, 0.596; 95% CI, 0.436-0.814). Based on these data, the FDA has accepted a biologics license application for the agent for use in this setting.

The Future Looks Bright

Although IMiDs are effective in myeloma, many patients will eventually develop resistance. To combat that challenge, investigators are exploring iberdomide (CC-220), a novel CELMoD cereblon E3 ligase modulator. In a phase I trial, the combination of iberdomide plus dexamethasone demonstrated a 32.2% ORR among 59 evaluable patients with R/R multiple myeloma who had received ≥2 prior lines of therapy, according to results presented at the 2019 American Society of Clinical Oncology Annual Meeting. Those who were IMiD-refractory (n = 51) had an ORR of 35.3% with the investigational doublet, while patients who were refractory to daratumumab and pomalidomide (n = 27) had an ORR of 29.6%.⁸

Immunotoxins are also showing promise in myeloma. For example, the BCMA-targeting auristatin immunotoxin GSK2857916 demonstrated a 60% ORR with a median PFS of 12 months in heavily pretreated patients with R/R disease.⁹ Overall, the agent was determined to be well tolerated with a manageable toxicity profile.

Although BiTEs are available for use in lymphomas and leukemias, there has yet to be an approval in myeloma. However, 5 different companies are currently evaluating these agents in this setting, said Anderson, adding that the furthest along in the developmental process is AMG 701.

Lastly, much work is being done with CAR T cells in myeloma, said Anderson. Most notable is bb2121,¹⁰ which has been shown to induce deep and durable responses in heavily pretreated patients with R/R disease. Specifically, results for the first 33 patients who received the agent showed an ORR of 85%; 45% (n = 15) of patients achieved complete responses. Furthermore, median PFS was 11.8 months with the agent (95% CI, 6.2-17.8).¹⁰

Future strategies with BCMA cellular therapies will include potentially expanding the T cells in the presence of a PI3K inhibitor, introducing RNA CAR products, peptide-stimulated T cells with a vaccine, and combinations composed of vaccination, IMiDs, and checkpoint inhibitors to prevent T-cell exhaustion and prolong response.

“In the future, we will be treating patients with RVd and a monoclonal antibody and we’ll achieve MRD negativity—but that’s not going to be enough,” warned Anderson. “We’re going to have to do something else, some new form of adoptive immunotherapy, which is going to be designed to correct the problem in the host, which is that they don’t have antimyeloma immunity that can maintain the response. Right now, we’re only treating half the problem, so stay tuned.”

References

1. 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. Copenhagen, Denmark: Genmab; July 8, 2019. bit.ly/32ffENb. Accessed July 8, 2019.
2. Darzalex [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2019. accessdata.fda.gov/drugsatfda_docs/label/2019/761036s024lbl.pdf. Accessed October 1, 2019.
3. Ocio EM, Rodriguez Otero P, Bringhen S, et al. Premlinary results from a phase I study of isatuximab (ISA) in combination with bortezomib, lenalidomide, dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM) non-eligible for transplant. Blood. 2018;132(suppl 1):595. doi: 10.1182/blood-2018-99-111244.
4. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124(20):4032-4043. doi: 10.1002/cncr.31680.
5. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811-1822. doi: 10.1056/NEJMoa1805762.
6. Dimopoulos MA, White DJ, Benboubker L, et al. Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of POLLUX. Blood. 2017;130(suppl 1):739. bit.ly/2H2NMCY.
7. Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15; abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004.
8. Lonial S, van de Donk NWCJ, Popat R, et al. First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15; abstr 8006). doi: 10.1200/JCO.2019.37.15_suppl.8006.
9. Trudel S, Lendvai N, Popat R, et al. Deep and durable responses in patients (pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. Blood. 2017;130(supp 1):741.
10. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726-1737. doi: 10.1056/NEJMoa1817226.