A Myeloma Pioneer Sees More Innovation

Kenneth C. Anderson, MD

When Kenneth C. Anderson, MD, first arrived at Dana-Farber Cancer Institute in Boston, Massachusetts, 40 years ago, he immediately joined ongoing efforts to develop and test what would become the first generation of monoclonal antibodies, agents subsequently used for the diagnosis and treatment of B-cell malignancies. He was on the leading edge of a treatment revolution in multiple myeloma.

The treatment of myeloma has benefited from many advancements over the ensuing years, and Anderson remains at the forefront of discovery in this disease type. A 2014 winner of the Giants of Cancer Care^® award in myeloma, Anderson is program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber.

He is also cochair of the 4th Annual Live Medical Crossfire^®: Hematologic Malignancies, to be held Saturday, July 11, 2020, at the InterContinental New York Times Square in New York. The 1-day conference gives oncologists and hematologists a practical overview of important developments in the myeloma treatment landscape.

"An Outstanding Investigator"

At Dana-Farber, Anderson is leading clinical trials that may bring both new immunotherapies and new targeted medications, alone or in combination, to patients with myeloma. His lab is undertaking foundational investigation needed to produce and design the next generation of medications and trials.

But research is not Anderson’s only professional interest. He maintains a full clinical practice and is passionate about sharing his wisdom with other physicians.

“Ken has made many seminal contributions to the field of myeloma over the past 3 decades,” said Shaji Kumar, MD, another leading myeloma investigator who has collaborated with Anderson many times over the years.

“His laboratory has played a key role in understanding the disease biology of myeloma, which has translated into development of several new therapies for the disease and led to improved survival,” said Kumar, a professor of medicine and a consultant in the Division of Hematology, Department of Internal Medicine, at Mayo Clinic in Rochester, Minnesota. “He is an outstanding investigator, a beloved clinician, and, importantly, an admired teacher who has drawn a generation of researchers into the field of plasma cell disorders.”

“Ken is a giant in the field of multiple myeloma,” added Noopur Raje, MD, a professor at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital in Boston. “His leadership has led to our better understanding of this disease, and he has been the force behind the approval of several drugs for myeloma, including bortezomib [Velcade], lenalidomide [Revlimid], and pomalidomide [Pomalyst]. Getting a perspective from Ken himself is a real treat, and I always continue to learn whenever he presents,” said Raje, who also collaborates frequently on investigations with Anderson.

Also the Kraft Family Professor of Medicine at Harvard Medical School in Boston, Anderson has mentored dozens of young myeloma investigators during his tenure at Dana-Farber. He has also participated in many conferences designed to provide continuing education for clinical practitioners.

Major Trends in Myeloma Care

At the Medical Crossfire^® conference on hematologic malignancies, experts will discuss trial results that are changing or have potential to change standards of care. Conference faculty include cochairs Elias Jabbour, MD, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and Anas Younes, MD, a professor and chief of the Lymphoma Service in the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

Anderson recently sat down for an in-depth interview with OncologyLive^® to preview the conference and share his thoughts about the major trends in myeloma care. “There has been very rapid progress, both in targeted therapy and immune therapy. The targeted therapy venetoclax [Venclexta], to use an example, is very effective in 11;14 translocation or BCL-2—expressing myeloma. On the immune side, there are B-cell maturation antigen [BCMA]–directed immunotoxins, bispecific T-cell engagers [BiTEs], and chimeric antigen receptor [CAR] T cells, all of which are looking very promising in clinical trials,” Anderson said.

And the progress extends beyond the creation of new monotherapies.

“We have been developing new classes of drugs and then combining them with existing agents based on preclinical rationale, suggesting that they’re either additive or synergistic. For example, in patients with newly diagnosed myeloma, the combination of lenalidomide, bortezomib, and dexamethasone [RVd] is used broadly and achieves a very high rate and extent of response,” Anderson said.

“The monoclonal antibody daratumumab [Darzalex] has now been added to RVd, and at December’s American Society of Hematology [2019 ASH] meeting, RVd/daratumumab was shown to achieve an even higher rate and an even deeper extent of response than RVd alone, including a high frequency of minimal residual disease [MRD]—negative responses,” Anderson noted.

Venetoclax, which blocks the BCL-2 family of proteins, made headlines in 2019 when investigators in the phase III BELLINI trial (NCT02755597) reported that in patients with myeloma, usage was associated with an increased risk of death, and the FDA temporarily suspended new enrollment in trials testing venetoclax in myeloma.¹ Subsequent analysis suggested, however, that in the treatment of hematologic malignancy, venetoclax provided significant benefits to nearly half of all patients whose myeloma was t(11;14) positive or high in BCL-2 expression.

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New Monoclonal Antibody Data

On March 2, the FDA approved isatuximab-irfc (Sarclisa) in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least 2 prior regimens, including lenalidomide and a proteasome inhibitor.

Investigators tested the monoclonal antibody, which binds to the CD38 receptor and produces antitumor activity via multiple mechanisms of action, in a similar population of 307 patients with relapsed/refractory (R/R) disease in the ICARIA-MM trial (NCT02990338). Patients were randomized equally to isatuximab, pomalidomide, and dexamethasone or pomalidomide and dexamethasone alone. At a median follow-up of 11.6 months, the median PFS was 11.5 months (95% CI, 8.9-13.9) in the isatuximab group versus 6.5 months (95% CI, 4.5-8.3) in the control group (HR for progression, 0.596; 95% CI, 0.44-0.81; P = .001).³

The approval makes isatuximab the second anti-CD38 therapy available to patients with myeloma. The first, daratumumab, was initially approved for the treatment of refractory myeloma in late 2015, but recently released trial data may be enough to make the agent part of the standard of care for most patients with newly diagnosed disease.

In the phase II GRIFFIN study (NCT02874742), investigators randomized patients with transplant-eligible multiple myeloma evenly to RVd with daratumumab (D-RVd) or without. The trial enrolled 207 patients, who received 4 induction cycles, stem cell mobilization, high-dose therapy, autologous stem cell transplant (ASCT), 2 consolidation cycles, and maintenance lenalidomide for 24 months.

According to data presented at 2019 ASH in December, the stringent complete response (sCR) rate after a median follow-up of 22.1 months was 62.6% with D-RVd and 45.4% with RVd (OR, 1.98; 95% CI, 1.12-3.49; P = .0177). The overall CR rate (sCR + partial CR) was also improved with D-RVd (79.8% vs 60.8%; P = .0045), and the proportion of patients achieving MRD negativity was twice as high with D-RVd. At 24 months, both regimens had led to PFS rates exceeding 85% and OS rates exceeding 90%.⁴

The addition of daratumumab to a similar regimen of bortezomib, thalidomide, and dexamethasone (D-VTd or VTd) had previously demonstrated improved response rates and PFS as induction and consolidation therapy for transplant-eligible patients with newly diagnosed myeloma in the phase III CASSIOPEIA trial (NCT02541383). Investigators randomized 1085 patients evenly to receive 4 pretransplant induction cycles and 2 posttransplant consolidation cycles of VTd or D-VTd. At day 100 after transplant, 157 of 543 patients (29%) in the D-VTd group and 110 of 542 patients (20%) in the VTd group had achieved sCR (OR, 1.60; 95% CI, 1.21-2.12; P = .001).

Investigators observed MRD negativity in 64% of patients receiving D-VTd and 44% of those on VTd. Neither group reached median PFS, but those who received D-VTd were less likely to progress by the time of analysis (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). Investigators reported 46 deaths (14 vs 32, respectively; HR, 0.43; 95% CI, 0.23-0.80).⁵

Another monoclonal antibody approved in the refractory myeloma setting, the immunostimulatory agent elotuzumab (Empliciti), which binds to the SLAMF7 protein on natural killer cells, also has shown promise as a frontline agent in a phase II study conducted in Japan.⁶

However, the addition of elotuzumab to lenalidomide and dexamethasone did not demonstrate a statistically significant improvement in PFS compared with lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma, previously untreated, transplant-ineligible myeloma in the ELOQUENT-1 trial (NCT01335399), according to a statement from Bristol Myers Squibb, a codeveloper of the drug. Full results are expected to be presented at an upcoming medical meeting.⁷

Noteworthy Lenalidomide Study

Another trial that Anderson believes is a potential practice changer is the phase III IFM/DFCI2009 trial (NCT01191060), which set out to randomize 700 patients ≤65 years with newly diagnosed myeloma to RVd and maintenance lenalidomide until progression, with or without ASCT and high-dose melphalan. The goal is to see whether modern medications work well enough to dispense with ASCT, which has been the cornerstone of myeloma care for decades. The trial has been under way since 2009, with continuous maintenance lenalidomide, and is still not mature.

Investigators published results in 2017 on patients treated identically, with the exception of 1 year of maintenance lenalidomide. Among these patients, median PFS was significantly longer in the group who underwent transplant than in the group who received RVd alone (50 vs 36 months; adjusted HR for disease progression or death, 0.65; P <.001). However, OS at 4 years did not differ significantly between the transplant group and the RVd-alone group (81% and 82%, respectively), and the rate of grade 3/4 adverse events (AEs) was significantly higher in the transplant group: neutropenia, 92% versus 47%, respectively; gastrointestinal disorders, 28% versus 7%; infections, 20% versus 9%.⁸

Bench to Bedside and Back

“These single agents and combination therapies that are currently undergoing trials have been informed by preclinical science, both in the laboratory and in animal models, which suggests cytotoxicity directed at myeloma cells. Preclinical research also suggests which combinations can act synergistically or at least additively. But this work in the lab is also refined by observations at the bedside, which are then brought back to the laboratory and result in further experimentation. That experimentation produces insights that go back to the clinic for testing, so there’s basically an iterative cycle of discovery and testing that has been producing improvements,” said Anderson. “It’s bench to bedside to bench to bedside.”

Approvals Likely for Immunotherapies

Several already approved myeloma treatments extend lives by stimulating immune response. Lenalidomide, pomalidomide, and thalidomide are all FDA-approved immunomodulatory drugs, and newer immunotherapies have produced such positive outcomes in early-stage trials that regulatory approvals could come soon.

“The excitement in the immune trials is in 3 main areas,” Anderson said. “First, there is the BCMA immunotoxin, where clinical trials are showing significant prolongation of progression-free survival in relapsed multiple myeloma that should provide the benefit for its FDA approval. Second, there are now [BiTEs]. The early data presented at ASH showed that once the correct dose is defined, these agents produce high rates of MRD-negative responses. Third, the clinical trials of CAR T cells are numerous and very promising. The responses in far-advanced myeloma are very common and extremely deep. Often, MRD-negative complete responses are achieved in spite of multiple lines of prior therapy.”

The BCMA immunotoxin belantamab mafodotin (GSK2857916) does not work solely by binding to BCMA. It is an antibody- drug conjugate that binds to BCMA and then releases the microtubule-disrupting agent monomethyl auristatin F. Investigators have shared results only from 1 early-stage study of belantamab mafodotin, but they were impressive. In the DREAMM-2 trial (NCT03525678), 196 heavily pretreated patients with R/R multiple myeloma were randomized to receive either 2.5 mg/kg or 3.4 mg/kg of the experimental drug once every 3 weeks. The ORR was 31% (97.5% CI, 20.8%-42.6%) among those who received the lower dose (n = 97) and 34% (97.5% CI, 23.9%- 46.0%) in those who took the higher dose (n = 99). Investigators considered the safety profile manageable; there were 2 deaths potentially related to treatment (1 case each of sepsis and hemophagocytic lymphohistiocytosis) and the most common grade 3/4 AEs included keratopathy, thrombocytopenia, and anemia.⁹

Other trials are already under way, including DREAMM-6 (NCT03544281), which is testing belantamab mafodotin in combination with dexamethasone and either lenalidomide or bortezomib in patients with R/R multiple myeloma.

BiTEs are antibodies with 2 components. The first binds to a particular protein commonly expressed in the target. The second activates immune cells and leads them to attack. The first such compound to win FDA approval was blinatumomab (Blincyto), which has been available for the treatment of acute lymphoblastic leukemia since 2014. A pair of BiTEs designed to target multiple myeloma, AMG 420 and AMG 701, have demonstrated the ability in vitro to kill myeloma cells and potentially induce autologous tumor cell lysis. Both agents are undergoing early-stage clinical trials,¹⁰ but only 1 of those trials has reported any results to date.

In that trial (NCT02514239), 42 heavily pretreated patients with R/R myeloma and high tumor burden were treated with AMG 420 for a mean of 2.5 treatment cycles. The compound produced some response in 13 patients (31%) patients. The data showed sCR in 6 patients (14.2%), very good partial response (VGPR) in 2 patients (5%), and partial response (PR) in 2 patients (5%). Among those who responded, 11 responded in the first treatment cycle, and the median duration of response was 1 month. Serious AEs were reported in 19 patients (45%). Four deaths were reported, 2 from AEs, neither of which was treatment related.¹¹

CAR T-Cell Activity

Trials of CAR T-cell treatments in myeloma are both more numerous and further advanced. CAR T cells targeting BCMA have been investigated in numerous studies and have demonstrated significant diseaseremitting activity.

In 2019, investigators published results for 33 patients with R/R multiple myeloma enrolled in a phase I CAR T-cell study of anti-BCMA CAR T-cell therapy idecabtagene vicleucel (ide-cel; bb2121). The objective response rate was 85% (95% CI, 68.1-94.9), and 15 patients (45%) experienced CRs. Median PFS was 11.8 months (95% CI, 6.2-17.8). Sixteen evaluable responders were MRD negative (≤10⁻⁴ nucleated cells), and CAR T cells persisted up to 1 year after the infusion. However, grade ≥3 AEs occurred in 97% of patients. The most common included neutropenia (85%), leukopenia (58%), anemia (45%), and thrombocytopenia (45%). Investigators observed cytokine release syndrome (CRS) in 25 (76%) patients, but it was grade 1 or 2 in 23 of those patients and grade 3 in the other 2.¹² The FDA granted ide-cel breakthrough status in 2017.

“The bb2121 CAR T-cell approaches are the furthest along in the testing process,” Anderson said. “The response rates are very high despite multiple lines of prior therapy, and I would anticipate that those CAR T cells would be FDA-approved either later in 2020 or early in 2021. There are also many other CAR T-cell therapies that are undergoing active development and testing.”

An oral presentation at 2019 ASH shared initial results from the phase Ib portion of CARTITUDE-1 (NCT03548207), which is evaluating the efficacy and safety of JNJ-68284528 (JNJ-4528), an investigational BCMA-directed CAR T-cell therapy. Among 29 heavily pretreated patients with R/R myeloma, the ORR was 100%; the sCR rate, 66%; and the VGPR, 86%. At the median follow-up of 6 months, 27 of 29 patients were progression free. A quarter of all patients experienced grade ≥3 AEs.¹³ Based on these data, the FDA granted JNJ-68284528 a breakthrough therapy designation in December 2019.

Another presentation at that meeting detailed results from another phase I trial of another CAR T-cell therapy, targeting both BCMA and CD38, in heavily pretreated patients with R/R multiple myeloma. The dose-climbing phase I study (ChiCTR1800018143) included 22 patients, 9 of whom had extramedullary tumors. The ORR was 90.1%, and 54.5% of patients achieved sCR. Investigators observed MRD negativity in 81.8% of patients. At the cutoff date of October 31, 2019, 19 patients were still alive, with 10 still in sCR, 1 with VGPR, and 4 with PRs. A trio of patients had experienced relapse, and 1 patient had progressive disease. Median PFS had not been reached. The 9-month rate of PFS was 78.9%. All but 2 of the patients experienced CRS, and CRS grade ≥3 occurred in 5 (22.7%).¹⁴

“Different groups are testing different approaches,” Anderson said. “There are experiments utilizing combinations of CD4- and CD8-positive CAR T cells. There are the CAR T cells that have been modified so that they bind to BCMA in 2 different domains, so-called bivalent CAR T cells. The initial experience was in China and very encouraging, showing that fewer CAR T cells are needed, and high rates of response and extent of response are also observed. Now in America, the same bivalent BCMA vector was used in the CARTITUDE-1 trial, and there are many other attempts and clinical trials to try to improve upon these first-generation CAR T-cell studies.”

Keeping Up With Rapid Change

How can busy clinicians keep up with the torrent of data and the practice-changing approvals that are likely to follow? The 4th Annual Live Medical Crossfire^®: Hematologic Malignancies makes it easy. Leading investigators serve as faculty and discuss the most important developments in the treatment of multiple myeloma in a practical style that leaves room for audience feedback and questions.

But great conferences need more than great teachers. They need great formats too.

“I think the Crossfire format is novel and innovative and a wonderful way of conveying rapidly evolving new information,” Anderson said. “There is a brief presentation of some of the most important progress that has occurred in terms of the treatment of newly diagnosed myeloma or, in another session, relapsed myeloma. Then we have panels of experts who are asked questions around management of newly diagnosed or relapsed patients, often based upon real-life cases. There is then the opportunity to probe the opinions of several different experts as to how they would manage a particular case of either newly diagnosed or relapsed myeloma.”

Anderson also enjoys the chance to meet clinicians from every different type of practice and to hear about the challenges they face in providing cutting-edge care without the resources of a major cancer center. Anderson began medical school with the firm intention of doing general clinical practice. He changed his mind when a mentor convinced him that he could benefit patients by being an investigator, if he devoted himself to research that improved diagnosis, prognosis, and treatments and thus provided practical benefits to patients and their families.

“The ability to interact with the attendees at the Crossfire session is very meaningful. This kind of a format makes it very real world for providers who come, and it shows them how novel advances can really be made to count for their patients,” said Anderson.

Those sentiments reflect his long-time motto: “Make science count for patients, and treat patients like family.”

References

1. FDA warns about the risks associated with the investigational use of Venclexta in multiple myeloma. FDA website. www.fda.gov/drugs/ drug-safety-and-availability/fda-warns-about-risks-associated-investigational- use-venclexta-multiple-myeloma. Published March 21, 2019.
2. Kumar SK, Harrison SJ, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: International Myeloma Workshop Scientific Program; September 12-16, 2019; Boston, MA. Abstract OAB-045.
3. Sarclisa [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US, LLC; 2020. www.accessdata.fda.gov/drugsatfda_docs/ label/2020/761113s000lbl.pdf. Accessed March 12, 2020. doi: 10.1182/blood-2019-02-895193.
4. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1; abstr 691). doi: 10.1182/blood-2019-123456.
5. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stemcell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study [erratum published online June 14, 2019, in Lancet. doi: 10.1016/S0140-6736(19)31403-5]. Lancet. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.
6. Kubo K, Hori M, Ohta K, et al. Elotuzumab plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma: a randomized, open-label, phase 2 study in Japan. Int J Hematol. 2020;111(1):65-74. doi: 10.1007/s12185-019-02757-0.
7. Bristol Myers Squibb reports primary results of ELOQUENT-1 study evaluating Empliciti (elotuzumab) plus Revlimid (lenalidomide) and dexamethasone in patients with newly diagnosed, untreated multiple myeloma [news release]: Princeton, NJ: Bristol Myers Squibb; March 9, 2020. bit.ly/3cJ17P9. Accessed March 9, 2020.
8. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.
9. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a twoarm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0.
10. Shaw Z, Malik MN, Batool SS, et al. Bispecific T-cell engager (BiTE) antibody based immunotherapy for treatment of relapsed refractory multiple myeloma (RRMM): a systematic review of preclinical and clinical trials. Blood. 2019;134(suppl 1; abstr 5567). doi: org/10.1182/blood-2019-129652.
11. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. J Clin Oncol. 2019;37(suppl 15; abstr 8007). doi: 10.1200/JCO.2019.37.15_suppl.8007.
12. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. New Engl J Med. 2019;380(18):1726-1737. doi: 10.1056/NEJMoa1817226.
13. Janssen presents initial results for BCMA CAR-T therapy JNJ-4528 showing early, deep and high responses in the treatment of relapsed or refractory multiple myeloma [news release]. Beerse, Belgium: Janssen Pharmaceutical Companies; December 7, 2019. businesswire.com/news/home/20191207005035/en/Janssen- Presents-Initial-Results-BCMA-CAR-T-Therapy
14. Li C, Mei H, Hu Y, et al. A bispecific CAR-T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Presented at: 2019 American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 930.

The phase III CANOVA trial (NCT03539744) is randomizing patients with relapsed myeloma and the t(11;14) abnormality to either venetoclax and dexamethasone or pomalidomide and dexamethasone. Success could lead to an approval in relapsed t(11;14)-positive myeloma. No equivalent phase III trial is evaluating patients with BCL-2—high myelomas because no validated assay exists to determine BCL-2 expression or identify appropriate cut points. Such a biomarker is under development, though, so a related trial may eventually take place.

In the BELLINI trial, patients in the venetoclax group with a t(11;14) abnormality did not reach a median progression-free survival (PFS) compared with a median PFS of 9.5 months in the placebo group (HR, 0.110; 95% CI, 0.022-0.560; P = .002). Neither treatment arm reached a median overall survival (OS). Among patients identified as BCL-2 high, the median PFS was 22.4 months in the venetoclax arm versus 10.2 months in the placebo arm (HR, 0.341; 95% CI, 0.146-0.560; P = .011). Neither arm reached OS.²