Pamela Crilley, DO

The current landscape of treatment options for patients with newly diagnosed or relapsed/refractory multiple myeloma is quite complex with a significant number of new therapies either recently approved or in clinical trials.

As myeloma is not yet considered curable, a patient will experience a series of relapses and require different treatment regimens at various time points in their course.

Initially patients are stratified as either high or standard risk based on fluorescence in situ hybridization (FISH) results. High risk FISH includes translocations t(4:14), t(14:16), t(14:20), and 17p deletion.

 In addition, eligibility for hematopoietic stem cell transplant is considered by the clinician at the time of the patient’s diagnosis.Regimens for induction therapy are selected based on these factors, as well as patient comorbidities and goals of care. For patients with symptomatic myeloma, initial chemotherapy often includes 3 or 4 drug regimens including an immunomodulatory drug, a proteosome inhibitor, dexamethasone, with or without a CD38-directed monoclonal antibody. Subsequently, based on response, the patient may undergo stem cell collection and transplant or store the cells for a later transplant. Post-transplant, the patient will go on a maintenance program depending on the risk stratification and response.

Eventually, a patient will develop relapsed/refractory disease and require immediate or delayed treatment. No single salvage regimen is the standard of care. At that point, a clinician will consider clinical trial eligibility, prior treatment, response and duration of response, performance status, transplant eligibility, and comorbidities.

Therapies for Relapsed/Refractory Disease

The paradigm for management of relapsed myeloma is evolving rapidly with a plethora of treatment options based on results of clinical trials. These treatments include novel targets such as agents directed against the B-cell maturation antigen (BCMA), bispecific T cell engagers, antibody drug conjugates, CELmods that target cereblon, among others.

One explosive area of scientific and clinical research is the investigation of chimeric antigen receptor (CAR) T-cell therapy. CAR T cells are genetically modified T cells employing autologous T cells altered ex vivo to express the antigen binding domain for a B cell receptor that is fused to an intracellular domain of CD3 TCR.

To date, autologous CAR T-cell therapy against B-cell maturation antigen has been the most studied with dramatic efficacy but there are other targets are under investigation in the relapsed/refractory myeloma space. Many of the initial trials have been carried out in the United States and China. BCMA is a member of the tumor necrotic factor receptor superfamily. It is expressed on plasma cells, plasmablasts and activated B-cells.

An important phase 1 trial (NCT02658929) reported by Noopur Raje, MD, et al, investigated ide-cel.

 This CAR T therapy involved transduction of autologous T cells with a lentiviral vector encoding a second-generation CAR with an anti-BCMA single-chain variable fragment, a CD137 costimulatory motif and a CD3 zeta signaling domain.

Of importance, eligible patients in the study had received at least 3 previous lines of therapy including a proteosome inhibitor and an immunomodulatory agent or were refractory to both classes. In addition, the dose-expansion phase of the study criteria included prior daratumumab treatment as well as demonstration of refractory disease to the most recent treatment. The primary end point was safety.

Results in the first 33 patients showed an overall response rate (ORR) of 85%, with a 45% complete response (CR) rate. Toxicities seen included a high incidence of hematologic effects with anemia, neutropenia, and thrombocytopenia. Cytokine release syndrome was seen in 76% of patients, primarily grades 1 or 2; neurologic toxicity was seen in 42%. Overall, 85% of patients had a clinical response lasting a median of 10.9 months and the median progression-free survival (PFS) was 11.8 months. Some evaluable patients achieved minimal residual disease (MRD) negative status.

An update on the phase 2 KarMMa trial (NCT03361748) was reported in the 

 These heavily pretreated patients demonstrated an ORR of 73% after receipt of a single dose of ide-cel post lymphodeleting agents. Patients received targets of 150-450 × 10-6 CAR T cells.

The primary study end point was ORR, with secondary end points of time to response, duration of response, PFS, overall survival, safety, pharmacokinetics and immunogenicity. Hematologic toxicity was common (97%). Cytokine release syndrome occurred in 84%, largely grades 1 or 2. CAR T cells were detected in 59% of evaluable patients at 6 months and 36% at 12 months. Ninety-four of 128 patients had a response with 42/128 with a CR or greater. MRD negative status was confirmed in 33 patients. The median duration of response was 10.7 months and response duration increased with the depth of response. Ide-cel showed persistence in the blood samples with 36% showing detectable CAR T cells at 12 months.

CARTITUDE-1 (NCT03548207) was a phase 1b/2 study of JNJ-4528 or cilta-cel. This is a BCMA directed CAR T-cell therapy with 2 BCMA single domain antibodies. At the 2020 American Society of Hematology (ASH) annual meeting, the investigators presented phase 1 and early phase 2 updated data.

 The phase 1b portion assessed safety and recommendations for the phase 2 dosing. The phase 2 portion sought to evaluate efficacy in a heavily pretreated relapsed/refractory myeloma population.

Ninety-seven patients who had received a median of 6 lines of therapy were treated and evaluated. The ORR was 94.8% with a single dose of cilta-cel with a stringent CR rate of 55.7%. Fifty-two patients were MRD evaluable, with 94.2 % negative at 10-5. The 6- month PFS rate was 87.4%, with an overall survival rate of 93.8%.

Adverse events reported in over 70% included cytokine release syndrome 94.8%, with grades 3 or 4 in 4.1%. Hematologic toxicity was significant with neutropenia at 90.7%, anemia at 81.4%, and thrombocytopenia at 79.4%. Neurotoxicity was noted in 20.6%, with grades 3 or 4 in 10.3%. Finally, 67% of patients who were evaluated at 6 months had cilta-cel CAR T cells below the level of quantification. The response rates in this group of patients were profound and clinical trials are now looking to move CAR T therapy earlier in the disease with strategies to improve durability of response with decreased toxicity.

An additional phase 1/2 clinical trial evaluated orva-cel (JCARH125) lentivirus fully human 4-1BB CAR T-cell therapy in a similar group of patients with relapsed/refractory multiple myelomain the EVOLVE study (NCT03430011). This trial studied BCMA CAR T doses of 300, 450, and 600 × 10-6CAR T cells in patients who had been treated with a median of 6 prior regimens. A 91% objective response rate was noted with a 39% CR rate. Toxicities quite similar to those seen in other BCMA CAR T trials were reported including cytopenias, cytokine release syndrome, and neurologic toxicity with grades 1 and 2 more commonly seen.

Autologous CAR T-cell therapy with BCMA targets demonstrated high response rates in the patients studied with advanced disease but the duration of response remains problematic. In addition, longer follow-up is needed to determine which patients will benefit and at what point in their treatment plan. Strategies to improve duration of response are under investigation in pre-clinical and clinical trials and include the study of other targets such as GPRC5D, SLAMF7, and CD38. Evaluations of the causes of lack of response durability include understanding and preventing antigen escape, use of dual-target antigen CAR Ts, and targeting the immunosuppressive tumor microenvironment.

One clinical trial (ChiCTR1800018143) evaluated a dual-targeted BM38 CAR in 16 patients in a phase 1 dose-climbing trial of a bispecific CAR. A high response rate with a longer duration of stringent complete remissions was seen with manageable toxicities.

Several ongoing clinical trials are examining the efficacy and toxicity of allogeneic donor CAR T cells with gene-editing techniques to moderate or eliminate graft-vs-host disease or rejection. The advantage of this approach is the use of healthier donor lymphocytes as well as timeliness of product availability. One such trial is the phase 1 Universal study (NCT04093596) of ALLO-715 in relapsed/refractory myeloma patients examining safety, efficacy, cell kinetics, and immunogenicity.This is a first-in-human study of a genetically modified anti-BCMA product. Thirty-one patients were treated and evaluated for safety. Cytokine release syndrome was largely grade 1 or 2 and there was no neurotoxicity or graft-vs-host disease. A higher dose of ALLO-715 exhibited greater anti-cancer activity.

A strategy to combat the issue of persistence of the CAR T is under study with bb212117. This is a modified CAR T product in which T cells are co-cultured with a phosphatidylinositol 3-kinase inhibitor to expand memory T cells. CRB 402 (NCT03274219) is a phase 1 dose escalation trial of bb212117 in patients with heavily pretreated relapsed/refractory disease. Forty-six patients in the initial report received escalation doses of 150, 300, or 450 × 10-6with primary end points of adverse events and dose-limiting toxicities. T cell analysis was performed to assess for long-lasting memory T cell formation.

 An update at the 2020 ASH annual meeting reported on 74 patients with significant ORRs and a median duration of response of 17 months. Enrichment for memory T cells correlated with improved patient responses.

Clinical trials with CAR T-cell therapy for patients with relapsed/refractory multiple myeloma are enrolling at a rapid pace. Strategies to enhance persistence of the CAR T cells, identify mechanisms of resistance, evaluate new targets, minimize toxicities, and determine which patients will most benefit remain under intense investigation.

1. Moreau P, Kumar S, San Miguel, et al.Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group. 

. 2021;22(3):e105-e118. doi:10.1016/S1470-2045(20)30756-7

2. Richardson P, San Miguel J, Anderson K.Interpreting clinical trial data in multiple myeloma: translating findings to the real world setting. 

. 2018;8(11):109. doi:10.1038/s41408-018-0141-0

3. Neelapu S, Tummala S, Shpall E. Chimeric antigen receptor T-cell therapy- assessment and management of toxicities. 

. 2018;15(1):47-62. doi:10.1038/nrclinonc.2017.148

4. Wudhikarn K, Mailankody S, Smith EL. Future of CAR T cells in multiple myeloma. 

. 2020;2020(1):272-279. doi:10.1182/hematology.2020000111

5. Raje N, Berdeja J, Lin Y, et al. Anti-Bcma CAR-T cell therapy bb2121 in relapsed or refractory multiple myeloma. 

. 2019;380:1726-1737. doi:10.1056/NEJMoa1817226

6. Munshi N, Anderson L, Shah N, et al. Idecabtagene vicleucel (ide-cel: bb2121), a BCMA-targeted CAR-T cell therapy in patients with relapsed and refractory multiple myeloma: initial KarMMa results. 

. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503

7. Munshi N, Anderson L, Shah, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. 

. 2021;384:705-716. doi:10.1056/NEJMoa2024850

8. Berdeja J, Madduri D, Usmani S, et al. Update of CARTITUDE-1: a phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy in relapsed/refractory multiple myeloma. 

 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505

9. Madduri D, Berdeja J, Usmani S, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 177. https://bit.ly/3diI1QV

10. Mailankody S, Htut M, Lee K, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a Phase 1/2 multicenter study (EVOLVE). 

 2018;132(suppl 1):957. doi: 10.1182/blood-2018-99-113548

11. Mailankody S, Jakubowiak A, Htut M, et al. Orva-cabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients with relapsed/refractory multiple myeloma: update of the phase 1/2 EVOLVE study. 

 2020;38(suppl 15):8504. doi:10.1200/JCO.2020.38.15_suppl.8504

12. 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. 

. 2019;134(suppl 1):930. doi:10.1182/blood-2019-130340

13. Mailankody S, Matous J, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 129. https://bit.ly/3u2hTRa

14. Berdeja J, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-Bcma CAR T cell therapy. 

 2019;134(suppl 1):927. doi:10.1182/blood-2019-126660

15. Alsina M, Shah N, Radje N, et al. Updated results from the phase I CRB-402 study of anti-Bcma CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 130. https://bit.ly/3u62oI8

Articles

The paradigm for management of relapsed myeloma is evolving rapidly with a plethora of treatment options based on results of clinical trials. One explosive area of scientific and clinical research is the investigation of chimeric antigen receptor T-cell therapy.

The Impact of CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses two important trials in breast cancer looking at extended hormonal therapy.

It is understood now that 10 years of tamoxifen is superior to 5 years in premenopausal patients with high-risk, early-stage disease. However, Tripathy says, most patients are postmenopausal and see benefit when treated with aromatase inhibitors. The question remains as to whether these patients could see benefit when treated with 10 years of an aromatase inhibitor compared to 5 years.

While these results may not be the most scientifically interesting, Tripathy says, they will surely affect many patients.

For patients who are premenopausal with high-risk, early-stage breast cancer, 10 years of tamoxifen has shown superiority to 5 years of tamoxifen

In postmenopausal women, aromatase inhibitors have demonstrated superiority and a better side effect profile

Two large studies look to answer the question as to whether extended use (10 years) of aromatase inhibitors will show benefit compared to 5 years

MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM)

Pomalidomide + LoDEX significantly extended PFS and overall survival vs. HiDEX in patients who failed lenalidomide and bortezomib. Pomalidomide + LoDEX should become a standard of care in relapsed/refractory multiple myeloma patients who have exhausted treatment with lenalidomide and bortezomib.

PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and carboplatin plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer

Preoperative gemcitabine and carboplatin plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.

Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates

Developmental Therapeutics - Immunotherapy

MPACT was a large, international study performed at community and academic centers. nab-paclitaxel + gemcitabine was superior to gemcitabine across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens.

A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors

MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A.

Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.

Nivolumab produced sustained survival with a manageable long-term safety profile in advanced melanoma, NSCLC and renal cell carcinoma, supporting its ongoing clinical development in controlled phase III trials with survival endpoints.

A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic and colorectal cancers

Preliminary results with NPC-1C show signs of clinical activity based on stable disease in heavily pretreated patients with pancreating and colorectal cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy.

A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results

Overall survival was not significantly different in any of the age subgroups. PFS was significantly longer in pemetrexed arm overall and for patients &le;70, but was similar for patients >70, >75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)

Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A.

CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer

The primary endpoint is overall survival; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The accrual goal is 600 patients randomized.

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.

In the phase III AFFIRM trial, patients with lung mCRPC had higher median overall survival than patients with liver mCRPC. Enzalutamide resulted in higher response rates in both liver and lung mCRPC patients. Overall survival and radiographic progression-free survival were also improved in both patient groups treated with enzalutamide.

Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization.

Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.

Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib

Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study).

The primary endpoint of this study is to evaluate if total PFS of sorafenib followed by pazopanib is non-inferior to pazopanib followed by sorafenib.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients with advanced or metastatic renal cell carcinoma previously treated with antiangiogenic therapy.

The primary endpoint is overall survival. Secondary endpoints include PFS, ORR, OR duration, adverse events, overall survival in PD-L1 positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling patients.

A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).

The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in folate receptor positive patients. Secondary objectives include overall survival, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing.

Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.

The results point out the potential importance of nibrin expression in the clinical outcome of patients with advanced ovarian cancer. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted.

Videos

Pamela Crilley, DO, explains the benefits and downfalls of prescribing tyrosine kinase inhibitors for the treatment of CML.


Pamela Crilley, DO | Authors

Articles

The Impact of CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Prescribing TKIs for the Treatment of CML