Saad Z. Usmani, MD

The treatment of multiple myeloma has evolved substantially in the last 3 decades with the introduction of multiple novel therapies and improvement in survival for patients.

 Up-front consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) after initial induction therapy has remained the standard of care for patients over this time.

 The introduction of novel therapies such proteasome inhibitors and immunomodulatory drugs with high response rates led to the reassessment of the role of up-front ASCT.

 Two recent randomized trials (NCT01208662, NCT01191060) have demonstrated significant progression-free survival (PFS) benefit with up-front compared with delayed ASCT even with modern induction therapies.

However, notably with median of 8 and 6 years of follow-up, overall survival has not been reached in either of the studies.

The development of BCMA-directed therapies including autologous CAR T cells is a new chapter in the remarkable progress for myeloma.

 There are now two different autologous BCMA CAR-T cell therapies for the treatment of relapsed or refractory myeloma patients with 4 or more prior therapies.

This includes idecabtagene vicleucel (ide-cel; Abecma®; Bristol Myers Squibb; 2SeventyBio), which has an overall response of 73% in relapsed and refractory myeloma, with 33% of patients achieving a complete response or better.

 The median duration of response (DOR) was 10.7 months and median PFS was 8.8 months. Ciltacabtagene autoleucel (cilta-cel; Carvykti™; Janssen, Legend Biotech) similarly showed an overall response of 98% and complete response or better in 82.5% of relapsed and refractory myeloma patients. The median DOR and PFS were not reached, with 54.9% of patients progression-free at a median follow-up of 27 months.

 The depth and durability of responses seen with these CAR T-cell therapies in refractory myeloma is unprecedented and raises again the question of the role of up-front ASCT in the era of immune therapies, including CAR T-cell therapies.

Lessons From CD19 CAR T-Cell Therapies for Diffuse Large B-Cell Lymphoma (DLBCL)

Similar to multiple myeloma, ASCT is an important treatment option for patients with DLBCL, particularly as second line treatment. The development of BCMA-targeted CAR T cells for multiple myeloma has generally followed the trajectory of CD19 CAR T cells for B-cell malignancies. There are now 3 different CD19 CAR T cells: axicabtagene ciloleucel (axi-cel; Yescarta®; Kite Pharmaceuticals), tisagenlecleucel (tisa-cel; Kymriah®; Novartis), and lisocabtagene maraleucel (liso-cel; Breyanzi®; Bristol Myers Squibb), approved for the third-line treatment of DLBCL.

 More recently, 3 randomized trials (NCT03391466, NCT03570892, and NCT03575351) compared treatment with CD19 CAR T cells to ASCT as a second line of treatment, and 2 of these 3 trials have shown a significant benefit in terms of event-free survival (EFS), and both studies also show a trend toward improved overall survival.

 These results have led to the US FDA approval of axi-cel and liso-cel for patients with refractory DLBCL after 1 prior line of therapy.

Moving BCMA CAR T-Cell Therapies to Earlier-Line Treatment in Multiple Myeloma

Based on the deep and durable responses with BCMA CAR T-cell therapies in advanced myeloma, 2 randomized trials have now completed accrual in earlier lines of treatment. The KARRMA-3 trial (NCT03651128) evaluated ide-cel compared with standard-of-care combination treatments in myeloma patients after 2 to 4 prior treatments. While the full results are not yet available, recent reports suggest the trial met its primary objective, demonstrating a statistically significant improvement in PFS with ide-cel.

 A similar trial (CARTITUDE-4; NCT04181827) has completed accrual and compares cilta-cel to standard-of-care triple-drug combination in patients with relapsed myeloma and 1 to 3 prior lines of treatment.

 These studies will hopefully establish the role of autologous CAR T-cell therapies in earlier lines of treatment for multiple myeloma.

Can CAR T-Cell Therapies Replace ASCT in Myeloma?

While the efficacy of ASCT is clear, there are substantial logistical challenges and potential short- and long-term side effects, including the risk of transplant-related mortality, second primary cancers, and infections. In the last 2 decades, every time a new class of treatment has emerged for myeloma, physicians and patients have questioned the need for up-front ASCT; despite this, ASCT has continued to remain the standard of care for transplant-eligible myeloma patients. However, with the introduction of CAR T-cell therapies, which provide deep and durable responses in advanced and refractory multiple myeloma and arguably the highest rates of complete responses noted with any treatment for myeloma, we believe it is reasonable to hope that CAR T-cell or other T-cell engaging therapies could potentially replace up-front ASCT as a standard treatment for many patients. Indeed, there are ongoing randomized trials that address this very important question; for instance, CARTITUDE-6 is a global phase 3 trial comparing cilta-cel and ASCT in patients receiving initial induction therapy with daratumumab (Darzalex®; Janssen), bortezomib (Velcade®; Takeda), lenalidomide (Revlimid®; Bristol Myers Squibb), and dexamethasone (DVRd).

 The availability of these therapies has the potential to change the natural history of this disease and improve outcomes for our patients.

"[W]ith the introduction of CAR T-cell therapies, which provide deep and durable responses in advanced and refractory multiple myeloma and arguably the highest rates of complete responses noted with any treatment for myeloma, we believe it is reasonable to hope that CAR T-cell or other T-cell engaging therapies could potentially replace up-front ASCT as a standard treatment for many patients.” – Sham Mailankody MBBS, and Saad Z. Usmani, MD, MBA

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6. Mailankody S, Landgren O. T-Cell engagers - modern immune-based therapies for multiple myeloma. 

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8. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study

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9. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. 

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13. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. 

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14. Bristol Myers Squibb and 2seventy bio announce topline results from KarMMa-3 trial showing Abecma (idecabtagene vicleucel) significantly improves progression-free survival versus standard regimens in relapsed and refractory multiple myeloma. News release. Bristol Myers Squibb. August 10, 2022. Accessed September 12, 2022. https://bit.ly/3xgm9kc

15. 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, bortezomib and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE-4). ClinicalTrials.gov. Updated September 9, 2022. Accessed September 9, 2022. https://bit.ly/3RXQRGI

16. A study of daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by ciltacabtagene autoleucel versus daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by autologous stem cell transplant (ASCT) in participants with newly diagnosed multiple myeloma (CARTITUDE-6). ClinicalTrials.gov. Updated February 25, 2022. Accessed September 9, 2022. https://bit.ly/3d4FcHc

Articles

The depth and durability of responses seen with these CAR T-cell therapies in refractory myeloma is unprecedented and raises again the question of the role of up-front autologous stem cell transplant in the era of immune therapies, including CAR T-cell therapies. 

CAR T-Cell Therapy Could Replace Auto Transplant in Multiple Myeloma

 The biggest impact we’ve made in patients with myeloma is for standard and intermediate-risk patients. The triplet-induction approach followed by consideration of stem cell transplantation, followed by maintenance, has become a standard of care for patients with myeloma. Now we’re thinking about quadruplet therapies for those patients to try to get deeper responses during that first year of diagnosis.

The challenge for us is in high-risk myeloma. Because myeloma is a heterogenous disease, we see high risk both with clinical features as well as specific biologic features on FISH [fluorescence in situ hybridization] cytogenetic.

There are a lot of newer drugs, newer platforms like bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptors T-cell and anti–T-cell therapies that are coming down the line. For our colleagues practicing in the communities, it is important to partner with your closest myeloma center to give your patients access to those kinds of therapies. I suspect that over the next 5 years, navigating the various options of treatment are going to be a big challenge. People like me are still trying to figure it out, and it’s going to be more challenging for our community colleagues. Strengthening that partnership is going to be important so we can deliver the best possible care for our patients with myeloma.

Case: A 75-Year-Old Woman With Multiple Myeloma

An active 75-year-old woman presented with new onset back pain and a 10-month history of fatigue, mild sensory neuropathy

PMH: hypercholesterolemia, diabetes, and atrial fibrillation; all medically controlled

PE: bony tenderness appreciated on the hips and lower back

Labs: Hb 10.2 g/dL, calcium 11.1 mg/dL, LDH 186 U/L, creatinine 1.3 mg/dL, albumin 3.7 g/dL, beta-2 microgloblulin 3.6 mcg/mL, potassium 1100 g/dL, M-protein 2.6 g/dL, lambda free light chains 4.1 mg/dL

X-ray showed L4 vertebral compression fracture

Skeletal survey showed multiple lytic lesions in femur

Bone marrow shows 40% clonal plasma cells IgG k with hyperdiploidy FISH

Patient is ineligible for ASCT due to comorbidities

Initiated treatment with daratumumab + lenalidomide + dexamethasone

Videos

Saad Usmani, MD, speculates on the current progress in treating multiple myeloma, while providing a glimpse into the future of cutting-edge treatments.

Current and Future Treatment Options for Multiple Myeloma Patients 

 The coronavirus pandemic has certainly impacted our clinical workflow as well as the way that we conduct patient care. Virtual visits and virtual medicine have made strong inroads into how we are managing patients. It’s going to be here to stay, even after the pandemic is over. We are also trying to see how we can streamline operations in the clinic so that patients have shorter exposures to the health care setting.

During the surge of the pandemic, we were modifying the patients’ regimens and trying to give them less frequent exposure to the infusion centers. Even in the absence of data, we had to do it for safety reasons. Then the subcutaneous formulation of daratumumab came along and made things a little easier for us because it reduces the period patients have to stay in the infusion center to receive daratumumab.

Subcutaneous formulation of daratumumab has improved the clinical workflow as well as patient satisfaction without impacting the efficacy of the drug. Our centers have gone to the subcutaneous formulation altogether, and we expect that most of our patients will be switching over to the subcutaneous formulation of daratumumab.

Saad Usmani, MD, reflects on the impact the coronavirus pandemic has had on his practice and the treatment of patients with multiple myeloma overall.

The Impact of COVID-19 on Treating Patients With Multiple Myeloma 

 More recently there was a study called PEGASUS that did an indirect comparison between the DRd [daratumumab, lenalidomide, dexamethasone] patients treated on the MAIA trial and the common standard-of-care regimens utilizing the Flatiron Health electronic medical record database. Patient data would be identified, and there were individual patient data.

These data were used to perform what is called an indirect treatment comparison, or an anchor treatment indirect comparison, with DRd [daratumumab, lenalidomide, dexamethasone]. The comparison was with VRd [bortezomib, lenalidomide, dexamethasone], Vd [bortezomib, dexamethasone], and Rd [lenalidomide, dexamethasone].

This is not a randomized up-front clinical trial. This is an indirect comparison. We have to take these results with a grain of salt. But in the absence of a direct-comparison clinical trial of DRd [daratumumab, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone], these are probably the best data for now.

It was encouraging to see that, when compared with the identified data sets for those patients, DRd [daratumumab, lenalidomide, dexamethasone] was associated with a lower risk of progression on depth compared with VRd [bortezomib, lenalidomide, dexamethasone]. And in the absence of a head-to-head trial comparison, these data tell us if you’re picking DRd [daratumumab, lenalidomide, dexamethasone] over VRd [bortezomib, lenalidomide, dexamethasone] for whatever reason in transplant-ineligible patients, it’s reasonable to do that.

We’re never going to—at least not in the immediate future—have a triplet-vs-triplet trial in the setting. But these may be the best data that we get.

Looking at DRd [daratumumab, lenalidomide, dexamethasone] as an option for our given patient, it will not give you the same kind of neuropathy as you would get with VRd [bortezomib, lenalidomide, dexamethasone], especially in the patient with diabetes who already has early signs of neuropathy.

The important piece is the overall tolerability. If you look at the MAIA data, there were no safety signals that led to this continuation of a drug that was unique compared with the Rd [lenalidomide, dexamethasone]. There were higher incidents of infections in the DRd arm [daratumumab, lenalidomide, dexamethasone], as well as neutropenia. But they did not result in discontinuation of treatments.

One of the key things I want to highlight is that older patients in general have an immunosuppressive state. It’s more important in older patients to watch for infections and do appropriate dose modifications of Revlimid [lenalidomide] specifically.

This is something we have observed in the clinic: Most patients require dose adjustments of lenalidomide, or even in the relapsed setting pomalidomide, when they’re combined with daratumumab. Our general practice is to start with the low dose of Revlimid [lenalidomide] in older patients along with daratumumab. Based on tolerability and response, we see if we can move the dose up. We generally don’t start with a 25-mg dose in our clinical practice.

Those are some of the clinically relevant points for when managing patients receiving DRd [daratumumab, lenalidomide, dexamethasone].

The MAIA & PEGASUS Trial and Managing Patients Receiving DRd

The MAIA trial was a randomized phase 3 trial in transplant-ineligible patients with an ECOG performance status of 0 to 2. The randomization was the combination of daratumumab, lenalidomide, dexamethasone, compared with the standard-of-care arm of lenalidomide-dexamethasone treatment, which was continued until relapse progression or intolerance with primary end point being PFS [progression-free survival]. Secondary end points were TTP [time to progression], CR [complete response] and single CR rate, MRD [minimal residual disease] negativity rate, PFS, overall survival [OS], as well as overall response rate.

Risk stratification on the trial was done with ISS [insulin sliding scale] staging and the patient’s age. One key element of this clinical trial was that of all 737 patients who were enrolled in the study, 44% of the patients were 75 years or older. This goes in line with what we’re seeing in terms of choices for this particular patient.

The original study was presented and published after a median follow-up of 28 months. And at that time the median PFS for the DRd [daratumumab, lenalidomide, dexamethasone]had not been reached, but for the Rd [lenalidomide, dexamethasone] had been reset at about 32 months. The study had shown more than 3-fold MRD-negativity rates at that time.

The MAIA data were updated at a median follow-up of 48 months at ASH [American Society of Hematology Annual Meeting] recently. Even after 48 months of follow-up, the median PFS on the DRd arm [daratumumab, lenalidomide, dexamethasone] had not been reached, which is quite unprecedented for a newly diagnosed transplant-ineligible study at this point.

And Rd [lenalidomide, dexamethasone] arm showed an improvement in the PFS that was supported with 34½ months with a hazard ratio of 0.54.

The depth of response continued to get better over time. The overall response rate was 93%, with a higher percentage of patients achieving CR and stringent CR in the DRd [daratumumab, lenalidomide, dexamethasone] arm compared with the Rd [lenalidomide, dexamethasone] arm. Looking at the MRD-negativity rates, those 2 continue to get better over time with a median follow-up of 48 months. Now MRD negativity rate on the DRd [daratumumab, lenalidomide, dexamethasone] arm was 31%.

Taking all these data together, I feel that DRd [daratumumab, lenalidomide, dexamethasone] would the best choice for this patient.

Saad Usmani, MD, analyzes the efficacy and safety data results from the phase 3 MAIA study.

Data Analysis from the Phase 3 MAIA Study 

 The way we approach taking treatments for patients with myeloma is by looking at patient-related factor and disease-related factors, and then obviously patient preference plays a role.

Performance status, comorbidities, and patient age are important factors. Comorbidities are also important: hypertension, corneal renal artery disease, diabetes, and other end-organ damage, such as renal insufficiency or for neuropathy. Significant cardiac diseasesare going to be important issues. Patients’ level of activity is going to be important. And from a disease perspective you must see if the patient has any high-risk features, because that influences the choice of treatments.

For a transplant-ineligible patient with revised ISS [insulin sliding scale] stage II disease without any high-risk features, the options would be to go for a VRd [bortezomib,lenalidomide, dexamethasone]–light approach or DRd [daratumumab, lenalidomide, dexamethasone] approach.

For this patient, my preference would be for DRd [daratumumab, lenalidomide, dexamethasone], given that she already has neuropathy. We are seeing phenomenal ongoing results with the MAIA clinical trial, which was a randomized phase 3 study that had looked at DRd [daratumumab, lenalidomide, dexamethasone] vs Rd [lenalidomide, dexamethasone] combination for patients such as this.

 in multiple myeloma is a challenge because you must consider disease burden as well as disease biology. There are some certain phenotypes or circulating plasma cells at the time of diagnosis or high-burden disease with venal insufficiency, which can impact survival outcomes. whereas there are other specific karyotype and FISH [fluorescence in situ hybridization] abnormalities, like chromosome 1q21 abnormalities, both gain amplification. Having 3 copies is called gain and having 4 or more copies of 1q21 is called amplification. Then having deletion 17p and translocation 1416 or 1420 are high-risk features.

We also consider translocation 4;14 outside the United States as a high-risk feature. But in the United States, because of the incorporation of proteasome inhibitors, the majority of translocation 4;14 patients do better than expected for a high-risk patient in the year 2020.

Saad Usmani, MD, discusses what first-line options are available for patients with multiple myeloma while highlighting the difficulties in defining high-risk characteristics associated with multiple myeloma.