Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine, course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses the role of daratumumab (Darzalex) in multiple myeloma.

Daratumumab is an FDA-approved monoclonal antibody that targets CD38, which is a target found on multiple myeloma plasma cells. This agent is being evaluated in new 3-drug and 4-drug combination regimens, Braunstein explains. For example, the phase 3 MAIA trial looked at the combination of daratumumab, lenalidomide (Revlimid), and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma, Braunstein says.

Updated results from the study, which were presented during the 2020 ASH Annual Meeting & Exposition, demonstrated a 48-month progression-free survival rate of 60% with DRd versus 38% with Rd. Ultimately, the findings indicated that adding daratumumab to Rd continued to elicit deeper responses with higher rates of complete responses (CR​s) compared with Rd alone, Braunstein explains.

In addition, the phase 2 GRIFFIN trial evaluated daratumumab plus lenalidomide, bortezomib (Velcade), and dexamethasone (D-RVd) compared with RVd alone in patients with transplant-eligible multiple myeloma. Updated results, presented during the 2020 ASH Annual Meeting & Exposition, showed that, the stringent CR rate was 63.6% in the D-RVd arm versus 47.4% in the RVd arm. Furthermore, the total minimal residual disease (MRD)–negativity rate in the D-RVd arm was 62.5% compared with 27.2% in the RVd arm. After only examining the MRD-evaluable group of patients, the MRD-negativity rate was 78.3% in those who received D-RVd versus 39.4% in those who received RVd alone, Braunstein concludes.

Videos

Marc J. Braunstein, MD, PhD, discusses the role of daratumumab in multiple myeloma. 

Dr. Braunstein on the Role of Daratumumab in Multiple Myeloma 

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine, course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses management strategies in multiple myeloma.

There is an art to managing multiple myeloma, says Braunstein. As such, patients are best served by experienced clinicians who are comfortable managing a host of different myeloma characteristics and are able to thoroughly explain available treatment options, Braunstein explains.

Notably, a patient’s fitness level plays a critical role in the treatment selection process, Braunstein says. Although fitness and performance status are not novel considerations in oncology, in multiple myeloma, data now support the use of frailty scores, which allows for a more comprehensive patient assessment. Moreover, this metric can assist in determining the role of autologous stem cell transplant (ASCT), says Braunstein. In the past few years, several studies have compared up-front ASCT with standard therapies in transplant-eligible patients. Notably, patients appear to derive better outcomes with consolidative ASCT, Braunstein concludes.

Marc J. Braunstein, MD, PhD, discusses management strategies in multiple myeloma. 
  


Dr. Braunstein on Management Strategies in Multiple Myeloma 

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses the expanding treatment armamentarium in multiple myeloma.

The treatment paradigm for newly diagnosed and relapsed/refractory multiple myeloma has undergone significant growth over the past 4 to 5 years, says Braunstein. Currently, patients who relapse on first-, second-, or later-line therapies have available options. 

Monoclonal antibodies have demonstrated utility in targeting various antigens expressed on the surface of myeloma cells for patients with newly diagnosed or relapsed/refractory disease, Braunstein explains. Other targets, such as XPO1 and BCMA, have been useful in developing novel targeted therapies.

Ultimately, the rise of targeted therapy lends itself to more precise and tailored treatment approaches. Future research efforts are needed to determine optimal combination strategies to ensure patients can derive the maximum duration of remission and overall survival from available options, concludes Braunstein.

Marc J. Braunstein, MD, PhD, discusses the expanding treatment armamentarium in multiple myeloma. 

Dr. Braunstein on the Expanding Armamentarium in Multiple Myeloma

In light of the recent approvals of combination anti-myeloma regimens containing monoclonal antibodies, as well as the robust pipeline of novel targeted agents likely to be approved in the next year, there is much optimism in the field of multiple myeloma (MM).

 However, elderly or frail patients with MM may not be eligible for certain treatments, such as adoptive T-cell therapies and bispecific antibodies, that hold the potential for serious adverse events (AEs) in this population. Therefore, inclusion of novel agents, such as monoclonal antibodies, as part of induction for elderly patients with newly diagnosed MM offers the potential to improve outcomes in this challenging population.

Considering the median age of diagnosis of MM is 69 years, and that most study results showing a benefit for consolidation with stem cell transplantation (SCT) have been limited to patients 70 years or younger, it is imperative to provide treatments that both prolong survival and maintain quality of life for older patients with newly diagnosed MM.

 Beyond biological age and performance status, geriatric assessments can provide quantitative measures of fitness that predictsurvivalandtreatmenttoxicities, there by stratifying patients fo rmore or less intensive therapies.

Because most phase 3 studies of novel agents have used conventional enrollment criteria based on factors such as performance status, SCT candidacy, and baseline organ function, rather than stratifying according to frailty measures, questions remain as to whether a one-size-fits-allapproach is suitable for all patients who are elderly/transplant ineligible. Nevertheless, recent randomized controlled studies of up-front triplet and quadruplet induction regimens including monoclonal antibodies have consistently demonstrated durability and tolerability in elderly patients with MM.

The 2014 publication of data from the FIRST trial (NCT00689936) showed a survival benefit with continuous lenalidomide (Revlimid) and dexamethasone compared with the combination of melphalan, prednisone, and thalidomide ( Thalomid) in transplant-ineligible patients ranging from 40 to 92 years (median overall survival [OS], 59 vs 49 months; P=.0023).

These data  demonstrated that prolongedexposuretonovelagentswas effective and tolerable in elderly patients.

Further, building on data that showed the efficacy of the monoclonal antibody daratumumab (Darzalex), particularly in elderly patients with relapsed MM,

 recent study findings have similarly demonstrated a benefit of up-front daratumumab in this population. According to data from the phase 3 ALCYONE study (NCT02195479) of patients with newly diagnosed MM ineligible for SCT aged 40 to 93 years,9 the combination of daratumumab with bortezomib (Velcade), melphalan, and prednisone (D-VMP) was superior to VMP alone. Updated survival analysis showed a 78% versus 68% OS at 36 months (HR, 0.60; P = .0003), again preserved in patients 75 years or older.

 Grade 3 or 4 hematologic AEs were similar between treatment groups, although respiratory tract infections were more common in the D-VMP arm (11.3% vs 4%).

In the phase 3 MAIA study (NCT02252172) comparing the combination of daratumumab, lenalidomide, and dexamethasone (D-Rd) to Rd in patients with a median age of 73 years (range, 45-90), a 38% reduction in progression was observed with D-Rd in the 44% of patients 75 years or older enrolled in the trial (HR, 0.62; 95% CI, 0.44-0.87).

Although the OS analysis has yet to be read out, the median progression-free survival (PFS) at 36.4 months was not reached in the D-Rd group compared with 33.8 months with Rd.11 As in the ALCYONE study, the rate of grade 3 or 4 infections was higher in the daratumumab-containing arm (32.1% vs 23.3%).

Although there were no overall differences in serious AEs (62.9% vs 62.7%), of note, fewer patients discontinued treatment in the D-Rd arm (7.1% vs 15.9%). The benefit of up-front daratumumab was not preserved in patients with high-risk cytogenetics; however, considering this was a relatively smaller subgroup of patients, it may take more time to see a benefit than has been demonstrated with daratumumab regimens in the relapsed setting.

 Health- related quality-of-life measures in the MAIA study were superior with D-Rd, with no statistical differences in cognitive decline between either arm at 12 months.

 In addition, in my practice, I favor giving subcutaneous daratu- mumab with these regimens, considering the lower rate of infusion reactions observed in the phase 3 COLUMBA study (NCT03277105).

Unpublished data using the anti-SLAMF7 monoclonal antibody elotuzumab (Empliciti) in combination with Rd compared with Rd alone in patients who are ineligible for SCT enrolled in the ELOQUENT-1 trial (NCT01335399) indicate that this study did not meet its primary end point of PFS.

 Encouraging early data from the combination of elotuzumab plus carfilzomib (Kyprolis), lenalidomide, and dexamethasone in the GMMG-CONCEPT trial (NCT03104842), which examined patients with newly diagnosed high-risk disease, showed a 100% overall response rate, with all 4 patients who were ineligible for SCT achieving a very good partial response.

With recent approvals of the anti-CD38 isatuximab-irfc (Sarclisa) and the BMCA-targeting antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) in the relapsed setting, it is likely that these agents will move into early lines of therapy. In fact, there are several ongoing studies of up-front monoclonal antibody combinations in elderly patients with MM or in cases which frontline SCT is not planned. Investigators are examining the oral proteasome inhibitor ixazomib (Ninlaro) in combination with daratumumab and low-dose dexamethasone in frail patients with MM in the phase 2 HOVON 143 study.

 In terms of quadruplet regimens, the ongoing phase 3 IMROZ (isatuximab plus lenalidomide, bortezomib, and dexamethasone; NCT03319667) and CEPHEUS (daratumumab plus RVD [lenalidomide, bortezomib, and dexamethasone]; NCT03652064) studies are both looking at patients with MM in which SCT is not planned as a frontline therapy. Notwithstanding the availability of alternative regimens that have also demonstrated efficacy in patients ineligible for SCT, such as RVD at either conventional or attenuated (RVD lite) doses,

 it is very likely that given their combined efficacy and tolerability, most elderly patients with MM will be candidates for frontline monoclonal antibodies. However, applying frailty measures may help stratify those who are more likely to develop higher-grade AEs. In these frail patients, dose-reduced triplet or doublet regimens may be more appropriate.

One question arises in the context of the largely positive data for up-front monoclonal antibody regimens in elderly patients with MM: Should all elderly patients receive these regimens? Although tolerability may be acceptable, the patients with higher frailty measures who were excluded from the phase 3 studies shown in 

 might be better served with less intensive regimens. For example, frail patients with MM may not be able to travel to an infusion center for the initial weekly daratumumab induction period over 2 months. In addition, the annual cost of treatment for a regimen such as DRD (daratumumab, lenalidomide, and dexamethasone) is estimated to be $290,000, which will be even higher with quadruplet regimens, particularly when expanded over a several-year period.

 Because both D-VMP and D-Rd regimens have category 1 National Comprehensive Cancer Network recommendations, insurers are likely to cover these treatments, although potential financial toxicity should be a consideration, particularly for elderly patients receiving regimens containing oral agents.

Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. 

 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). 

. 2018;36(suppl 15):4074. doi:10.1200/JCO.2018.36.15_suppl.4074

Bristol-Myers Squibb announces results from CheckMate -459 study evaluating Opdivo (nivolumab) as a first-line treatment for patients with unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. June 24, 2019. Accessed October 20, 2020. https://bit.ly/37lhP73

Zhu AX, Kang YK, Yen CJ, et al; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2019;20(2):282-296. doi:10.1016/S1470-2045(18)30937-9

Galle PR, Foerster F, Kudo M, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. 

. 2019;39(12):2214-2229. doi:10.1111/liv.14223

Articles

In light of the recent approvals of combination anti-myeloma regimens containing monoclonal antibodies, as well as the robust pipeline of novel targeted agents likely to be approved in the next year, there is much optimism in the field of multiple myeloma. 

Should All Elderly Patients With Newly  Diagnosed Multiple Myeloma Receive Monoclonal Antibodies?

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses the utility of maintenance therapy in patients with multiple myeloma.

​In both prospective studies and meta-analyses, maintenance therapy has demonstrated an overall survival benefit in patients with multiple myeloma, particularly after autologous stem cell transplantation (ASCT), says Braunstein.

Maintenance therapy can target the multiple myeloma clone over time with ​reduced-dose therapies, explains Braunstein. Implementing active surveillance throughout treatment can identify resistant clones.

Multiple myeloma remains an incurable disease because patients have multiple non-identical plasma cell clones ​at diagnosis. Moreover, some of these clones may persist in the bone marrow microenvironment following ASCT, Braunstein concludes.

Marc J. Braunstein, MD, PhD, discusses the utility of maintenance therapy in patients with multiple myeloma.

Dr. Braunstein on the Utility of Maintenance Therapy in Multiple Myeloma

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses updated results from the GRIFFIN trial in multiple myeloma.

The phase 2 GRIFFIN study evaluated the addition of daratumumab (Darzalex) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) versus the standard triplet regimen of RVd in transplant-eligible patients with myeloma. The results showed an improvement in progression-free survival with the quadruplet. Additionally, the primary endpoint, which was stringent complete response (sCR), was superior at every evaluable timepoint in the quadruplet arm compared with the triplet arm.

The quadruplet could become the new standard of care for transplant-eligible patients, says Braunstein. However, longer-term follow-up data are needed in order to see which patient benefits the most from this treatment, concludes Braunstein.

Marc J. Braunstein, MD, PhD, discusses updated results from the GRIFFIN trial in multiple myeloma.

Dr. Braunstein on Updated Results of the GRIFFIN Trial in Multiple Myeloma

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses updated results from the GRIFFIN trial in multiple myeloma.

The phase 2 GRIFFIN study evaluated the addition of daratumumab (Darzalex) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) versus the standard triplet regimen of RVd in transplant-eligible patients with myeloma. The results showed an improvement in progression-free survival with the quadruplet. Additionally, the primary endpoint, which was stringent complete response (sCR), was superior at every evaluable timepoint in the quadruplet arm compared with the triplet arm.

The quadruplet could become the new standard of care for transplant-eligible patients, says Braunstein. However, longer-term follow-up data are needed in order to see which patient benefits the most from this treatment, concludes Braunstein.

Marc J. Braunstein, MD, PhD, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discusses quadruplet therapies in multiple myeloma.

The field has had quadruplet therapies for many years in the form of multi-chemotherapy agents and involve cytotoxic agents. Although these combination chemotherapies were not specifically designed for multiple myeloma, but they were effective against aggressive plasms cell clones, explains Braunstein.

Now that more targeted therapies and monoclonal antibodies are available, physicians are able to consider quadruplet therapies for many more patients because these drugs are much more tolerable since they are targeted.

As such, research efforts are now focused on taking the monoclonal antibodies, which have been approved for use in the second- or third-line setting, and using them in combination with standard triplet regimens up front for myeloma, concludes Braunstein.

Marc J. Braunstein, MD, PhD, discusses quadruplet therapies in multiple myeloma.

Dr. Braunstein on Quadruplet Therapies in Multiple Myeloma

Marc J. Braunstein, MD, PhD, clinical assistant professor in the Department of Medicine and co-director of the Autologous Stem Cell Transplant Program at NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, factors to consider when determining whether a patient with multiple myeloma is eligible for stem cell transplant.

It is important to be able to assess a patient not just when first meeting them and making a diagnosis of multiple myeloma, but at every step of their induction therapy to determine how fit they are for stem cell transplant, says Braunstein.

Ultimately, the time at which a patient is assessed for fitness of transplant is when they are first diagnosed and then right before stem cell transplant. Typically, the patient will be referred to a bone marrow transplant specialist, says Braunstein.

Some of the factors to consider when determining a patient’s eligibility for the procedure include: performance status, functional status, response to treatment, whether they achieved a partial remission or a very good partial remission, vital organ function, whether the patient understands the risks and benefits of the procedure, and whether they have a support system to allow them to go through the process, concludes Braunstein.

Marc J. Braunstein, MD, PhD, factors to consider when determining whether a patient with multiple myeloma is eligible for stem cell transplant.

Dr. Braunstein on Considerations for Stem Cell Transplant Eligibility in Myeloma

Marc J. Braunstein, MD, PhD, clinical assistant professor, Department of Medicine, co-director, Autologous Stem Cell Transplant Program, NYU Winthrop Hospital, NYU Langone Health’s Perlmutter Cancer Center, discusses transplant eligibility in multiple myeloma.

Historically, patients with newly diagnosed disease were evaluated to determine if they were fit to receive high-dose chemotherapy with melphalan followed by autologous stem cell transplant (ASCT), says Braunstein.

Now, a patient’s general fitness informs whether they should receive intensive or less intensive upfront treatment, says Braunstein. It is important to consider the trajectory of the patient, regardless of whether or not they will continue on to high-dose consolidation with chemotherapy and ASCT.

Transplant-ineligible patients typically receive a doublet, triplet, or quadruplet regimen, says Braunstein. The goal is for these patients to achieve remission and then continue onto maintenance therapy.

For transplant-eligible patients, triplet or quadruplet therapies are standard induction regimens followed by consolidation with ASCT, concludes Braunstein.

Marc J. Braunstein, MD, PhD, discusses transplant eligibility in multiple myeloma.

Marc J. Braunstein, MD, PhD

Articles

Dr. Braunstein on the Role of Daratumumab in Multiple Myeloma

Dr. Braunstein on Management Strategies in Multiple Myeloma

Dr. Braunstein on the Expanding Armamentarium in Multiple Myeloma

Should All Elderly Patients With Newly Diagnosed Multiple Myeloma Receive Monoclonal Antibodies?

Dr. Braunstein on the Utility of Maintenance Therapy in Multiple Myeloma

Dr. Braunstein on Updated Results of the GRIFFIN Trial in Multiple Myeloma

Dr. Braunstein on Updated Results of the GRIFFIN Trial in Multiple Myeloma

Dr. Braunstein on Quadruplet Therapies in Multiple Myeloma

Dr. Braunstein on Considerations for Stem Cell Transplant Eligibility in Myeloma

Dr. Braunstein on Transplant Eligibility in Multiple Myeloma