Deborah Abrams Kaplan

Until recent years, cancer treatment revolved around surgery, chemotherapy, and radiation. But the FDA approval of ipilimumab (Yervoy) in 2011 led to a fourth leg of that treatment stool: immunotherapy. This enabled new treatment paradigms, sometimes with shocking levels of success.

The types of immunotherapy treatments available are proliferating, with approved immune checkpoint inhibitors (ICIs) and cellular therapies like chimeric antigen receptor (CAR) T cells as well as other modalities in the research and discovery phases. Some even include more established approaches like vaccines that are being revisited with new information and iterations.

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy. The Bacillus Calmette-Guérin vaccine, used to prevent tuberculosis for a century, has also been used as an immunotherapy to treat non–muscle invasive bladder cancer since 1990.

 And rituximab (Rituxan), a monoclonal antibody therapy approved in 1997 for B-cell malignancies, is seen by some as an early immunotherapy as well.

What many clinicians think of in terms of immunotherapy, however, are treatments targeting CTLA-4 and PD-1/PD-L1 pathways, brought from the bench by James P. Allison, PhD, and Tasuku Honjo, PhD, respectively, leading to a Nobel Prize awarded jointly to them in 2018.

Immune responses are tightly controlled by T cells, and these T cells have on/off switches that help control their responses, according to Padmanee Sharma, MD, PhD, a professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine and the scientific director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center in Houston. Previously, she said, clinicians were not aware of the off switches. Allison showed that CTLA-4 was an inhibitory pathway and that by blocking it, the T cells could stay longer to eradicate the tumors.

With 8 ICIs approved for immunotherapy in hematological and solid tumors,

 researchers are not only investigating newer forms of therapy, but also combining them to fi nd more effective and durable treatments and introducing them into earlier lines of treatment (TIMELINE). Current research is also attempting to predict who will respond to which therapy based on current and emerging biomarkers.

Ipilimumab, which kicked off the current era of cancer immunotherapy treatment with FDA approval in 2011, targets CTLA-4 for newly diagnosed or previously treated unresectable or metastatic melanoma.

 Ipilimumab blocks CTLA-4, removing its inhibitory signals. This allows the T cells to activate and launch an immune response to the tumor’s antigens.

“CTLA-4 is basically the fi rst inhibitory pathway that comes up on the T cells,” Sharma said. CTLA-4 is a member of an immunoglobulin-related receptor family responsible for some immune regulation aspects of T cells.6 It is thought to regulate T-cell proliferation mostly in lymph nodes, early in an immune response, by having an inhibitory role.

“What ipilimumab really did and what the immune checkpoint inhibitors really did is they opened up this whole different way to approach the immune system,” Elizabeth Buchbinder, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said. Ipilimumab provided amazing durable responses in patients with melanoma with widely metastatic disease, some of whom were alive 10 years later, she said.

The PD-1 and PD-L1 blockades build on ipilimumab’s success. Like CTLA-4, PD-1 is a negative regulator of T-cell immune function, inhibiting the target to increase immune system activation. PD-1 suppresses T cells mostly in the peripheral tissues.

 As of November 2021, 8 ICIs have been approved that target CTLA-4, PD-1, and PD-L1 pathways and treat 18 types of cancer.

The percentage of people who benefi tted from ipilimumab was on the low side, Buchbinder said, with only an 11% response rate and 20% of people doing well long term in clinical trials. With PD-1 inhibition, however, there was approximately a 40% response rate and many more patients doing well long term, as demonstrated in clinical trials. “So [PD-1 inhibition is] both far more effective and also less toxic,” Buchbinder said.

When choosing an agent in the PD-1 class, “we don’t need to differentiate them. They’re all anti–PD-1,” Sharma explained. “There aren’t any data to indicate that patients will respond any differently to pembrolizumab [Keytruda] vs nivolumab [Opdivo]. The mechanism of action for both drugs [is] exactly the same.”

Instead, clinicians should consider the FDA approvals for each drug’s indications and combinations. “But from a scientific standpoint, there’s no distinguishing between [them],” Sharma said.

PD-1 and PD-L1 targeting drugs were found to work beyond melanoma and kidney cancer, the early indications for treatments targeting the CTLA-4 pathway, Buchbinder said. “That was a huge opening up of this fi eld to all of these other cancers, like lung cancer, head and neck cancer, GI [gastrointestinal] cancer, breast [cancer], and beyond,” she said.

Before receiving these immunotherapies, patients may need to show PD-1 or PD-L1 expression, although this may not identify all patients who can benefi t from the treatments. Researchers continue to try to identify additional and better biomarkers to indicate which patients may respond.

In March, the FDA approved the newest ICI, nivolumab and relatlimab-rmbw (Opdualag), for adult and pediatric patients (12 years and older) with unresectable or metastatic melanoma. 3 Nivolumab is a PD-1 inhibitor, and relatlimab blocks LAG3 proteins on immune cells. “It is being tested in a lot of other tumors,” Buchbinder noted.

Another target in the discovery phase is T cell immunoglobulin and mucin domain 3, which is a checkpoint receptor expressed by many immune cells and leukemic stem cells.

It is activated by several ligands and is being tested in different cancer types.

Also in clinical trials are tumor-infiltrating lymphocytes (TIL) that recognize cancer cells as abnormal, entering the tumor to kill the cells. TILs already recognize the targets because they originate from the tumor itself.

Although they need to be expanded, they are not the same as CAR T cells, which must be engineered to recognize the targets.

In addition, older therapies are experiencing a resurgence, with research underway to make interleukin 2 (IL-2) help cytokines function better. “That work is trying to optimize what those cytokines do in the body and the immune system,” Buchbinder said. “There are so many areas where the goal of the therapy is activation of the immune system.”

One of these areas includes a return to vaccines. In earlier vaccine therapy, “We had no idea that while we were giving therapy to turn on the cells, we were also rapidly turning off the cells because an ‘on’ switch will automatically drive an ‘off’ switch for the immune system,” Sharma said. “The yin and the yang of the immune response is very important to understand” because when the immune response is driven in one direction, it will always try to control itself. With that in mind, newer vaccines might work better if given in combination with an anti–CTLA-4, for example, to block the inhibitory pathways, she said.

Vaccines are taking many forms, including the mRNA vaccine used for COVID-19, peptide vaccines that include a tiny bit of protein that is expected to be expressed on the tumor surface, and vaccines constructed from dendritic cells, which stimulate T cells, Buchbinder said.

There are also viral therapies injected directly into tumor vaccines, such as talimogene laherparepvec (Imlygic) approved in 2015 for the treatment of some patients with metastatic melanoma that cannot be surgically removed.

 It is a is a modifi ed herpes virus directly injected into the tumor to bring about a local immune response, Buchbinder said.

According to Sharma, approximately 60 targets are currently being evaluated for immunotherapy development.

The FDA has approved 2 CAR T-cell therapies, both in 2017: tisagenlecleucel (Kymriah) for patients 25 years and younger with relapsed B-cell precursor acute lymphoblastic leukemia

 and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to fi rst-line chemoimmunotherapy or that relapses within 12 months of fi rst-line chemoimmunotherapy.

These treatments involve collecting T cells from the patient and engineering them to express CARs that recognize the patient’s cancer cells. The cells are then enlarged and infused back into the patient, where they can target the antigen- expressing cancer cells. CARs have been shown to greatly improve clinical response and disease remission in some patients.

“I think CAR T cells are clearly building on the concept that T cells are the soldiers of immune response. They are basically engineering the cell to have an antibody that recognizes a specifi c antigen,” Sharma said, adding that it’s important to ensure the targeted antigen is part of the cancer.

CAR T cells have had limited effectiveness in treating solid tumors, given the low T-cell infiltration and immunosuppressive environment that challenges the immune system from successfully reaching and killing solid tumor cancer cells.

Natural killer (NK) cells are another cell type being researched to attempt tumor eradication, and this therapy is in the early stages, according to Sharma. CAR NK cells can be generated from allogenic donors, making them more attractive as “off the shelf” treatments compared with CAR T cells, which are collected from the patient. As of early 2021, more than 500 CAR T-cell trials and 17 CAR T-cell/NK-cell trials were in the works globally.

A major consideration when choosing any treatment, including immunotherapies, is the adverse event (AE) profile. Immunotherapy drugs have different AEs than oncology treatments like chemotherapy or radiation. “[With immunotherapy,] what we see is infl ammation because you’re turning on the immune system in such a powerful way,” Sharma said. Inflammatory reactions include a skin rash or dermatitis, infl ammation in the colon (colitis and diarrhea), and/or infl ammation in the lung with pneumonitis. Clinicians are now aware of these AEs and can monitor them closely, stopping therapy if needed to control them before they become severe, Sharma said.

Toxicities with ipilimumab can be severe, and patients requiring hospital admission might need high-dose steroids, Buchbinder noted. Common AEs for the CTLA-4 inhibitor are typically GI related, including diarrhea, colitis, and hepatitis. Some patients may experience fatigue or a small rash, but most generally make it through treatment with minimal AEs.

The stronger AEs with ipilimumab can be seen from a trial comparing ipilimumab plus nivolumab to nivolumab and relatlimab. Almost 60% of patients experienced AEs with the ipilimumab combination vs 20% in the latter group.

PD-1 and PD-L1 inhibition typically involve AEs that cause lung issues rather than GI. The types of organ systems affected by immunotherapy AEs can vary based upon which checkpoint inhibitor you use “but in some ways, the mechanism by which these occur is very similar,” Buchbinder said. “It’s all an overactivation of the immune system leading to infl ammation in an organ, and there are very few organs that we have not seen toxicity from immunotherapy.”

Buchbinder noted that cellular therapies can cause more severe AEs, such as cytokine release syndrome (CRS). “Patients can get very sick very quickly,” she said, because the therapies given with the cells—including the chemotherapy given before and the IL-2 given after—cause most of the AEs. With a lot of the injection therapies, the AEs are related to delivery method, like injection-site issues, but there are also potential systemic AEs like fever, chills, and reactions someone would get to a virus. “It’s really a huge range in terms of the different [adverse] effects,” Buchbinder said.

CRS is the most common AE of CAR T-cell therapy, and it is caused by large numbers of T cells activating, which releases inflammatory cytokines. Although this demonstrates that the therapy is working, it can cause worrisome symptoms. The CRS and the related neurotoxicity can be treated with tocilizumab (Actemra).

One question in the immunotherapy world is whether the development of immune-related AEs predicts a positive or negative response to treatment. “With melanoma, we think the data have been very tricky,” Buchbinder said. Early trials appeared to show a higher response rate for patients who developed severe symptoms, but as trials developed, that signal was not always there. “I think the overall impression is that yes, severe AEs are associated with a better response,” she said. A cosmetic AE that clinicians who treat melanoma are excited to see, she said, is vitiligo. “It suggests that the immune system is attacking normal melanocytes and that it is attacking cancer cells as well. Those patients generally do far better than patients who don’t get vitiligo.”

A meta-analysis of 30 studies on the topic, including 4971 individuals, showed that patients who developed immune-related AEs experienced an overall survival benefi t and a progression-free survival benefi t using ICI therapy compared with those who did not. The authors stated that more studies are needed and that the results are controversial.

Melanoma has been the proving ground for ICIs, Buchbinder said, “But now the bar is higher in terms of immunotherapy.”

ICIs are now being tested in more immuneresistant tumors. “Although there are huge hurdles in terms of some cancers where it’s going to be hard for immune therapy to do much—like pancreatic cancer or prostate cancer—there are still diseases where there’s opportunity and a possibility that the correct approach or combination might get to some great therapy for those diseases,” Buchbinder said 

Immunotherapies are being combined with conventional therapies to better integrate treatment. “We don’t see cancer as a death sentence anymore,” Sharma said. “We really do see a lot of hope, [and patients with cancer] should be encouraged to discuss immunotherapy with their physician either in a clinical trial or an FDA-approved agent. If you do have a response, it’s a pretty phenomenal response.”

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Articles

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy.

10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes

Treatment options have expanded widely for patients with multiple myeloma
over the past several years, resulting in significantly improved outcomes for these patients.

Two decades ago, the median survival was approximately 3 years, and now it is 8 to 10 years

 — and can be even longer for many patients, according to Kenneth C. Anderson, MD, 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, Massachusetts. The reason? Anderson attributed it to combining classes of drugs like proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies for newly diagnosed patients and those with relapsed/refractory multiple myeloma. “We can increase the frequency of response and the extent of response, so we get very deep responses,” he said. 

In 2021, there were an estimated 34,910 new cases of myeloma, accounting for 1.8% of all new cancer cases. Last year, approximately 12,410 individuals died from myeloma. Death rates have decreased slightly in the past decade, from 3.4 per 100,000 in 2012 to 3.0 per 100,000 in 2019, the last year data were available (FIGURE).

In the past decade, the FDA approved 13 new agents and 29 treatments for multiple myeloma, which have transformed the treatment paradigm for patients with newly diagnosed and relapsed/ refractory multiple myeloma, according to Anderson. “Most importantly, it’s changed the outlook and the outcome for our patients,” he said in an interview with 

What follows are the 10 top advances in multiple myeloma from the past decade. 

In the 1980s, doctors relied on high-dose chemotherapy and autologous stem cell transplantation (ASCT) from bone marrow, Anderson said. In the 1990s, treatment included high-dose therapy and peripheral blood as a source of stem cell transplant.

 By the late 1990s and the first decade of 2000, IMiDs and proteosome inhibitor drugs were approved for use in multiple myeloma. 

Around 2012, lenalidomide (Revlimid) and dexamethasone (Rd), followed by ASCT, became a standard-of-care treatment option. Intermediateor high-risk patients might have received a bortezomib (Velcade)–based induction therapy, followed by ASCT, with bortezomib-based maintenance. Patients ineligible for ASCT might have received Rd for standard-risk disease or a bortezomib-based treatment for intermediate- or high-risk disease.

“The big debate at that time was, ‘Was is it good to combine our 2 most active agents, or should we try and sequence agents so that we preserve or save treatments for later on?’” Sagar Lonial, MD, FACP, said. Lonial is chief medical officer of Winship Cancer Institute of Emory University and professor and chair of the Department of Hematology and Medical Oncology as well as the Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine in Atlanta, Georgia. 

These patients may have experienced increased survival rates from the treatment, but almost all would relapse.

The past decade saw paradigm shifts in myeloma management, including early intervention. The International Myeloma Working Group updated its diagnostic criteria in 2014 to add validated biomarkers beyond the standard CRAB features (hypercalcemia, renal failure, anemia, and bone lesions) for defining multiple myeloma.

 Additionally, treatment options were added for some patients with smoldering multiple myeloma; patients could be treated earlier, based on their risk of end-organ damage, according to Shaji Kumar, MD, a professor of medicine and consultant for the Division of Hematology at Mayo Clinic in Rochester, Minnesota. 

“Clinical trials have shown that there’s an advantage to starting to treat patients with smoldering multiple myeloma who are at a very high risk of disease progression,” Kumar said. 

Previously, patients with smoldering myeloma were treated only when they developed complications, such as high blood calcium, kidney dysfunction, anemia, or bone disease, Anderson said. With the advent of effective and well-tolerated novel agents, these complications may be prevented.

The current standard induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd)

 and single ASCT for eligible patients, followed by risk-adaptive maintenance, has shown median progression-free survival (PFS) of 65 months for all patients and 76.5 months for standard-risk patients. The median overall survival (OS) is 126.6 months.

“I think what allowed us to do that was combining drugs together, getting deep responses, building on those deep responses with transplant, and then using risk-adapted maintenance,” Lonial said. Physicians currently debate the need for 4-drug regimens, such as with the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex), to further improve outcomes. 

Transplant remains a standard of care for those who are eligible. “If you put the RVd and daratumumab before and after a transplant, you can get minimal residual disease [MRD]–negative responses in 70% of patients, which is quite remarkable, and that does correlate with much better outcomes,” Anderson said.

RVd lite is a modified regimen with a lower dose of lenalidomide, which also has high response rates and a long PFS, with a favorable adverse event profi le for nontransplant candidates, Anderson said. The median PFS with the modified regimen was found to be 35.1 months,

 and this triplet as well as the daratumumab with lenalidomide and dexamethasone triplet have become preferred regimens for patients who are ineligible for transplant.

Eliminating ASCT is a topic of discussion but not currently advised.

 “I would be cautious about throwing out transplant,” Lonial said. “We’ve been trying to do that for 15 years, and it continues to survive and thrive even in the context of new treatments.” That is because every trial comparing transplant to no transplant, even with new drugs, has shown that transplant deepens the response and offers significant benefits, he said. 

In the past decade, the proteosome inhibitor class of drugs has expanded, with the FDA approval of carfilzomib (Kyprolis) in 2012

 the first FDA-approved oral proteasome inhibitor (TIMELINE). Carfilzomib acts as a single agent or a doublet with dexamethasone.

“Pomalidomide [Pomalyst] and carfilzomib are playing a much greater role in the management of patients throughout their disease course now than they [did] a decade ago, and they have significant advantages in terms of toxicity as well as potency that I think makes them...great drugs for us to have available for our patients,” Lonial said. 

Carfilzomib is considered the more potent of the proteasome inhibitors.

 In the ENDEAVOR trial (NCT01568866), carfilzomib was compared with the first-generation proteasome inhibitor bortezomib, both in combination with dexamethasone, in patients with relapsed/refractory multiple myeloma. The median PFS was approximately double for carfilzomib/dexamethasone compared with bortezomib/dexamethasone at 18.7 months vs 9.4 months, respectively (HR, 0.53; 95% CI, 0.44-0.65;

Ixazomib is advantageous as an oral agent, with the phase 3 TOURMALINE-MM1 trial (NCT01564537) showing a PFS advantage for oral ixazomib plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone alone (20.6 months vs 14.7 months, respectively; HR, 0.74; 

 .01) in patients with relapsed/ refractory disease.

 Although patients can get some peripheral neuropathy, recent clinical trials show it is not as potent as with some other proteosome inhibitors,

Anderson defines this past decade as the “immune era,” and Lonial agrees, noting that the revolution in myeloma treatment during the past 10 years has been in immune-based therapies. That includes daratumumab, which has become important for patients who are ineligible for ASCT, based on the results of the MAIA trial (NCT02252172).

 Investigators found a significant PFS benefit for daratumumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone alone in transplant-ineligible patients with newly diagnosed multiple myeloma (not reached vs 34.4 months, respectively; HR, 0.53; 95% CI, 0.43-0.66; 

< .0001). “The average remission is around 5 years. That’s better than anything else we’ve seen in that patient population,” Lonial said. “But it’s continuous therapy.” 

Daratumumab has single-agent activity and “is potent in pretty much every combination we tested, whether it’s a proteosome inhibitor or an IMiD or in combination with other immune therapies,” Lonial noted. 

Daratumumab targeting CD38 and elotuzumab (Empliciti) targeting SLAMF7 were both approved in 2015.

Elotuzumab “doesn’t have single-agent activity but does have effects in combination with both lenalidomide and pomalidomide in phase 3 trials, demonstrating superiority over lenalidomide and pomalidomide alone,” Lonial said. 

In the phase 3 ELOQUENT-2 trial (NCT01239797), elotuzumab in combination with lenalidomide and dexamethasone showed a significant increase in PFS compared with lenalidomide and dexamethasone alone (19.4 months vs 14.9 months, respectively; HR, 0.70; 95% CI, 0.57-0.85; 

A new formulation of daratumumab with hyaluronidase-fi hj (Darzalex Faspro) was approved in 2021.

 “[It] has been a big game changer for myeloma because it’s been combined with a variety of different drugs, and the combinations of it are quite effective,” Kumar said, noting that it is also well tolerated. Usage of the subcutaneous formulation became especially important during the COVID-19 pandemic, when oncologists sought to reduce the number of office visits to safeguard patients’ health. 

Pomalidomide was approved in 2013 as a second-generation IMiD that can overcome resistance to lenalidomide and thalidomide (Thalomid).

 In the phase 3 NIMBUS/MM-003 trial (NCT01311687) that enrolled patients with relapsed/refractory multiple myeloma and at least 2 prior therapies, pomalidomide and low-dose dexamethasone showed an improved PFS compared with high-dose dexamethasone (4.0 months vs 1.9 months, respectively; HR, 0.48; 95% CI, 0.39-0.60; 

In the past decade, patients with multiple myeloma benefi ted from development and approvals in other treatment classes, including antibody-drug conjugates (ADC), nuclear transport inhibitors, and IMiDs. The ADC belantamab mafodotin-blmf (Blenrep) was approved in 2020

; it has single-agent activity in relapsed/refractory myeloma and is being considered in combinations as well. The agent is labeled for use after at least 4 prior therapies, but the prescribing label comes with a boxed warning for alterations in vision. Lonial highlighted that it is the first of the B-cell maturation antigen (BCMA)–directed treatments, a promising novel therapeutic target in multiple myeloma due to its expression on mature B lymphomas and limited expression on hematopoietic stem cells.

The XP01 nuclear transport inhibitor selinexor (Xpovio) was approved in 2019.

 It has a new target and mechanism of action, Lonial noted, and is approved alone, with dexamethasone, in combination with proteasome inhibitors, and in earlier lines of relapse. 

The histone deacetylase inhibitor panobinostat (Farydak) received accelerated approval in 2015 from the FDA for previously treated multiple myeloma,

 but the indication was withdrawn in 2021 because the manufacturer could not complete the necessary postapproval clinical research to maintain approval.

 “At this point, it’s something that cannot be easily used [for myeloma],” Kumar said. 

One of the decade’s big stories in myeloma is chimeric antigen receptor (CAR) T-cell and bispecific T-cell engager (BiTE) therapies. The CAR T-cell therapy idecabtagene vicleucel (Abecma) was approved in 2021.

The anti-BCMA targeted therapy “clearly has activity and depth of response in a refractory patient population and is being tested in earlier lines of therapy as well,” Lonial said. He added that the average response is approximately a year and that the average response for ciltacabtagene autoleucel (cilta-cel; Carvykti), which was recently FDA approved,

 looks to be about 2 years. “CAR T cells offer us a window into a way to use BCMA as a mechanism by which to eradicate the clone,” he said. Cilta-cel was approved by the FDA on February 28, 2022, for adults with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

“The 2 CAR T-cell therapies have been remarkable in that they have achieved complete and even MRD-negative responses in patients with far advanced relapsed/refractory myeloma, who literally have no other options,” Anderson said. 

BiTEs are not yet FDA approved but look promising. “I think many of us were skeptical that [BiTEs] would be active in myeloma, given that T-cell health may be suboptimal in a refractory myeloma patient population. But that’s clearly not the case, with response rates between 60% and 80% with any of the BCMA-directed CAR T cell or bispecifics,” Lonial said, noting that he is excited about the potential of having an off-the-shelf immune-stimulator product, which could be a great adjunct to CAR T cells. 

Between 6 and 12 BiTEs are in clinical trials for myeloma, Anderson said. Most CAR T and BiTE products target BCMA, as does belantamab mafodotin.

 “It’s a good target, and right now it’s only being targeted in far-advanced myeloma—but it’s going to be used earlier in the disease course,” he said.

MRD: The Potential End to Continuous Therapy 

Clinicians are using end points like MRD to begin to potentially move away from continuous therapy, Lonial said. “With the availability of potentially sustained MRD negativity as an end point, we may be getting to a point where we can stop therapy,” he said. 

MRD is assessed with multicolor flow cytometry or gene sequencing,

 Anderson said. Triplet and quadruplet treatments can achieve MRD negativity in patients with newly diagnosed and relapsed/refractory multiple myeloma, he noted, and a durable response correlates with marked PFS and OS advantages. 

Cytogenetics-Based Stratification Standards 

Myeloma is a heterogenous disease, and this newer revelation is leading to genetic risk stratification at diagnosis to determine therapy, Kumar said. “A one-size-fits-all approach may not be the best way to deal with patients with multiple myeloma,” he said. Different prognostic factors allow clinicians to better defi ne potential outcomes, helping them formulate individual treatment strategies. 

Fluorescence in situ hybridization testing is an accepted standard to help define whether a patient has standard- or high-risk multiple myeloma. This has markedly improved the prognostication in myeloma, Anderson said. 

There’s also a move toward molecular testing with gene sequencing or mutation analysis to determine disease risk, as well as mass spectrometry to determine treatment paths based on protein analyses. “Because mass spectrometry is a little bit more reproducible, it’s a little bit more objective,” Lonial said, noting that can make a difference when using antibodies like daratumumab and elotuzumab and potentially the BiTEs. 

Each therapy is a building block to new treatments. The words “cure” or “functional cure” are now in play, Kumar said. By extending the duration that myeloma is under control, at least for older patients, myeloma may not be the cause of death. Due to drug combinations and better supportive care, each treatment line can control the disease for 3 to 6 years, so patients are living longer with myeloma, he noted. 

Perhaps ASCT will be eliminated if BiTEs and/or CAR T cells can show better results than ASCT. The future for multiple myeloma treatment includes determining optimal therapy combinations based on disease characteristics, with the possibility of discontinuing treatment. “But, of course, our goal is to try and cure the disease,” Kumar said.

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Deborah Abrams Kaplan | Authors

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