NCCN Guidelines Include an Abundance of Options Across Multiple Myeloma Paradigm

Shaji K. Kumar, MD

The National Comprehensive Cancer Network (NCCN) guidelines for the management of frontline and relapsed/refractory multiple myeloma were updated to incorporate novel agents and combination strategies, providing a wide range of category 1 recommended therapies for patients, said Shaji K. Kumar, MD, during the 2021 NCCN Virtual Annual Conference.¹ 

“The treatment paradigm of multiple myeloma continues to evolve at a rapid pace with the introduction of several new therapies and changing concepts in terms of treatment goals of this chronic disease,” said Kumar, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic. “Clearly the long list of different drugs and combinations that [we can use to underscore] the progress that we have made in this field.”

Despite a wide range of systemic options, autologous stem cell transplant remains a key part of frontline treatment for eligible patients with newly diagnosed multiple myeloma, said Kumar. Updated findings from the IFM 2009 study showed that at a median follow-up of 93 months, the median progression-free survival (PFS) was 47.3 months with transplant after induction with the combination of bortezomib (Velcade), lenalidomide (Revlimid) and dexamethasone (VRd) vs 35.0 months with VRd alone (HR, 0.70; 95% CI, 0.59-0.83; P = .0001).² 

“Even with an effective induction therapy like VRd, transplant still has a role to play,” Kumar said. 

In the transplant-eligible setting, VRd remains the frontline standard of care for patients with newly diagnosed multiple myeloma and is included in the NCCN guidelines as a category 1 recommendation.¹ 

Findings from the SWOG S0777 study demonstrated an overall response rate (ORR) of 81.5% with VRd vs 71.5% with lenalidomide plus dexamethasone (Rd) alone in this patient population.³ The median PFS was 43 months with VRd vs 30 months with Rd (one-sided P = .0018). The median overall survival (OS) was 75 months vs 64 months, respectively (two-sided P = .0250). 

Updated data from the study demonstrated a median PFS of 41 months with VRd vs 29 months with Rd at a median follow-up of 84 months (HR, 0.742; 96% Wald CI, 0.594-0.928; one-sided P = .003).⁴ The median OS was not reached with VRd compared with 69 months with Rd (HR, 0.709; 96% Wald CI, 0.543-0.926; two-sided P = .0114). 

Attempts have been made to improve upon the VRd regimen, Kumar said. For example, the phase 3 ENDURANCE trial swapped bortezomib for carfilzomib (Kyprolis; KRd); however, the data failed to demonstrate an improvement in PFS with KRd vs VRd in patients with newly diagnosed multiple myeloma.⁵ In addition, the carfilzomib-based regimen induced additional toxicity.

“The [ENDURANCE] trial included only standard-risk patients and also deferred stem cell transplant to the time of first relapse in those patients who were eligible to go to stem cell transplant,” said Kumar. “Nevertheless, it is important to note that as a result of this trial, we still consider VRd the standard initial therapy for these patients.”

Despite these findings, KRd is a recommended regimen per the NCCN guidelines.¹ 

Although quadruplet regimens are not yet commonly utilized as induction therapy in the United States, the combination of daratumumab (Darzalex), bortezomib, thalidomide (Thalomid), and dexamethasone (D-VTd) is included as a useful regimen in certain circumstances in the NCCN guidelines. 

“Given that thalidomide-based triplets are not common induction therapies in the US, the results of the GRIFFIN trial are more pertinent,” Kumar said.

The randomized phase 2 GRIFFIN trial demonstrated a 42.4% stringent complete response (sCR) rate with the combination of daratumumab and VRd vs 32.0% with VRd alone (odds ratio, 1.57; 95% CI, 0.87-2.82; P = .068).⁶ Long-term data for PFS are pending. 

“There are certain settings, such as a high-risk patient population, where a quadruplet might be more appropriate given that these regimens are associated with higher minimal residual disease negativity, a characteristic that often appears to improve the outcomes of high-risk patients,” said Kumar.

“[However], while we are awaiting more data with [daratumumab and VRd], the standard approach is still thought to be a triplet containing a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD] in the transplant[-eligible] setting,” added Kumar. 

Additionally, the guidelines indicate that lenalidomide is a category 1 preferred maintenance regimen.¹ Recommended maintenance options include ixazomib (Ninlaro) and bortezomib, with the combination of bortezomib and lenalidomide being a maintenance option in certain circumstances.

In the transplant-ineligible setting, category 1 preferred regimens include VRd, daratumumab plus lenalidomide and dexamethasone, and lenalidomide plus low-dose dexamethasone per the NCCN guidelines.¹ 

The phase 3 ALCYONE trial demonstrated improved PFS, depth of response, and OS with daratumumab plus bortezomib, melphalan, and prednisone;⁷ however, like thalidomide, melphalan is not commonly used in the United States, said Kumar. 

“In the US, we don’t use melphalan-based regimens as much in the up-front setting,” said Kumar. “For us, IMID-containing regimens [serve as] a backbone on which we want to try to improve upon.”

The phase 3 MAIA trial randomized patients with transplant-ineligible newly diagnosed multiple myeloma to daratumumab plus lenalidomide and dexamethasone or lenalidomide plus dexamethasone alone. Updated findings revealed that at a median follow-up of 47.9 months, the median PFS was not reached with the triplet vs 34.0 months with the doublet (HR, 0.54; 95% CI, 0.43-0.67; P < 0.0001).⁸

Additionally, the phase 3 TOURMALINE-MM2 trial demonstrated a median PFS of 35.3 with oral ixazomib plus lenalidomide and dexamethasone vs 21.8 months with placebo plus lenalidomide and dexamethasone in patients with transplant-ineligible newly diagnosed multiple myeloma (HR, 0.830; 95% CI, 0.676-1.018; P = 0.073).⁹ Although the trend for PFS was positive with the triplet, these results were not statistically significant.

Daratumumab plus lenalidomide and dexamethasone is included in the guidelines as a category 1 preferred regimen, but ixazomib plus lenalidomide and dexamethasone is also included as a recommended regimen.¹ 

As in the frontline setting, the armamentarium of relapsed/refractory multiple myeloma is rich with preferred and recommended triplet regimens per the NCCN guidelines.¹ 

For example, bortezomib in combination with daratumumab and dexamethasone, and pomalidomide (Pomalyst) plus dexamethasone are recommended options. Lenalidomide-based triplets, such as lenalidomide plus carfilzomib and dexamethasone, lenalidomide plus daratumumab and dexamethasone, and lenalidomide plus ixazomib and dexamethasone, are also category 1 preferred regimens. 

“All of these 3-drug combinations have led to an improvement in PFS and, in some cases, improved OS as well [compared with the control regimens],” said Kumar. 

However, many patients with early relapsed multiple myeloma are refractory to lenalidomide, having received it as frontline induction or maintenance therapy, Kumar added. 

As such, the phase 3 ICARIA-MM trial randomized patients with relapsed/refractory multiple myeloma to isatuximab-irfc (Sarclisa) plus pomalidomide and dexamethasone or pomalidomide plus dexamethasone alone. At a median follow-up of 11.6 months, the median PFS was 11.53 months with the triplet vs 6.47 months with the doublet (HR, 0.596; 95% CI, 0.436-0.814; i = .001).¹⁰ The median 12-month OS rate was 72% vs 63%, respectively (HR, 0.687; 95% CI, 0.461-1.023; P = .0631). 

Similarly, the phase 3 APOLLO trial randomized patients who had received at least 1 line of prior therapy, including lenalidomide and a PI, to receive daratumumab plus pomalidomide and dexamethasone or pomalidomide plus dexamethasone alone. At a median follow-up of 16.9 months, the median PFS with the triplet was 12.4 months vs 6.9 months with the doublet (HR, 0.63; 95% CI, 0.47-0.85; P = .0018).¹¹ OS data are immature, and follow-up is ongoing. 

“Either of these monoclonal antibodies, [daratumumab or isatuximab], which target CD38, can be added to pomalidomide and dexamethasone, or we can elect to add a different monoclonal antibody like elotuzumab [Empliciti] to pomalidomide plus dexamethasone,” said Kumar. 

With the latter approach, elotuzumab plus pomalidomide and dexamethasone demonstrated a median PFS of 10.3 months compared with 4.7 months with pomalidomide and dexamethasone alone at a median follow-up of 9.1 months (HR, 0.54; 95% CI, 0.34-0.86; P = .008).¹² 

Beyond these regimens, IMiD-free combinations are also listed as category 1 preferred regimens for patients with relapsed/refractory multiple myeloma. 

The combination of carfilzomib, dexamethasone, and daratumumab (KdD) demonstrated efficacy in this patient population in the phase 3 CANDOR trial. After a median follow-up of approximately 17 months, the median PFS was not reached with KdD vs 15.8 months with carfilzomib/dexamethasone alone (HR, 0.63; 95% CI, 0.46-0.85; P = .0027).¹³ 

Additionally, interim findings from the phase 3 IKEMA trial showed that the median PFS was not reached with the combination of isatuximab, carfilzomib, and dexamethasone vs 19.15 months with carfilzomib/dexamethasone (HR, 0.531; 99% CI, 0.318-0.889; P = .0007).¹⁴ 

“[The IKEMA study] suggested that a monoclonal antibody in combination with a next-generation PI would be quite an appropriate choice for someone who is relapsing on lenalidomide maintenance treatment,” Kumar said. 

In the setting of late-relapsed, heavily pretreated multiple myeloma, novel agents, such as selinexor (Xpovio) and belantamab mafodotin-blmf (Blenrep), are also listed as recommended treatment options.¹

Initially, in the phase 2 STORM trial, selinexor in combination with dexamethasone demonstrated an ORR of 26.2%, including 2 sCRs in patients who had received a median of 7 prior lines of treatment for multiple myeloma.¹⁵ The median duration of response was 4.4 months, the median PFS was 3.7 months, and the median OS was 8.6 months with selinexor plus dexamethasone.

“The PFS [with selinexor/dexamethasone] is only about 4 months, but when you look at the OS, especially in those patients who are responding to therapy, you can see that these patients do derive benefit by using this agent,” said Kumar. “Compared with historic controls of similar groups of patients, there definitely appears to be a benefit [with selinexor], which led to its FDA approval.”

Building on these results, the phase 3 BOSTON trial randomized patients with relapsed/refractory myeloma who received 1 to 3 prior lines of therapy to once-weekly selinexor plus bortezomib and dexamethasone or twice-weekly bortezomib plus dexamethasone. The median PFS was 13.93 months with the triplet vs 9.46 months with the doublet (HR, 0.70; 95% CI, 0.53-0.93; P = .0075).¹⁶ 

As such, the once-weekly triplet regimen is now included as a category 1 recommended regimen per the NCCN guidelines, whereas other selinexor-based regimens, such as selinexor plus dexamethasone, selinexor plus daratumumab and dexamethasone, and selinexor plus pomalidomide and dexamethasone may be useful in certain circumstances. 

In terms of BCMA-directed therapy, single-agent belantamab mafodotin induced an ORR of 31% in patients who received the recommended dose of 2.5 mg/kg, according to findings from the phase 2 DREAMM-2 trial.¹⁷  

“In patients with relapsed disease, it is important to change the classes of therapy that we use. With the different therapies that have been approved, we can clearly develop combinations that will allow us to do exactly that.”

Additionally, immunotherapies, such as CAR T-cell therapy and T-cell engagers, are emerging in multiple myeloma, explained Kumar. “Immunotherapy is going to play a major role not only in relapsed disease, but also in the up-front setting,” Kumar said.

Notably, supportive care and toxicity management for patients with multiple myeloma remains a key aspect of the NCCN guidelines, Kumar explained.¹ 

The guidelines recommend supportive care for patients with multiple myeloma who develop bone disease, hypercalcemia, hyperviscosity, anemia, infection, renal dysfunction, and coagulation/thrombosis. 

Additionally, according to the guidelines, toxicities such as cytopenias, neuropathy, infusion-related reactions, fatigue, and long-term toxicities should be monitored closely and treated with appropriate prophylactic or active treatment, concluded Kumar.

Notably, specific guidelines for the management of renal dysfunction and monoclonal gammopathy of renal significance should be consulted to inform tests, treatment options, and supportive care for patients. An additional set of guidelines are available to inform the initial workup and clinical findings of patients with monoclonal gammopathy of clinical significance.

“We have introduced over time a separate category for monoclonal gammopathies of clinical and renal significance, which are important evolving areas in plasma cells disorders. [We’ve developed] increasing awareness that many clinical situations that were not previously considered to be related to monoclonal gammopathies are clearly [related to] an underlying, driving plasma cell disorder,” concluded Kumar. 

References

1. Kumar SK. NCCN guidelines® update: multiple myeloma. Presented at: 2021 NCCN Virtual Annual Conference; March 18-20; 2021; Virtual. 
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3. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X
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5. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6
6. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288
7. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3
8. Kumar SK, Facon T, Usmani SZ, et al. Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 Maia study. Blood. 2020;136(suppl 1):24-26. doi:10.1182/blood-2020-134847
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11. Dimopoulos MA, Terpos E, Boccadoro M, et al. Apollo: phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(suppl 1):5-6. doi:10.1182/blood-2020-135874
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13. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0
14. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 2316.
15. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455
16. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
17. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0