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Frontline treatment regimens for patients with multiple myeloma and renal impairment

Jul 14, 2020

Renal impairment, a common complication and a poor prognostic factor in multiple myeloma (MM), often leads to poor tolerability of common therapies. 1Data has shown that the recovery of renal function in patients with MM is associated with better survival outcomes compared with patients with non-reversible renal dysfunction. 2Clinical trials often exclude patients with MM with severe renal impairment, and data investigating the effects of induction treatment in this difficult-to-treat patient population is limited. These patients may also be ineligible for autologous stem cell transplant due to the severity of renal insufficiency. 2Another unmet medical need exists in the management of skeletal complications in patients with MM and renal dysfunction. 3  

Here, we provide a review of three abstracts presented at the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting, and one from the 6th World Congress on Controversies in Multiple Myeloma (COMy), that investigated the impact of treatment regimens in patients with MM and renal insufficiency.

Frontline therapy for patients under dialysis 4,5

About 50% of patients with MM have some degree of renal impairment at presentation, with 20% having acute kidney injury (AKI). About 1 5% of patients with MM require long-term dialysis. Renal failure in patients with MM is associated with an increased risk of infection and early death.

During COMy, Paula Rodriguez Otero (Clínica Universidad de Navarra, Pamplona, ES) discussed the current challenges of frontline treatment in patients requiring dialysis.

General recommendations on management of MM-related AKI

  • Diagnosis established as fast as possible and MM therapy started immediately after confirmation of diagnosis to rapidly restore renal function
  • Supportive care
    • Adequate hydration with fluids (≈ 2 L/m 2/day)
    • Control fluid balance
    • Avoid nephrotoxic drugs and check dose-adjustments
    • Urine alkalinization (controversial role)
    • Rapid management of intercurrent complications that may contribute to renal failure:
      • Infections
      • Hypercalcemia
        • Avoid bisphosphonates in creatinine clearance (CrCl) < 30 ml/min
        • Calcitonin + steroids
    • Furosemide is not recommended (increase cast formation)

Outcomes of patients with NDMM requiring dialysis 2

A single-center study analyzed the outcomes of patients with newly diagnosed MM (NDMM; N = 52) requiring dialysis. The median age of the patients was 69 (37─88) years, and 100% of patients had renal disease International Staging System Stage 3. The 82% (n = 43) of patients received bortezomib (V)-based treatment:

  • 21% (n = 11) V plus dexamethasone (d; Vd)
  • 44% (n = 23) V plus cyclophosphamide (C) and d (VCd)
  • 15% (n = 8) V plus thalidomide (T) and d
  • 2% (n = 1) PS-341/bortezomib plus doxorubicin and d (PAD)

Renal responses were observed in the 50% (n = 26) of patients, and dialysis independence in 49% (21/43) of V-treated patients. The MM response was:

  • Overall response rate: 64%
    • Complete response: 6%
    • Very good partial response: 32%
    • Partial response: 26%

Achieving a partial response in the first 2 months was associated with a higher probability of renal responses (68% vs27%; p = 0.004). Responders were able to discontinue dialysis and benefit of a better overall survival (median overall survival: 47 vs21 months in patients who discontinued dialysis vspatients who remained on dialysis, respectively).

Table 1. Regimens frequently used to manage MM related AKI in frontline setting 4

AKI, acute kidney injury; CR, complete response; d, dexamethasone; DRd, daratumumab plus Rd; IMiD, immunomodulatory drugs; MM, multiple myeloma; NDMM, newly diagnosed MM; ORR, overall response rate; PR, partial response; Rd, lenalidomide, dexamethasone; VCd, bortezomib, cyclophosphamide, dexamethasone; Vd, bortezomib, dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone; VTd, bortezomib, thalidomide, dexamethasone

Therapy

Recommendations

Proteasome inhibitor-based therapy

Bortezomib

  • Quick response and no dose adjustment required
  • Combination with high dose d (40 mg/day 4 days on, and 4 days off)
  • ORR (≈ 80%) and CR (20─38%) rates are comparable to patients without renal impairment
  • Major renal response (≥ renal PR) 41─87%
  • The addition of a third drug seems to be beneficial (VTd, VCd, VRd)

Carfilzomib

  • Safe, no dose modifications needed even in dialysis-dependent patients
  • Efficacy is maintained

Ixazomib

  • Dose modifications needed, with a starting dose of 3 mg instead of 4 mg in end-stage renal disease or dialysis
  • Efficacy is maintained

IMiD ®-based regimens

Thalidomide

  • Safe, no dose modifications needed, but is not well tolerated in elderly patients

Lenalidomide

  • Requires dose modification (5 mg/day after dialysis)
  • Monitor for hematological toxicity, specially anemia
  • When administered with Vd showed suitability in patients with renal impairment within 3 months, regardless of transplant eligibility (read next section)
  • No data in elderly patients in dialysis with the new combinations (DRd)
  • No information on efficacy with Rd in patients with NDMM non-transplant eligible requiring dialysis

Monoclonal antibodies

Daratumumab

  • Appears to be safe with no dose modifications needed, but because of the limited data in severe renal impairment and dialysis-dependent patients, there is an on-going trial evaluating daratumumab in this setting ( NCT03450057 )
  • Administer after dialysis

  In conclusion, acute renal insufficiency is a myeloma emergency, and rapid diagnosis and management is the key to survival and renal recovery. In patients requiring dialysis, a rapid response to V-based treatments is associated with higher probability of renal recovery and independence from dialysis. Consequently, V-based treatments remain the standard of care for the management of myeloma-related renal impairment, but further improvement is needed in this patient population to improve general outcomes and renal recovery rates.

Results from the Connect MM Registry | Bortezomib-lenalidomide-dexamethasone (VRd) induction in patients with NDMM and renal insufficiency 2

This multicenter, prospective, observational study ( NCT01081028 ) investigated the impact of VRd induction on renal function in transplant eligible and noneligible patients with NDMM from the Connect MM Registry and was reported by Sikander Ailawadhi et al.at ASCO 2020.

A total of 3,011 patients were enrolled from September 2009 to April 2016. Eligible patients were aged ≥ 18 years and had symptomatic MM diagnosed ≤ 2 months prior to enrollment, as defined by the International Myeloma Working Group criteria. A total of 421 patients who received VRd as first-line treatment for ≥ 3 cycles were included in this analysis and grouped according to transplant eligibility and renal function at baseline. Transplant eligible vsnoneligible subgroups: CrCl < 30 (20 and 16 patients), 30–50 (36 and 50 patients), > 50–80 (117 and 63 patients), and > 80 (248 and 83 patients), respectively. Patients with progressive disease at baseline were excluded from this analysis.   

Results

Improvement of renal function was reported within 3 months in all patients receiving VRd induction, including those with moderate (30–50 mL/min CrCl) and severe (< 30 mL/min CrCl) renal insufficiency at baseline ( Table 2).

Table 2. Baseline characteristics 3

CrCl, creatinine clearance; VRd, bortezomib + lenalidomide + dexamethasone

*Severe, CrCl < 30 mL/min; Moderate, 30–50 mL/min; Mild, > 50–80 mL/min; Normal > 80 mL/min

In bold, percentage of patients that improved their renal function from baseline

Baseline renal function*

Renal function after ≥ 3 cycles of VRd

Normal

Mild

Moderate

Severe

Transplant eligible, %

Mild (n = 117)

42

44

3

2

Moderate (n =36)

14

47

28

3

Severe (n=20)

10

15

30

35

Transplant noneligible, %

Mild (n = 63)

33

51

6

0

Moderate (n = 50)

20

30

40

0

Severe (n = 16)

13

6

25

44

  Consistent results in terms of real-world median progression-free survival were reported in patients with > 60 mL/min CrCl, and ≤ 60 mL/min CrCl at baseline. Find median progression-free survival reported in transplant eligible and noneligible subgroups in Table 3.     

Table 3. The median PFS in transplant eligible and noneligible subgroups 3

CrCl, creatinine clearance; PFS, progression-free survival

Baseline renal function (CrCl)

Median PFS, months

Transplant eligible

> 60 mL/min (n = 332)

48.6

60 mL/min (n = 89)

43.2

Transplant noneligible

> 60 mL/min (n = 130)

36.4

60 mL/min (n = 82)

30.6

  Conclusion

This analysis from the Connect MM Registry demonstrated that patients with NDMM with renal impairment, including those with moderate and severe dysfunction, who received VRd induction for ≥ 3 cycles, can improve renal function within 3 months, regardless of transplant eligibility. Thus, showing VRd treatment’s potential suitability in the real-world for patients with renal impairment. These results support further investigation of VRd in patients with moderate or severe renal insufficiency.  

Head to the Multiple Myeloma Hub to watch the first author of this study, Sikander Ailawadhi, discuss the suitability of VRd induction for patients with NDMM and renal impairment, by clicking here.

Denosumab in patients with MM and renal insufficiency 3

Bone destruction is a consequence of MM, and little information is available on the management of skeletal complications in patients with MM and renal insufficiency. Regardless of the documented effectiveness of intravenous bisphosphonate therapy for bone lesions, its application is limited where renal dysfunction is present.

Denosumab is a monoclonal IgG2 antibody to receptor activator of NF kappa B ligand (RANKL), and has demonstrated non-inferiority to zoledronic acid for skeletal-related event (SRE) rates in MM. It also appears to not elicit the same renal toxicity as the bisphosphonates, and therefore, confers greater suitability for patients with renal impairment. Elizabeth O'Donnell et al.reported a multicenter study ( NCT02833610 ) at ASCO 2020, that investigated the efficacy and safety of denosumab administration in patients with MM and renal insufficiency to improve bone health.

This study enrolled patients with NDMM or relapsed MM with a CrCl of less than 30 mL/min. At the time of analysis, 20 out of the planned 40 patients who were enrolled, had received a 120 mg subcutaneous injection of denosumab every 4 weeks. Of the patients treated, eight completed the planned 12 cycles of therapy. All patients also received standard doses of vitamin D and calcium supplementation (at least 2,000 mg calcium citrate and 1,000 IU of vitamin D), until hypercalcemia was observed.

Response to therapy

The primary objective of assessing the effect of denosumab on serum C-terminal telopeptide (sCTX), a biomarker of bone turnover, was reported from 12 evaluable patients; there was a median 78.65% decrease in sCTX between Cycle 1 and Cycle 2. 

Safety

The most frequent AEs were hypocalcemia (35%) and fatigue (22%). Grade 3 or more hypocalcemia AEs were reported in 20% of patients, Grade 2 or less in 15% of patients. Of the six hemodialysis patients, three had at least one episode of hypocalcemia. Of the 12 non-hemodialysis patients, four had at least one episode of hypocalcemia. Osteonecrosis of the jaw was developed by 11% of patients, 5% had Grade 1, and another 5% had Grade 4.

Conclusion

In conclusion, the data showed denosumab was able to decrease sCTX levels following one cycle, indicating a reduction in bone turnover, in patients with MM and severe renal impairment. Early reports suggest denosumab can safely be used in this patient population.

The incidence of hypocalcemia, despite the use of aggressive prophylactic calcium, reiterates the importance of clinical trials to inform safe practice in this difficult-to-treat population. This trial is ongoing to report on the SREs and assess the long-term safety and efficacy of denosumab in patients with MM, and a creatinine clearance of less than 30 mL/min.

In 2018, denosumab was approved by both the U.S. Food and Drug Administration (FDA) and the European Commission , to treat SREs in adult patients with MM.

To listen to the first author of the trial, Elizabeth O'Donnell, discuss the optimal treatment for bone lesions, including patients with renal insufficiency, click here .

  1. Lee HC, Cohen AD, Chari A, et al. DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment. Abstract #8519. 2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  2. O'Donnell E, Yee AJ, Nadeem O, et al. A phase II, single-arm study of denosumab in multiple myeloma patients with renal insufficiency. Abstract #8520.2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  3. Ailawadhi S, Lee HS, Omel J, et al. Impact of lenalidomide-bortezomib-dexamethasone (RVd) induction on patients with newly diagnosed multiple myeloma and renal impairment: Results from the Connect MM Registry. Abstract #8518.2020 ASCO Annual Meeting; May 29–31, 2020; Virtual.
  4. Rodriguez-Otero P. Frontline therapy under dialysis (elderly patient). Oral Abstracts – Session 14 (The challenging cases forum). 2020 COMy Congress; May 16, 2020; Virtual.
  5. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Outcomes of newly diagnosed myeloma patients requiring dialysis: Renal recovery, importance of rapid response and survival benefit. Blood Cancer J. 2017;7(6):e571. DOI: 1038/bcj.2017.49